General Constitutional genetics Flashcards

Question

Cause HMSN

Answer 1

transient recurrent episodes of focal weakness and sensory loss- usually caused by pressure or injury

Answer 2

PMP22 gene flanked by repeat regions; CMT1A-REP| NAHR between these regions leads to recurrent dels/dups

Answer 3

- vertical transmission of carrier females to affected sons (50% chance)- all daughters of affected males have the pathogenic variant (obligate carriers)- daughters of female carriers have 50% chance of being a carrier- affected homozygous females are rare- affected males usually born to unaffected parents (may have affected male relatives)- no male to male transmission- pedigree mostly affected males, females are carriers only

Answer 4

- DMD, BMD, -SBMA- androgen insensitivity syndrome- XLRP (retinitis pigmentosa)- haemophilia A and B - Christmas disease

Answer 5

- 1/4000 births affected- rapidly progressive muscular weakness proximal > distal & lower> upper limbs with calf hypertophy- gower movement- early childhood age of onset & first signs are delayed milestones, delayed sitting and standing - cardiomyopathy >18 years, most common cause of death with respiratory complications- wheelchair bound by 12 - few survive beyond 30 yrs- males do not usually reproduce- full penetrance in males, females can be unaffected to severe (manifesting carrier)- >10x creatine kinase levels, less in females. CK is an enzyme released from muscle into the bloodstream following damage- out of frame deletions (be careful with duplications as dont always follow the rule)

Answer 6

-1/18 000 male births- in-frame deletions in DMD- less severe & later onset- longer life expectancy (mid 40s)wheelchair bound >16- heart failure from DCM still common cause of death- females with DMD pathogenic variant at increased risk for DCM- preservation of neck flexor muscle strength (differs from DMD)- >5x creatine kinase levels , less in females

Answer 7

- DCM between 20-40 years in males and later in females- usually no skeletal muscle disease- rapid progression to death in males and slower progression in females-increased creatine kinase levels , less in females

Answer 8

immuno staining shows lack of dystophin in skeletal muscle, cardiac and smooth muscle cells. Dystrophin plays a role in sarcolemma stability. In DMD it is absent but in BMD it is 20-100% - may be normal levels but reduced function

Answer 9

- MLPA (80% mutations) - QF-PCR required or single del/dup or SNP array can offer higher resolution may be done solely by NGS in future- sequencing, NGS allows mosaics to be detected. sanger for familial mutations- RNA analysis deep intronic variants or complex rearrangements. usually muscle or urine but need to confirm in genomic DNA. can also confirm splicing outcomes and orientation of duplicationsTwo deletion hotspots: 30% exons 2-19 and 70% exons 45-55

Answer 10

steroids (improve muscle strength and motor function), physical therapy, anti-congestives and cardiac transplant in severe cases

Answer 11

- stop codon readthrough eg. translana. 15% of patients have PTC. Tretments allows alternative amino acids to be inserted at the site of the mutated stop codon & results in dystophin expression at 10-20% providing some function- exon skipping eg. exondys51 (80% of patients in theory). Interferes with splicing skipping the specific exon in DMD pre-mRNA to restore open reading frame and allow expression of shorter but functional protein

Answer 12

X linked disorder affecting males 1/300 000caused by CAG repeat in exon 1 of AR geneprogressive neuromuscular disorder with degeneration of motor neurons resulting in muscle weakness and muscle atrophy and reduced fertility (due to mild androgen insensitivity)GOF mutation. the more repeats there are the earlier the age of onsetonly occurs in Europeans or Asiansfemales not usually affected

Answer 13

complete = total insensitivity to androgen and child develops female genitals. abnormal secondary sexual development at puberty and infertility in those with a 46, XY karyotypepartial = level of insensitivity determines how genitals develop (predominantly female, male or ambiguous)mild = typically male genitaliaAffects 2-5/100 000 who are genetically maleinfertility

Answer 14

XLR disorders caused by mutations in F8 (A) and F9 (B) causing F8 and F9 to be inefficient at coagulation in the blood. Disorders are indistinguishable clinically. Clotting deficiency results in prolongued bleeding after injury. 10% of female carriers are at risk for bleeding. 1/6000 males have haem A and 1/30 000 males have haem B.

Answer 15

XLR lysosomal-storage disorder caused by mutations in GLA which encodes the galactosidase enzyme (breaks down a fatty substance). pathogenic variants prevent the enzyme from breaking down this substance leading to it damaging cells. symptoms include pain in hands and feet, inability to sweat, cloudiness in eye, angiokeratomas *dark red spots on skin), GI problems, tinnitus and hearing loss. life-threatening complications include kidney damage, heart attack and stroke. 1/5-10 000 affected. childhood onset. females may be affected

Answer 16

trinucleotide repeat expansions in successive generations in which the signs and symptoms of some genetic conditions tend to become more severe, more frequent or occur at an earlier age- these dynamic expansions are unstable and expand on transmission to next generation- eg. FRAX (XL) maternal CGG expansion- HD HTT CAG AD paternal- DM1 CTG DMPK maternal expansion

Answer 17

replication slippage - mispairing, hairpin loops causing replication fork blockage, unequal crossing overresulting in one expanded and one contracted tract

Answer 18

Mosaicism is defined as the presence in an individual, or in a tissue, of two or more cell lines that differ in genetic constitution. As we age, somatic/germline mutations accumulate over the course of a person‚Äôs life resulting in age-related mosaicismeg. loss of X in males and females is normal age-related anaphase lageg. cancer is an example of age related mosaicism - mutations accumulate as we age

Answer 19

degree to which phenotype is expressed varies between individuals with same genotypeeg. MArfan FBN1 - some are just tall and thin whilst others have heart conditionseg. NF1 - mildly affeected have cade au lait skin but more severely affected have neurofibromas. may also develop tumours. may also have ID, short stature or seizures.

Answer 20

proportion of individuals carrying a particular variant of a gene (allele or genotype) that also expresses an associated trait (phenotype)eg. BRCA1 - penetrance = 80% risk of BC. also affected by environmental modifiers such as smoking, diet, pregnancies etc

Answer 21

penetrance is often expressed as a frequency, determined cumulatively, at different ages

Answer 22

Sex-limited genes are genes which are present in both sexes but expressed only in one sex, and causes the two sexes to show different traits or phenotypeseg. Familial Male Precocious Puberty - males only have signs of puberty at 4 years

Answer 23

interaction between nonallelic genes in which one combination of such genes has a dominant effect over other combinations eg. Bombay phenotype

Answer 24

Pleiotropy occurs when one gene influences two or more seemingly unrelated phenotypic traits eg. usually metabolic pathway that affects different phenotypes such as PKU. depending on mutation involved may have reduced conversion of phenylalanine to tyrosine or ceased entirely. the failure to convert normal levels of phenylalanine to tyrosine results in less pigmentation being produced causing the fair hair and skin typically associated with phenylketonuria. also causes mental retardation and abnormal gait and posture.

Answer 25

the expression of a gene resulting in competing effects, some beneficial but others detrimental to the organism.Antagonistic pleiotropy hypothesis ‚Äì some genes responsible for increased fitness in the younger, fertile organism contribute to decreased fitness later in life. An example is the p53 gene, which suppresses cancer, but also suppresses stem cells, which replenish worn-out tissue.

Answer 26

Amorphic = LOFhypomorphic = partial loss through reduced function. usually recessive but occasionally dominant due to haploinsufficiency eg. Friedreich‚Äôs ataxia homozygous GAA repeat expansion. some cases are compound het with a point mutation. Homozygosity for inactivating mutations is embryonic lethal.hypermorphic = GOF - increased activity of normal functionantimorph = dominant negative (gene product adversely affects the normal, wild-type gene product)NEOMORPHIC - DOMINANT GAIN OF GENE FUNCTION that is different from normal function

Answer 27

a pyrimidine for a pyrimidine (C for T or vice versa) or a purine for a purine (A for G or vice versa)‚Äî

Answer 28

Substitution of a pyrimidine by a purine or vice versa (C to an A)

Answer 29

A situation in which half amount of a gene product is not enough to maintain normal function for instance, individual with heterozygous mutation or hemizygous at a particular locus is clinically affected.

Answer 30

: Linkage disequilibrium is the phenomenon by which there is a non-random association of alleles at two or more loci i.e. when variants co-occur together in an allele more than should be expected if random distribution of variants was occurring.Phe508del 98% occurs in cis with 9T - important if patient also has c.350G>A p.(Arg117His) and 5T (causes CF with 5T only)

Answer 31

Fragile X, - CGG trinucleotide repeat in FMR1X linked Alport syndrome - COL4A5. most common. kidney disease, hearing loss and eye abnormalities

Answer 32

rett syndromeIntercontinentia pigmenti

Answer 33

- expressed in males and females- an affected female has a 50% chance of having an affected child- an affected male has affected daughters and unaffected sons- higher proportion of females affected than males- affected males have more severe phenotype - variability in females- may be mistaken for AD, unless there is an affected male who will have all affected daughters and no affected sons

Answer 34

1/3 affected females, 1/3 unaffected females and 1/3 affected males

Answer 35

- disorder observed exclusively in females- affected males rarely seen (except XXY)- history of miscarriages as 50% of males die- sex ratio of offspring is therefore skewed

Answer 36

-Cellular ‚Äòinterference‚Äô between wild-type and mutant cell populations is the cause for the severe disease manifestation in CFNS females-males are asymptomatic/mild phenotype

Answer 37

- skewed x inactivation- variants in PAR regions are expressed on both X's as escape X inactivation and can behave in AD manner eg. SHOX on PAR1- XLD- XO- deletion on one X

Answer 38

<5-10 Mb, can be recurrent-monosomy and haploinsufficiency of dosage sensitive --genes. Also involves imprinted genes, unmasking recessive mutation, and positional effects- can result in clinically recognisable syndromecan be mendelian or contiguous eg. di george syndromefor every deletion there should be a duplication - reciprocal microdeletion/duplications from NAHR eg. HNPP/CMT1A 17p12 and Smith-Magenis syndrome (SMS)/Potocki-Lupski syndrome (PTLS) (17p11.2)Interstitial microdeletions: Di GEorge 22q11.2PWAS 15q11-q13NF1 17q11.2Miller-Dieker 17p13.3williams syndrome 7q11.23terminal microdeletions: wold-hirschorn del4ptercri du chat del 5pter

Answer 39

<5-10 Mb, can be recurrentregional trisomy and effects dosage sensitive geneseg. mendelian -PMP22 HNPP, - milder than deletions as cells more tolerant to gain than loss- FISH less sensitive for duplications-variable expressivity and reduced penetranceInterstitial eg. Duplication 7q11.23 (williams syndrome region duplication syndrome)

Answer 40

- low copy repeats up to 0.5Mb that have high homology >97% and result in structural aberrations from NAHR. NAHR hotspots cause recurrent CNVs- may be interchromosomal- intrachromosomal (between 2 chromatids)- intrachromatid (within chromatid)- results in deletions, duplications, inversions and dicentric

Answer 41

17p11.2- reciprocal 1.4Mb duplication/deletion including PMP22- caused by NAHR between two LCRs with 99% homologyCMT1A (80% of CMT1) = PMP22 duplications. CMT1 is a demyelinating peripheral neuropathy. distal muscle weakness and atrophy, slow nerve conduction. slowly progressive. foot drop, calf hypertrophy. HNPP - milder neuropathy. numbness, tingling and muscle weakness in the limbs. deletion of PMP22 (80%). other 20% have pathogenic mutation.

Answer 42

17p11.23.7Mb recurrent del/dup generated by NAHR between LCRs. common del/dup occurs due to NAHR between proximal and distal low copy repeats. smith-magenis syndrome = developmental delay, hypotonia and distinctive facial features. caused by de novo 17p11.2 deletions. (70%)potocki-lupski syndrome - dev delay, autism and hypotonia. de novo duplications of 17p11.2

Answer 43

PWS = hypotonia, feeding difficulties, obesity, dev delay, insatiable appetite. - paternal contiguous gene deletion resulting from NAHR between low copy repeats (75%) of 15q11q13 leading to absence of expression of paternally-imprinted genes. also caused by mat UPD and IC deletion. there are 4 large clusters of complex repeats termed BP1-4, with common deletion ranging from BP1 or 2 to BP3. SNURF-SNRPN, MAGEL2, C15orf2 involved.angelmann = severe developmental delay/intellectual disability, severe speech impairment, gait ataxia , happy demeanor, microcephaly, sezures. Disruption of UBE3A in 15q11q13. 70% have maternal deletion.

Answer 44

del 17q11.2multiple caf√©-au-lait spots, neurofibromata, learning difficultiesheterozygous loss of function mutations in the NF1 gene at 17q11.2 as well as by an LCR-mediated 1.5Mb deletion that encompasses NF1 and other flanking genes and pseudogenes

Answer 45

del 4ptercraniofacial features (greek warrior helmet appearancedev delay, growth delay, ID, seizurescontiguous gene deletion up tp 60% de novo and 40% have unbalanced translocation with deletion of 4p and partial trisomy of different chromosome arm. may require FISH for detectionCandidate genes that may contribute to the WHS phenotype include WHSC1, LETM1 (seizures) and FGFRL1 (craniofacial phenotype).

Answer 46

del 5ptercat-like crysevere dev delay/IDmicrocephaly, hypotonia, hyperterlorism, variable seized deletions of 5p from 5p13-5p15size of del correlates with phenotype85% are de novo deletion and 15% are unbalanced translocationCTNND2 causes ID

Answer 47

both copies of a gene need to be functional in order to express the wildtype. 50% of the normal gene product/expression/activity is not enough. Inactivation/loss of a single allele (leaving the second allele unaffected) produces a clinical phenotypeA gene is likely to be haploinsufficient if all mutation types (missense, nonsense, gene deletion etc.) produce the same phenotype

Answer 48

PMP22 - HNPP 80% caused by deletion of a ~1.5Mb region at 17p11.2 and 20% caused by mutationrepeated focal pressure neuropathies HNPP is haploinsufficient whilst PMP22 dup CMT1A is GOF

Answer 49

22q11.2 Di George syndrome - tbx1 HI causes heart defects and dysmorphology

Answer 50

TP53 - Thought to be typical two-hit model BUT LFS tumours analysed for LOH (loss-of-heterozygosity) show it occurs in ~60%, so ~40% of tumours have a presumably functioning second copy

Answer 51

- increase in gene expression or product develops new functionÔÉò Hypermorph: an allele that produces an increase in quantity or activity of its productÔÉò Neomorph: an allele with a novel activity or product.

Answer 52

HD = CAG TNR exon 1 HTT polyglutamine tract 36 repeats or more. acquires novel deleterious function - deletions of region do not cause disease so GOF. forms inclusion bodies containing huntingtin which forms abnormal B sheetsDM1 - CTG toxic gain of function in DM1 and CCTG in DM2Achondroplasia - inherited short stature FGFR3 tyrosine kinase receptor which negatively regulates bone growth. mutations activate the receptor, limiting bone growth. Gly380Arg) accounts for >99% of cases. high de novo mutation rate. FGFR3 mutations also cause thanatophoric dysplasia TD1 and 2, hypochondroplasiaBCR-ABL1 fusion gene in CML: t(9;22)(q34;q11) - novel tyrosine kinase. imatinib is TKI. MRD by RT-PCR quantifies levels of BCR-ABL1 mRNA transcripts in blood and bone marrow samples. determines treatment response. CMT PMP22 - 1.5Mb duplication 17p11.2 - 80% of CMT1 cases. PMP22 codes for peripheral myelin protein. duplication generated by NAHR between sequences that flank the gene. reciprocal deletion causes HNPP

Answer 53

mutations that reduce the function of the protein encoded by the normal copy of the gene- only seen in heterozygotes and cause more severe effect than no gene product- <50% residual function-

Answer 54

osteogenesis imperfecta- COL1A1 or COL1A2 causes 90% of cases- Haploinsufficiency (type 1): null variants and NMD results in milder phenotype as amount of collagen produced is reduced- Dominant negative (Type 2): 80% caused by replacement of Glycine in Gly-X-Y in triple helix domain. disripts formation of triple helix and causes severe diseaseMarfan - FBN1- haploinsufficiency or dominant negative- dominant negative: usually cysteine substitutions Haploinsufficiency - nonsense/FS lead to NMD and decreased amount of fibrillin and aortic wall strength

Answer 55

class 1, 2 and 3levels of pancreatic function correlate well with CFTR genotype.

Answer 56

- exon 9 is 90% skipped when the length of the tract is reduced to 5T- The pathogenicity of the poly(T) tract is also mediated by the length of the adjacent poly(TG) tract, where long TG tracts are more likely associated with disease phenotype than shorter tracts (higher penetrance). Common TG lengths = 11, 12 or 13.- Increased skipping of exon 9 is caused by TG12, TG13 and 5T

Answer 57

- modifies the expression- 5T/Arg117His hets together with a typical severe pathogenic variant can cause classical CF of variable severity- 7T/Arg117His hets (most 7T associated with TG11) and a typical severe mutation result in much more variable phenotype and can even be benign- 9T/Arg117His hets are very rare and thought to be benign- highly variable and more likely CFTR related disease eg. CBAVD, bronchiectasis/pancreatitis

Answer 58

neonatal stress (low Apgars), respiratory distress, hypoglycaemia, or serious congenital abnormalities such as trisomies 13 and 18PPV is low for IRT

Answer 59

- sCD means cells are unable to deform as they pass through narrow capillaries- serious infection, chronic pain, pulmonary hypertension, proliferative retinopathy, organ damage, aplastic crisis, stroke or even death- haemaglobin A accounts for 95% normal haemoglobin and accounts for two alpha and two beta chains. SCD is caused by mutation in B haemoglobin gene HBB. - more common in people from tropical and/or sub-tropical regions where malaria was common as carrying a single sickle cell gene conferred an advantage- screen positive = immunisations and antibiotics- screened using HPLC, isoelectric focussing and capillary electrophoresis- caused by HBB gene, c.20A>T p.Glu6Val detected by ARMS or pyrosequencing- HBB, HBA1 and HBA2 genes can be tested for thalessaemia

Answer 60

- problems breaking down fats leading to illness or death- AR ACADM - Single common mutation c.985A>G (p.Lys304Glu) is responsible for 88% - screen positive infants are put on special diet- mass spec of C8 levels relative to c10- targeted testing of the c.985A>G followed by extended screening

Answer 61

X linked dominant, variable penetrance, 5' UTR CGG repeat >200 causes methylation gene silencing- small proportion of cases due to point mutations or partial or whole gene deletions or duplicationsfragile X tremor ataxia syndrome/ primary ovarian syndrome, fragile X syndrome

Answer 62

- PMP22 17p11.2= peripheral myelin protein 221.5 Mb deletion causes HNPP Hereditary Neuropathy with Liability to Pressure Palsies. muscle weakness and atrophy. CMT1A = PMP22 duplication 1.5Mb duplication/GOF mutation. progressive muscle weakness. - FGFR3 - tyrosine kinase receptor that negatively regulates bone growth. GOF mutations cause hypochondroplasia, achondroplasia, TD, Muenke Syndrome. somatic activating mutations cause bladder cancer. - AR gene. polyglutamine expansion causes SBMA. muscle weakness. onset decreases as expands. het females usually unaffected. androgen-insensitivity syndrome- complete, partial and mild

Answer 63

cardiomyopathy - shortness of breath, chest pain progressive heart failure to sudden cardiac deathMost common genes mutated= MYH7 (40%), MYBPC3 (40%), TNNT2 (5%), TNNI3(5%), TPM1 (5%)Incomplete penetrance and variable expressivityCaused by dominant negative, haploinsufficiency and GOF mutations

Answer 64

occurs when one gene influences two or more seemingly unrelated phenotypic traits

Answer 65

quantify cumulative effects of no. of genes, which may individually only have small effect on susceptibility; score reflects sum of all known risk alleles, weighted by how risky each variant known to bepredict persons likelihood of displaying a trait‚Ä¢ Genome-wide data allows access to millions of common genetic variations associated with these conditions; risk score for each person calculated with aim to inform clinical management

Answer 66

‚Ä¢ Helpful in targeting people at higher-risk of conditions where increased surveillance + preventative treatment/surgery available‚Ä¢ Help to match drugs in clinical trials to individuals who are most likely to benefit from them- personalize preventative measures

Answer 67

‚Ä¢ Not diagnostic: high risk score doesn‚Äôt mean person will definitely develop condition + vice versa‚Ä¢ Results need to be communicated carefully to minimise risk of confusion‚Ä¢ Requires consent for genetic testing; may be difficult to obtain‚Ä¢ Accuracy; majority calculated from European DNA sequences; less accurate for other populations

Answer 68

premutations: can expand or contract when transmittedDynamic mutations also show somatic instability, which accounts for some of the phenotypic variability.strand slippage during DNA replication in actively dividing cells

Answer 69

AD c9orf72 hexanucleotide repeat GGGGCC expansion

Answer 70

tetranucleotide repeat CCTG in intron 1 ZNF9muscle weakness, muscle pain, Full penetrance, mutation alleles >75 repeats, up to 11,000 repeats

Answer 71

Fragile X Syndrome (both FRAXA and FRAXE) and Friedreich Ataxia (FRDA)expansions result in loss of gene product or functionPoint mutations are rare in affected patients (<1% Fragile X cases, ~2% FRDA cases)

Answer 72

- AR so anticipation not observed, carriers unaffected- most common form of ataxia with 1/50 carrier frequency- progressive ataxia (co-ordination, balance and speech) muscle weakness and HCM- homozygous expansion of a polyE glutamic acid GAA repeat in intron 1 of frataxin (FXN)- 2% of patients have expansion and LOF mutation- Nonsense, missense, frameshift, and splicing defect in trans- mutation causes defective transcription of the FXN gene, leading to deficiency of frataxin (mitochondrial protein)-PCR, TP-PCR and southern blot can be used to test & MLPA + sequencing if strong clinical suspicion and only one expansion identified

Answer 73

SBMA, HD, DRLPA, SCAs

Answer 74

DM1, DM2, SCA 8 + SCA 12

Answer 75

-GoF - Haploinsufficiency caused by CTG expansion-RNA GoF- CUG expansions in 3' UTR fold into RNA hairpins that accumulate in ribonuclear foci-encoding DMPK protein ‚Äì serine-threonine kinase, mainly expressed in heart + skeletal musclemuscle weakness + wasting ,cataracts, cardiac defects, floppy baby + respiratory distressnormal = up to 36 repeats (same as HD)premutation 37-50full penetrance alleles 51-150 juvenile > 150congenital = >2000

Answer 76

CAG expansion in exon 1 HTT, higher repeats = earlier onset<27 = normal27-35 = intermediate36-39 = reduced penetrance (some elderly unaffecteds)>39 = expansion>60 = juvenile- chorea, dystonia (muscle spasm), psychiatric disturbance, involuntary movements, cognitive decline- large expansions exclusively paternal- exclusion testing can be offered where parent doesn't want to know status (25% risk to child)

Answer 77

1. Antisense oligonucleotides- IONIS-HTT: nhibit expanded mRNA to reduce concentration of mutant HTT protein2. RNAi- mouse model of SCA1, with adeno-associated virus (AAV) vectors expressing short hairpin RNAs that efficiently reduced expression levels of mutant protein3. Protein aggregation inhibitors e.g. (2)-Epigallocatechin-3-Gallate (EGCG) for HD

Answer 78

FSHD - Facioscapulohumeral muscular dystrophy- 95% of cases are FSHD1- muscle weakness- FSHD1 caused by AD contraction of D4Z4 repeats (contains DUX4 gene)<10 repeats = pathogenic- results in reduced transcription of DUX4- diagnosed by southern blot due to large size using restriction enzymes- FSHD2 caused by SMCHD1 mutations and diagnosed by bisulphite PCR and NGS

Answer 79

XLMR - x-linked mental retardation ARX geneHand‚Äìfoot‚Äìgenital syndrome - HOXA13

Answer 80

mitochondrial genome is circular and double-strandedmitochondrial genome contains 37 genesThere are no introns - only 3% is non-codingmitochondrial mode of inheritance is strictly maternalEach cell can contain 100 to 10,000 copies of the mt genome but only one copy of nuclear

Answer 81

mtDNA can all be identical (homoplasmy)mixture of two or more mt genotypes (heteroplasmy)The percentage level of mutant mtDNA may vary among individuals within the same family, and also among organs and tissues within the same individual (mt genetic bottleneck).‚Ä¢ The threshold effect is that there is a level of variant mtDNA that can be tolerated by the cell, however above a certain level (which is tissue specific) oxidative phosphorylation cannot be maintained and disease manifests

Answer 82

Homoplasmic variants inherited from a homoplasmic clinically unaffected mother are unlikely to be pathogenic.mitomap - phenotypes and genbank frequencyThe level of heteroplasmy must be accurately determined and interpreted in the context of the tissueEvolutionary conservation and functionality eg. MitoTIP

Answer 83

- variant differs by tissue type and age of patient- Some pathogenic variants (e.g. m.3243A>G) are lost from tissues such as blood that undergo rapid mitotic division- a neg result doesnt mean the patient doesnt have variant- DNA extracted from the affected tissue is preferred - Genotype-phenotype correlations are poor

Answer 84

MT-ND1 m.3460G>A , MT-ND4 m.11778G>A and MT-ND6 m.14484T>C targeted testing of 3 common mutations eg. pyrosequencingmitochondrial WGSDNAJC30 single gene sequencingreferred from Consultant Ophthalmologist, Neurologist or Clinical Geneticistclinical assessment, family history, biochemical testing, histopathological examination (muscle biopsy) and direct molecular testing

Answer 85

Mitochondrial encephalopathy, lactic acidosis and stroke-like episodesMT-TL1 m.3243A>G urine or muscle best samples

Answer 86

MT-ATP6 m.8993T>C (also MT-ND1, 4 and 6)Encephalopathy, lactic acidosis

Answer 87

common mutations = sequencing/pyrosequencingrearrangements such as deletions = long range PCR. multiple mtDNA deletions may be due to nuclear gene mutation such as POLG for exampleRT-PCR - copy number and WGS if increased copy number as likely to be a mtDNA mutationif not mt DNA gene need to consider nuclear sequencing - encodes mt subunits and mt genome maintenancemuscle is the best tissue to test

Answer 88

- heteroplasmy difficult to interpret- % heteroplasmy in CVS may not represent other tissues and levels may change during development- difficult to predict severity of disease- ooctye donation or nuclear transfer where the nuclear genome from the oocyte or embryo of an affected woman is transplanted into a donor enucleated oocyte or embryo with healthy mt. nuclear DNA can be transferred between unfertilised oocytes using polar body transfer or maternal spindle transfer or between fertilised zygotes using pronuclear transfer

Answer 89

inability to repair a particular type of DNA damageusually ARhypersensitive to certain drugs leading to chromosomal rearrangementsincreased predisposition to cancerdiagnosed through cytogenetics biochemical and molecular methods

Answer 90

most common breakage syndromeFANCA is the most common cause, but 15 different groupsmostly AR, but also XL (FANCB - males affected) and ADgrowth retardation, dev delay, skeletal malformations, increased susceptibility to leukaemia, anaemiaMutated cells have deficient ability to excise UV-induced pyrimidine dimers from the cellular DNA - it leads to double-strand breaks in the S phase of the cell cycleTesting: culture cells with cisplatin (interstrand cross-linking agent) causes breakage and sequence FA genes

Answer 91

AR BLM gene - DNA helicase tumour suppressor gene that suppresses inappropriate recombinationsun sensitive rash, growth deficiency, immunodeficiency, predisposition to cancer, infertility in malesincreased SCE levelgene sequencing and count SCE frequency in 20 metaphases

Answer 92

AR disorderataxia-jerky movements, immunodeficiency, cancer predisposition - leukaemiasATM gene sequencing - usually compound het mutations but also some dominant negative heterozygous missense variants. Gene codes for a kinase which signals ds breaks and nonhomologous exchange. cytogenetics - radiation causes chromosome breakage

Answer 93

sun sensitivity, cancer predisposition, hearing loss, cognitive impairment, genetic sequencing- 8 genes involved in nucleotide excision repeair (NER) eg. XPC, ERCC2 and POLHcaused by UV radiation damaging genes that control growth and division - cells die or grow uncontrollably leading to cancers

Answer 94

1. gene disruption (most common cause) - truncated or no protein produced. may unmask recessive condition if SNV in other allele. FISH can detect this and NGS with paired end reads. can help to refine breakpoints. can create fusion genes.2. cyrptic imbalance - more complex (>3 breaks the more likely to have cryptic imbalance). may have dels, ins or inv near breakpoint or not at breakpoint site. may be inherited or de novo. phenotype depends on size of cryptic imbalance. 3) position effect - moves gene away from cis elements such as enhancer, inhibitor or closer to enhancer of another gene causing cancer, regulatory element may be moved closer to another gene altering expression levels and euchromatic material may be moved to heterochromatic region causing silencing and vice versa. 4) imprinting disturbance - imprinted region moved away from IC5) UPD - robertsonian and translocation carriers may have offspring with UPD. relevant if genes are involved in imprinting or unmasks recessive allele eg. isodisomy. very rare6) X;autosome rearrangements - males always infertile. due to spermatogenic arrest. Females - if normal X inactivated it is balanced. If abnormal X with XIC inactivated it will result in some autosome being inactivated too and translocated X will not be inactivated causing abnormal dosage. also if derivative autosome contains XIC it will also be unbalanced. t(Y;autosome) carriers usually infertile due to spermatogenic arrest. 7) mosaicism - may be mosaic for unbalanced karyotype in certain tissues Eg Pallister-Killian - normal in blood. or may have interchange trisomy followed byl loss of normal chromosome to give balanced karyotype in blood8) may be IF and cause is due to something else

Answer 95

disrupt gamete formation especially in malesfailure of pairing of homologous regions in the quadrivalent formed at meiosis I by a reciprocal translocation, which then interfere with the X-Y bivalent disrupting meiosis.robertsonian translocation - p arms interfere with X;Y bivalentfertility may vary between males in same family

Answer 96

up to 40% geneticup to 30% environmentalrest unknown1-3%prognosis, clinical care and educational needs, support groups and prenatal diagnosis. currently incurable

Answer 97

Increases detection of chromosome abnormalities by up to 6% compared to karyotype for USS findings

Answer 98

25% - usually done after a normal array or WGS

Answer 99

use of arrays increased the detection rate from approx 3% with karyotyping to approx 15-20% and represent a 100 fold higher resolution approach

Answer 100

structurally abnormal chromosome that cannot be identified by conventional banding alone and is equal to or smaller in size than chromosome 20 of the same metaphase spreadmajority derived from acrocentric chromosomesCan be inverted duplication, ring, centric (have centromere), neocentric (new centromere)some produce abnormal phenotype but more than half don't- clinical outcome difficult to predict - especially prenatally. If identifyable use der(chr) instead of marker50% are mosaic - almost all pallister-killian are mosaicmay cause infertility by interfering with meiosis80% are de novo - usually abnormal phenotype & low recurrence risk<0.1% of live births23% inherited but most without clinical signs (mostly maternal)‚Ä¢ Very small markers are prone to loss during cell division ‚Äì mosaicism often seen

Answer 101

15 - 50% have abnormal phenotype when PWAS region is present- emanuel syndrome der(22)

Answer 102

- numerical monosomy or trisomy rescue, gamete complementation or unbalanced structural rearrangement. Can be meiotic or mitotic.- inverted duplication chromosomes -U-shaped exchange - crossover mistakes of chromatids of two homologous chromosomes during meiosis(monosomy rescue likely UPD) - test if derived from imprinted chromosome eg. 6,7,11,14,15&20

Answer 103

- size and origin or euchromatin- mosaicism percentage- UPDGenerally, smaller markers with low or no euchromatin ‚Üí low risk, larger markers with euchromatin ‚Üí high risk. But interpret with caution, as presence of euchromatin does not necessarily lead to clinical effects. If the marker is inherited from a normal parent, this is likely to indicate a benign marker, BUT need to consider levels of mosaicism and affected tissue types. A number of familial cases have been reported where a parent carries a marker in mosaic form with no phenotypic effect, while their child carries the same marker in non-mosaic form and is severely affected.

Answer 104

1) pallister killian tetrasomy 12p. (12% of markers)- severe MR, seizures, diaphragmatic hernia + facial dysmorphism. blood normal, detectable in fibroblast tissue. false negative rate in CVS/prenatal is 10% due to mosaicism2) emanuel syndrome + der(22)t(11;22)(q23;q11) . Trisomy for11q23-qter and 22q11-ptersevere MR, cleft palate, Micrognathia (undersized jaw), renal/heart defects3:1 segregation of recurrent t(11;22) resulting in only viable tertiary trisomyCarriers of the balanced translocation have 10% chance of conceiving a child with the syndrome

Answer 105

variant turner - 46, X + SMC or may be in addition to XX/XY phenotype depends on if XIST - if absent, clinical complications may ariseidic Y/inv dup Y46, X+SMC - absence of SRY = turner syndrome phenotype with increased risk of gonadoblastoma, if SRY present but Yq- = male infertility

Answer 106

up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomescatastrophic single event producing complex chromosomal rearrangementcauses rare disease, infertility and cancerchromothripsis derives from chromosome shattering followed by the random restitching of chromosomal fragments with low copy-number change

Answer 107

erroneous DNA replication of a chromosome through serial fork stalling and template switching with variable copy-number gains

Answer 108

an accumulation of translocations involving several chromosomes no copy-number alterations

Answer 109

1. no function protein produced2. misfolding eg. F508del - lumacaftor3. channel gating eg. G551D - Ivacaftor4. faulty channel conductance5. normal protein created but insufficient quantity

Answer 110

Genetically engineered recombinant factor 9 - patients can develop immune response.Adeno-associated viruses - A gene and promoter are inserted into the viral genome. doesn't cause disease but may have immune response. Haemophilia A - R338L encoded by AAV. gain-of-function mutation that has approximately eight times the specific activity as wild-type factor IX. in phase III trials - only suitable if dont have neutralising antibodies.

Answer 111

genotype determines residual PAH activity and may help determine BH4 responsiveness in some instances2 null variants highly predictive of non-responsiveness ‚Äì response test not recommended

Answer 112

5fu used in treatment of solid tumours5FU toxicity seen in 10% of patientsDPYD metabolises 5FU & deficiency causes cytotoxicityARMS, sanger, NGS can be used to detect variants in DPYD that cause poor metabolism and so dose-management is criticalDPD activity values assigned to certain variants - sum up allelespoor metabolisers = avoid 5FUintermediate = 50% of dosenormal = full doseNeed short TAT- actionable time frame

Answer 113

Genomic England ongoing research study to assess use of WGS for actionable genetic conditions Timely diagnosis, access to treatment pathways, and enable better outcomes and quality of life preventativelifetime storageresearch - identify new conditionsNo phenotype in healthy newborns- carrier statusincidental findingswhat should be reported TATconsent, data storage, eligibility, reanalysisdiscrimination

Answer 114

MT-RNR1 variants - ototoxicity(hearing loss) when treated with amnioglycosides (eg. Gentamicin given for translational read-through in CF)- m.1555A>G MT-RNR1 - results in destruction of sensory hair cells in the inner ear- urgent R65 in TD- portable GeneDrive kit Detects m.1555A and m.1555G by melt curve analysis (30 mins rapid bedside testing)- 100% sensitivity and specificity

Answer 115

high GC content regions/ amplification biasRepetitive regions where short reads will not map uniquelySVs and STRsphasepseudogenes

Answer 116

de novo assembly - spans repetitive regions for accuracybetter for pseudogenes and phasestructural variants (e.g. segmental duplications, gene loss and fusion events)STRscharacterization of methylation

Answer 117

DNA sample must be of high/sufficient quality low sequencing accuracy compared to short readscostmay be lower throughput than short reads

Answer 118

neurotrophic tyrosine kinase (NTRK) gene family responsible for the normal development and function of both the central and peripheral nervous system, regulating neuronal growth, proliferation and survival

Answer 119

occur in 1% of solid tumoursTRK fusion proteins - Oncogenic drivers of adult and paed cancers eg. thyroid, breast, lung, CRCNTRK gene fusions are also detected in ALL and AML at a frequency of <5%.over 80 different partners - 3' end of NTRK gene (kinase domain) fuses with 5' end of other gene creating chimeric oncoprotein

Answer 120

- NGS multiplex detection of FFPE samples- dual colour breakapart FISH BUT unable to identify novel fusion gene partners - RT-PCR: only able to detect known fusions included in the assay, primer design challenging - IHC: antibody targeting NTRK C-terminal domain: false positives, not amenable to multiplex

Answer 121

TKI eg. larotrectinib or entrectinibsecond line TKIs if resistance mutation

Answer 122

Phenomenom where the features of a genetic condidiotn becomee more severe and have an earlier onset with each successive generation.typically associated with TNR disorders as the dynamic mutations are unstable and prone to expand on transmissioseen in FRAV, DM1, HD, SCA1,3 and 7 and DRPLA

Answer 123

Exapansion can occur ion the germline (passed to offspring) or in somatic cells resulting in size mosaicism)Normal (stable) not prone to expansion and will not expand to FM in a single generationIntermediate- not associated with disease and offpsring will not be affected but repeat length ay show instaability on tranmissionPM- prone to expansion to F. Not pathogenic except ion FXTAS/FXPOIFM- expansion need to reach a threshold length for the phenotype to be expressed.

Answer 124

HD expansions are predominantly male due to CAG instability in spermatogenesisDM1 large expansions are maternally inherited. only small rpt can be paternally inherited possibly due to selection against sperm with FM

Answer 125

Replication slippagestrand miss-pairing results in formation of secondary structures (e.g. hairpin loops) which cause rep fork blockage, this result in slippage of the lagging strand and misplacing of okzaki fragments = unequal crossing over and one expanded and one contracted allele

Answer 126

preferential ascertainment of parents with late onset disease as early onset would have reduced sexual fitnesspreferential ascertainment of children with severe disease earlier preferential ascertainment of child-parent pairs with simultaneous onset

Answer 127

mosaicism (somatic or germline) due to the accumulation of mutations over the course of an individuals lifetime- e.g. loss of X or Y is a characteristic of ageing to give a 45,X cell line- knudson hypothesis (2 hits for cancer= sporadic is later onset)

Answer 128

pehnotype expressed to different degrees in different individuals with the same genotype.May show variability within the same familye.g. NF1 range from cafe au lait skin patches to large disfiguring neurofibromasmarfans range from tall with long slender fingers to having life threatening heart conditions.

Answer 129

Penetrance is the proportion of individuals with the same genotype who express the phenotype. e.g. BRCA1 shows 80% lifetime risk of breast cancerin complete penetrance all individuals with the genotype will have the associated phenotype

Answer 130

not everyone with the genoytpe will show the phenoytpe- affected by genetic modifiers, environmental factors, lifestyle, age, sex hard to predict. Non penetrant parents can have penetrant children e.g. 22q11.2 making genetic counselling a challenge.

Answer 131

attributable risk looks at the amount of risk that can be atributed to an allele- can develop breast cancer without BRCA mut so not all the risk can be attributed to having the allele

Answer 132

Genes present in both sexes but only expressed in one e.g.lactation in females and beards in males

Answer 133

a variant or allele in one locus that prevents a variant or allele at another locus exerting its affect- interactions between non-allelic genes in which one has a dominant effect over another- explains deviation from simple mendelian ratios- play a major role in susceptibility to complex diseasethe masked locua is called hypostaic and the masking locus is epistaticcan occur at the gene level where one gene may encode a protein which prevents the transcription of another gene or at the phenotype level e.g. the gene for albinism would hide the gene controlling a persons hair or skin colour

Answer 134

Pleitropy is when one gene influences 2 seemingly unrelated traits as the encoded protein is used in different cells of for different signalling functionse. g. PKU is associated with ID and hypopigmented skin and hair- affects phenyalanine hydroxylase which converts phenyalanine to tyrosine- build up of phenyalanine is toxic to the nervous system resulting in ID and DD- lack of try which is required for melanin production which is required for skin and hair pigmentation

Answer 135

non random association between 2 alleles at 2 didfferent loci- when variants co-occu togehter in one allel more often than would be expected by normal distributione.g. CF F508 is in LD with the 9T variant of the polyT tract. Useful as if the 9T and 5T plyTs are detected with R117H and F508, the R117H must be in cis with 5T which confirms a diagnosis of CFTR-RD

Answer 136

X-linked AlportsX-linked hypophosphatemia/ vitD resistant ricketsFragile X- inheritance is debated but widely considered XLD

Answer 137

Rett syndromeIncontentia Pigmenta

Answer 138

Craniofrontonasal syndrome (CFNS)

Answer 139

XLD is a condition that is expressed in hemizygous males and heterozygous females- males are generally more severely affected and females show variability- 50% risk of all offspring of an affected female being affected- 100% of female and 0% or male offspring from an affected male will be affectedcan be mistaken from AD inheritance as passed from both parents but is differentiated by the lack of male to male transmission. Because of this there will be more affected females than males.

Answer 140

Most common cause of phosphatemiafully penetrant with variable severity and patients may not present until 6-12 monthsSymptoms are similar to Vit D deficient Rickets- bone deformities- dental abnormalities- hearing loos- low phosphate levels- resistance to treatment with Vit DCaused by PHEX mutations- result in inhibition of kidney being able to reabsorb phosphate from the bloodstream affecting normal bone growth and development

Answer 141

Most common form of Alport syndrome- associated with Kidney disease, hematuria and proteinuria, hearing loos and eye abnormlaitiesCLO4A5 variants (Col4A3/4 in AR forms)- encodes type IV collagen which plays a role in kidneys, vision and hearing

Answer 142

- only seen in females, rare in males and if present they are mosaic if XXY- increased miscarriage rate in families as males pregnancies do not get to term- sex ratio of offspring is skewed= 1/3 unaffectd females, 1/3 affected females and 1/3 unaffected males

Answer 143

Characterised by normal development in the first months, followed by rapid regression of language and motor skill ans then stability of symptoms. characteristic hand flapping also develops- life expectancy 15-20yrscaused by variants in MECP2 (classic Rett)- generally de novo and low recurrence risk although some reports of germline mosaicism

Answer 144

~1% of males with severe MR- Males with MECP" variants are born with neonatal encephalopathy resulting in death before age two years- adult males with classical Rett are 47,XXY or mosaics and have the same phenotype as females or have less severe neurological maifestations but carry variants not seen in females with Rett- presumably to mild to cause disease in het state

Answer 145

Variant Rett is caused by variants in FOXG1 (Chromosome 14, distinguished by congenital microcephaly and corpus callosum abnormalities) and CDKL5 (X chromosome, distinguished by early onset seizures)

Answer 146

affects hair, skin, teeth, nail and CNS- nail dystrophy, and eye and dental abnormalities and born with a rash. males spontaneously miscarry in the first trimester or have some mosaicismDue to mutations if IKBKGhigh penetrance and variable severity

Answer 147

CFNS is a XLD disorder with affects females but not males. females have frontonasal dysplasia, craniofacial asymmetry and craniosynostosis, whereas males typically show only hypertelorismCaused by mutations in EFNB1- encodes a TM protein involved in bi-directional cell signallingfemales are affected as skewed X-inactivation leads to a population of mutant and non-mutant cells. This interface between the normal and mutant protein population is the cause for the phenotype in males. Therefore a mosaic male may also express an phenotype.

Answer 148

AR or AD as the PAR regions is found on both the X and Y chormosome

Answer 149

truncating mutations are more severe and there is stronger selection against them in the 5' of the gene. missense mutations are less severe so may only be seen in male Rett

Answer 150

MECP2 is implicated in the transcription in neuronal cells e.g. regulated BDNF transcription - affects synaps plasticity and neuronal development

Answer 151

bi directional sequencing detect 85-90% of mutations. dosage analysis by MLPA can also be performed.

Answer 152

PCR of polymorphic CAG repeat in the 1st exon of the androgen receptor. DNA is digested by a methylation snsitive restirction enzyme to determine which CAG repeat length (and therefore which X) is silenced. Can be used to determine the degree of skewing by comparing the level of digestion of each allele.

Answer 153

In XLR females are generally not affected whereas in XLD females are affected. However the standard definitions of AR or AD do not capture the variable expressivity due to skewed x inactivation.

Answer 154

vertical transmission from mothers- 50% of sons will be affected and 50% of daughters will be carriers.Male transmission- all daughters will be carriers. there is no male-male transmission so no sons will be affected.pairing of an affected male with an affected female can give the false impression of male-male transmission.

Answer 155

skewed X-inactivation45,XInheritance of mutation from both parentsUPD for X chromosome

Answer 156

SBMA is a late onset progressive neuromuscular disorder that results in muscular atrophy and distal to proximal muscle weakness and wastingonset is 30-50 yrs and require a wheelchair within 10yrs

Answer 157

caused by a CAGn polyglutamine expansion in the 1st exon of the AR gene. 35-37 repeats is variable penetrance38+ repeats is full penetranceshows anticipationGOF , precise mechanism is unknown but it is thought to result from the CAG tract being cleaved into a polyglutmaine fragment which is retained in the nucleus where it forms nuclear inclusions.female carriers asymptomatic

Answer 158

AIS is caused by pathogenic LOF mutations in the AR gene. Encodes the androgen receptor which allows cells the respond to testosterone and is required for male sexual developmentcharacterised by female external genitalia and abnormal secondary sexual development at pubertymainly missense mutations and dela and dups are rare. Testosterone levels are normal or elevated

Answer 159

complete AIS- normal female external genitalia, raised as females. Associated with variants throughout the coding regionpartial AIS- Nearly normal female genitalia or ambiguous. Variants mainly in the steroid ir DNA binding domainsMild AIS- typically have male external genitalia and mutations in ex 5 or 7 or amino terminal domain

Answer 160

Due to mutations in the coagulation factors factor VIII (F8 in haem A) and factor IX (F9 in haem B). Mutations cause F8 and F9 to be ineffective in coagulation cascade. Clinically indistinguishable. diagnosed by a deficiency in clotting of the relevant factorcomplications arise from bleeding into joints, muscle, brain or other internal organs. female carriers are biochemically abnormal but clinically unaffected. 10% of females are symptomatic and at risk of bleedingF8- large gene. Intron 22 is the most common mutation. 1 in 6000 malesF9- small gene, mainly SNVs and 1 in 30,000

Answer 161

Due to mutations in the IDS gene- this encodes the enzyme for the breakdown of mucopolysacharides. without this enzymes MPS build up resulting in tissue damage. variable severity, age of onset and rate of progression. In the severe disease there is CNS involvement and progressive airway and cardiac disease result in death. In the attenuated form the CNS is spared.

Answer 162

Genes are described as HI when inactivation/loss of a single allele (leaving the second allele unaffected) produces a clinical phenotype. A gene is likely to be HI is all mutation types (missense, nonsense, deletion etc) result in the same phenotype. Show AD inheritance Note that genes on sex chromosomes cannot show haploinsufficiency.

Answer 163

Current theories focus on the specific function of the gene and the context of the gene‚Äôs function. - Genes encoding enzymes are rarely haploinsufficient- genes linked to srtuctural and regulatory function or are members of complexes or celullar signalling networks are more sensitive to changes in dosage.

Answer 164

imprinted geneshighly expressed genesdosage sensitive genes

Answer 165

in imprinting only one of the 2 alleles of a gene is expressed in a parent of origin depending manner, therefore mutations in the expressed gene are dominant. e.g. UBE3A mutation causes AS

Answer 166

Highly expressed show HI as they need a very high amount of gene product and a single functional copy is insufficient in producing enough. e.g, Elastin- Loss of one copy has no effect in skin and lung (low levels of product required), but can cause supraventricular aortic stenosis because the aorta requires high expression levels.

Answer 167

Dosage sensitve genes include:- gene whose products are part of a quantitative signalling system depending on partial occupancy or competition for binding to DNA or receptor- gene products that compete to determine a metabolic swith- gene products that cooperate in interactions with stoichiometry. Includes many structural proteinsIn these situations the gene product is titrated against something in the cell, therefore relative not absolute levels are important. Genes whose products are essentially alone e.g. soluble involved in metabolism, rarely show dosage sensitivity

Answer 168

Some genes with AD inheritance also have a recessive form. e.g. Marfans syndrome. A phenotype cause by complete loss of one allele could also be caused by a 50% reduction in the activity of 2 alleles. Variation in penetrance & expression of both mono-allelic and bi-allelic mutant alleles highlights the fact that external factors are involved in such systems. These may include expression of other genes, environment, age, developmental status, ability of the individual to up-regulate expression of other genes or (in heterozygous individuals) the unaffected allele to compensate.

Answer 169

less likely to be found in segmentally duplicated regions which are prone to mutation (CNV) but NAHR. This suggests a selective pressure to maintain HI genes at their correct CN

Answer 170

hypertrophic cardiomyopathy (HCM)HNPP Aniridia

Answer 171

22q11.2 Di George syndrome| del5p Cri-du-chat syndrome

Answer 172

HI affects TSGsTP53BRCA1PTEN

Answer 173

Clinical features: - Left-ventricular hypertrophy (LVH) in the absence of predisposing cardiac/cardiovascular conditions.- Characteristic abnormal ECG. - highly variable and can include palpitation, progressive heart failure and heart congestions- Sudden cardiac death (often in early adulthood and associated with exertion, e.g. sport) is a major cause of mortalityOnset varies from childhood to middle age, LVH occurs in ~1 in 500. Between half and three-quarters of these patients have an HCM mutation

Answer 174

70-80% of mutations are found in MYH7 and MYBPC3 About 10% of mutations are in Troponin-coding TNNT2 and TNNI3,Clinical sensitivity of the four-gene panel is ~50% Haploinsufficiency can be demonstrated in MYBPC3 by the lack of incorporation of truncated proteins into HCM cardiac tissue (evidence against dominant-negative effect), along with a lowered expression level of full-length protein, which suggests haploinsufficiency Interaction of multiple genes in a large system (presumably requiring cooperation & fixed stoichiometry between gene products) is characteristic of a haploinsufficiency syndrome, and probably explains some of the variability in presentation & phenotype.

Answer 175

PAX6 mutaion result in lack of irises. other symptoms include: nystagmus, cataracts, defects in vision. PAX6 is a control gene involved in eye development with very high conservation in all organisms with eyes Homozygous loss of PAX6 is known to cause wide-ranging defects including complete lack of eye formation and is fatal in mice.WAGR syndrome is caused by a contigous deletion on 11p13 and includes WT1 (wilm tumour gene) and PAX6 resulting in Wilms tumor, aniridia, genitourinary anomalies and mental retardation syndrome.

Answer 176

HNPP is charactersied by focal pressure neuropathies- carpal tunnel syndrome, peroneal palsy and foot dropDue to LOF of PMP22- 80% are due to a recurrent 1.5Mb deletion mediated by NAHR between CMT1A-REPS. 20% are due to LOF sequence mutations. PMP22 encodes an essential component of the peripheral myelin sheathreciprocal dup results in the more severe CMT1Ashows that gene is HI and TS

Answer 177

DiGeorge syndrome, 22q11.2 deletion on one allele causing haploinsufficiency of the TBX1 T-box transcription factor gene (important in developmental regulation).

Answer 178

Cri-du-chat syndrome caused by deletions of 5p15, - a critical region between 5p15.2 is responsible for the observed dysmorphism and intellectual disability - the proximal region of 5p15.3 is associated with the cat-like cry and speech delay.

Answer 179

Mutated in over 50% of all tumours. - Germline mutations responsible for Li-Fraumeni syndrome (LFS) (early-onset breast and multiple other poor prognosis soft tissue & bone cancers).

Answer 180

TSG mutated in a wide array of tumours- Germline mutations cause Cowden syndrome & PHTS. - PTEN is a ‚Äúgatekeeper‚Äù that negatively regulates cellular proliferation. - ‚Äúobligate haploinsufficiency‚Äù; heterozygous loss is more tumourigenic than homozygous loss. Reason for this is a ‚Äúfailsafe‚Äù p53-dependent cellular senescence mechanism that works when PTEN is completely lost; this ‚Äúmasks‚Äù the cellular proliferation signal that would be the result of losing both copies of PTEN, so heterozygous PTEN loss is more tumourigenic. Loss of p53 (e.g. in tumours) prevents the ‚Äúfailsafe‚Äù senescence mechanism, so cases with complete loss of both PTEN AND p53 show faster rates of tumour development than heterozygous PTEN losses.

Answer 181

TSG associated with hereditary breast cancer: women carrying a heterozygous inactivating mutation have an 85% lifetime risk of developing breast cancer, and increased risk of other cancer types. - Conforms to the two-hit model of tumorigenesis (- BRCA1 -/- mice show embryonic lethality:

Answer 182

result in increase in gene expression/product or gene developing a new aberrant function

Answer 183

PMP22- GOF CMT1A (dup) and LOF HNPP (del)AR- triplet repeat expansion >35 = SBMA (GOF), LOF SNV = AIS

Answer 184

Unstable triplet repeats- HD, DM!, SCAOverexpression - CMT1Anovel function - BCR-ABL1 t(9;22)(q34;q11)Highly mutable codon- Achondroplasia

Answer 185

HD is caused by a CAG repeat expansion (>36 variable penetrance- 40rpts = disease) in the 1st exon of the HTT gene at 4p16.3result in a polyglutamine tract which is though to develop novel deleterious function when expanded

Answer 186

he presence of intranuclear inclusions is the characteristic sign of HD and are more abundant in the brains of patients with juvenile onset HD it is thought that the polyQ expansion results in the formation of intranuclear inclusions containing HTT, chaperone proteins and ubiquitin. HOWEVER, the inclusions do not appear to cause the disease themselves. In mouse models the location of inclusions does not correlate with cell toxicity.

Answer 187

the seq of pathogenesis in HD is unclearMutant HTT forms abnormal protein structures - Bsheets and is truncated by caspase-6 into toxic N-terminal fragments. this is though to lead to altered processing of abnormal proteins in HDMutant Htt interferes with gene transcriptions (PGLC1a) and may have a direct or indirect affect on the mitochondria = affecting metabolism and leading to oxidative stressthere is also abnormal vesicle transport and release of BDNF and increased exocitotoxicity

Answer 188

DM1 is caused by a CUG repeat expansion in DMPK

Answer 189

Though to act via a toxic RNA GOF mechanismRepeat structures in RNA form stable hairpin structures that sequester RNA binding proteins CUG-BPI and MBNL in riobonuclear inclusion. This result in upregulation of CUG-BP1 and down regulation of MBNL. the altered expression of these affects alternative splicing and embryonic splicing patterns are seen instead of adult patterns in patients with DM1

Answer 190

Achondroplasia is the most common inherited disproportionat short statureincidence is 1 in 26-28,000caused by mutations in the Tm domain of FGFR3

Answer 191

Due to a highly mutable codon - GOFFGFR3 is a TM tyr kinase receptor responsible for -vely regulating bone growth. Mutations that constitutively activate the receptor result in reduced bone growth99% of disease is due to 2 mutations - achondroplasia is relatively common considering it requires very specific gene mutations- it has been suggested that the high de novo rate is because there is a proliferative advantage in spermatogonal cells. other mutations in FGFr3 result in different disorders e.g. thanapophoric dysplasia and hypochondroplasia

Answer 192

found in nearly all CML (major breakpoint) and some ALL (minor breakpoint)fusion gene formed by the t(9;22)(q34;q11) rearrangement resulting in the formation if a constitutively active tyr kinase - aberrant signalling promotes genome instabilitytreated by TKI imatinib

Answer 193

CMT1A is caused by gene overexpression 70-80% is due to a recurrent 1.5Mb duplication at 17p12 whihc includes PMP22. remaining cases are due to GOF SNVs. PMP22 encodes peripheral myelin protein and is present in the myelin membrane of peripheral neurons where it plays a role in arresting schwann cell divisionrecurrent dup is due to NAHR between CMT1A reps which flank the duplicated region. Reciprocal deletion result in HNPP

Answer 194

Mutations generally impair the function of a protein that are involved in protein complexes or reduce the activity of the WT alleleonly seen inhetsmore severe than null alleles of the same goenMND probably developed to protect against dominant negative truncated proteins proteins that are part of multimeric structures are particularly vulnerable to dominant negative effects as they are dependent on oligomerisation for activity- in a multimer a variant subunit with intact binding but altered catalytic activity can affect the function of the entire multimer

Answer 195

dominant negative- result in deafnessGJB2 and 6 encode connexin 26 and 30- these are major gap junction proteins expressed in the cochlear.connexins are TM proteins and 6 oligomerise to form to form a hemi channal (connexon)- connexons of neighboring cells align symmetrically to from continuous gap junctions- they can be homopolymeric or heteropolymeric with different functional propertiesCx26 and 30 are involved in K+ recycling in the ear- K+ is required for NT release from hair cells of cochlear. dominant missense mutation in Cx26 result in the formation of full length aberrant proteins- these form gap junctions with WT Cx26 and 30 forming connexons with impaired permeability = hearing loss in hets

Answer 196

dominant negative mutations in CLO1A1 and COL1A2encode fibrillar collagens which are the major structural proteins of connective tissuespre-pro collagen contains N and C terminal globular pro-domains flanking a central repeat seq with a gly every 3rd residue3 pre-procollagen chain associate to forma triple helix under the control of the globular domain- C and N terminal domain cleaved to form mature collage and this process is disrupted in OI

Answer 197

Missense mutations result in the expression of abnormal protein and severe OI. - dominant -ve (type II, II, IV)- 80% of muts replace gly in triple helix domain- tupe 1 procollagen comprises 2 chains encoded by COL1A1 and COL1A2- helix assembly starts at c-terminal domain therefore mutations close to the c-terminus are more deleterious than those near the N-terminusOI type 1- due to LOF mutations- reduced production of type 1 procollagen as abnormal protein degraded by NMD- less severe

Answer 198

Most commonly mutated gene in cancer and mutations can be LOF, GOF and dominant negativeNormally TP53 acts as a TSG- transcription factor whcih activates transcription of genes involved in cell cycle control, damage repair, and apoptosis. missense mutations in the DNA binding domain affect the ability of the protein to recognise DNA or inactivates TP53 by altering the conformation- dominant neagtive as TP53 binds DNA as a tetramer- WT and mutant p53 proteins form tetramers with impaired ability to bind DNA and trnscriptional activity- c-terminal domain is requird for dimerisation therefore truncating mutations in this domain are not dominant -ve as they cannot bind WT

Answer 199

Mutations result in the connective tissue disorder Marfansfibrillin has a structural role in the walls of large arteriesdominant negative variants:- missense and exon skipping variants result in a stable but altered protein- impared interactions between variant and WT fibrillin and other proteins results in impaired ECMLOF mutations- nonsense and frameshift result in NMD- decreases the amount of fibrillin in vasculature and the aortic wall strength is weakened- increased risk of cardiovascular disease

Answer 200

Pleitropy descibes when a single gene infulences more than 1 seemingly unrelated genetic traits- 1 gene many phenotypes

Answer 201

clinical heterogeneity is one gene causing multiple diseases

Answer 202

Ret is an RTK and a proto-oncogenerecpetor dimerisation results in phosphorylation of tyrosine residue for downstream signallingConstitutive GOF mutations in RET are associated with MEN2- 3 types of MEN2 all are associated with and increased risk of medullary thyroid cancer1. MEN2A = early adulthood MTC + phaeochromocytoma and hyperparathyroidism2. MEN2B is more severe with onset in childhood = MTC + ganglioneuromas and marfanoid features3. familiary medullary thyroid carcinoma = MTC in midle adulthoodConstitutive LOF mutations in RET are associated with hirschprungs disease- also an example of locus hetergoeneity as Hirschsprungs can also be caused by mutations in ERDNRB and EDN3somatic mutations in RET occur in cacners and are found in NSCLC and thyroid cancers

Answer 203

COL2A1 encodes the alpha chain of type II collagen- involved in endochondral ossification and the replacement of cartilage with boneMutations result in a spectrum of skeletal disordersMissense mutations result in the expression of abnormal protein and severe OI. Mutations replace a gly residue in the triple helix so that the collagen fibre does not form properly due to expressed abnormal protein (dominant negative) - dominant -ve (type II, II, IV)- 80% of muts replace gly in triple helix domain- type 1 procollagen comprises 2 chains encoded by COL1A1 and COL1A2- helix assembly starts at c-terminal domain therefore mutations close to the c-terminus are more deleterious than those near the N-terminusOI type 1- due to LOF mutations- reduced production of type 1 procollagen as abnormal protein degraded by NMD- less severe

Answer 204

FGFR3 is a TM tyr kinase receptor responsible for -vely regulating bone growth. Mutations that constitutively activate the receptor result in reduced bone growthAchondroplasia is due to 2 relatively common AD mutations (suggesting it is a highly mutable codon)other mutations in FGFR3 result in different disorders e.g. thanapophoric dysplasia and hypochondroplasiaSomatic activating mutations are associated with bladder cancer

Answer 205

PMP22 is found at 12p12. Expressed by schwann cells in the peripheral nervous system and is involved in the differentiation and regulation of schwann cells.

Answer 206

PMP22 is a doage sensitive gene increased dosage (dup or GOF mutation) is associated with CMT1A. The increased dosage of PMP22 protein means that it is not processed effectively in the ER and golgi reducing the amount of folded protein and this impairs the formation of the myelin sheathin HNPP HI ( deletion or LOF mutation) results in a decrease of PMP22 protein reducing the amount of myelin and making nerves more susceptible to mechanical forces e.g. presssure.

Answer 207

CMT is the most common inherited peripheral neuropathy- pes cavus- proximal to distal progressive muscle weakness- reduced sensory and motor nerve conduction velocities- Decreased sensation in hands and feet- Reduced or absent deep-tendon reflexes1. Demyelinating (velocity <38 m/second), CMT12. Axonal (reduced amplitudes with >38 m/second), CMT2CMT is a genetically heterogeneous condition, with over 90 genes and loci known to cause the condition when mutated.

Answer 208

- repeated focal pressure neuropathies such as carpal tunnel syndrome - peroneal palsy with foot drop. - Onset is usually in 20s-30s and a full recovery can be made. If recovery is not complete the disability is generally mild. In HNPP the deletion accounts for 84% of cases. Loss of function mutations in PMP22 also result in HNPP.

Answer 209

Duplications/deletions are associated withCMT1A-REPs. >99% of rearrangements are mediated by non-allelic homologous recombination (NAHR). CMT1A-REPs flank the region duplicated in CMT1A and act as substrates for NAHR. The proximal CMT1A-REP and distal CMT1AREP share 24,000bp of approximately 99% DNA sequence identity. Misalignment of the two repeat units allows unequal crossing over to take place resulting in duplications and deletions. The do novo rate of duplication is estimated to be 10-20%.

Answer 210

AR is an X-linked geneThere is a CAG repeat in the 1st exon. Expansion over 38 is associated with SBMA which results in progressive muscel weakness, cramps, twitching in males. females are generally asymptomatic but may have milde features. - shows anitcipationLOF SNVs that partially or fully impair the AR gene are associated with androgen insensitivity. The androgen receptor is crucial for primary and secondary male sexula development in response to testosterone- CAIS = female genitalia, raised as females and not suspected until puberty. Associated with mutations throughout the whole gene- PAIS nealry normal female genitalia or ambiguous- mild AIS mlae genitalia but may be small- mainly muts in steroid and DNA binding domains

Answer 211

One disease many genes

Answer 212

CMT is the most common inherited neuropathy with a prevalence of 1 in 2500-3000 in European populations. CMT encompasses a range of diseases which are clinically similar but genetically heterogeneous. CMT is also known as Hereditary Motor and Sensory Neuropathy (HMSN). CMT is caused by reduced nerve conduction velocities which can be demyelinating (CMT1) or axonal (CMT2).All inheritance patterns described. AD most common, then XL and ARMore than 90% of CMT cases in which a molecular diagnosis has been reached are associated with changes in four genes (PMP22, GJB1, MFN2 and MPZ). e.g. PMP22 GOF/dup associated with most common form CMT1AMPZ- major myelin protein in PNS- MPZ mutations can cause a demyelinating phenotype (CMT1B) or an axonal phenotype (CMT2I/2J) as well as intermediate formsGJB1Loss of function mutations in GJB1 are the primary cause of CMTX1. - X- linked second most common formMFN2 - mitochondrial membrane protein - associated with CMT2 (AD)

Answer 213

left ventricular hypertrophy in the absence of other cardiac or systematic disease. Can range from asymptomatic and heart palpitations to heart failure and sudden cardiac death. Due to mutations in sarcomere proteins- can be dominant negative where incorporation of mutant gene interacts with WT and disrupts sarcomere function- GOF - some mutations in MYH7 and TNNT2 result in increased contracile forces adn Ca2+ release and impaired relaxation- HI e.g. lack of detectable MYBPC3 due to NMD

Answer 214

is a genetic condition characterized by kidney disease, hearing loss, and eye abnormalities. People with Alport syndrome experience progressive loss of kidney function and hematuria which indicates imparied kidney function85% are XLD due to mutations in COL4A5 gene (encode type IV collagen)15% are autosomal (mainly due to COL4A4 and COL4A3) and can show AD or AR inheritance.

Answer 215

The liklihood of a sinlge variant causing a specific phenotype can be expressed as a percentage. PRS aim to quantify the cumulative effect of a number of genes whihc individually only have a small affectGWAS has been used to study PRS for complex diseases e.g. diabetes and coronary artery disease.

Answer 216

imperfect triplet repeats GCN (GCA, GCG,GCC, GCU)Present in >500 genes and expansions are implicated in 9 disorders, 8 of which affect transcription factors

Answer 217

found mainly in transcription factor, expecially homobox containing proteinsAct as a spacer between functional regions and are key for allowing correct folding and conformation of proteins. Expansion of the repeat is though to dysregulate protein and in turn transcription of genes involved in developmental processes.

Answer 218

500 proteins with polyalanine repeats- shorter repeats than polyQ disorders- expansions of 7-14 rpts undertake variable levels of conformational transition from a-helix to B-sheet. - peptides with>19 rpta are completely converted to B-sheets and the proteins aggregate and form intranuclear inclusions

Answer 219

- once a threshold rpt lenght is met (>19) there is protein misfolding resulting in aggregation, degrdation, mislocalisation or aberrant interactions. - aberrant B-sheet proteins form intranucelar inclusion and sequester WT indicating that they can act in a dominant -ve manner

Answer 220

There is a correlation between increasing repeat length and severity of the disease for SPD1 and CCHS- largest recorded expansion is 33 in CCHS (PHOX2B gene)

Answer 221

Chaperones are involved in protein folding- chaperones can become sequestered in the expanded protein aggregates along with ubiquiting and proteosome subunits.- formation of aggregates occurs whent he cells chaperone system cannot keep up and the build up unfolded proteins eventually results in apoptosis- also observed in polQ diseases indicating that misfolded proteins are recognised by their non-native conformation and are targeted to the ubiquitin-proteosome pathway

Answer 222

1. agregated proteins become dysfunctional2. protein aggregates can recruit essential cellular componenets and compromise there function- dominant -ve3. expansions may result in protein mislocalisation without aggregation resulting in aberrant DNA or protein interactions

Answer 223

chaperones- involved in protein folding and degradation and can protect cells from apoptosis- inducing HSP70 and 40 has been shown to reduce cellular toxicity in cells with expanded PHOX2B in patients with CCHS

Answer 224

CCHS- congential central hypoventialtion syndrome- PHOX2B exp- GOF and LOF mechanisms- autonomic nervous system abnormalities- also caused by SNVssyndromic and non-syndromic XLR mental retardation- ARX expansion- also caused by SNVs- GOF- MR, infantile seizures

Answer 225

collaboration between the NHS and wellcome sanger institute- array and trio exome of pateints with idiopathic LD- identified 12 new disorders- grew out of decipher database and aims to extend the reach of decipher to diagnoses a broader spectrum of disorders

Answer 226

Fragile X syndrome.| Alports syndrome.

Answer 227

Rett syndrome.| Incontinentia pigmenti

Answer 228

CAG trinucleotide expansion (>35 rpts) of exon 1 of the AR gene Xq12

Answer 229

Age of onset: 30-50yrs. Progressive neuromuscular disorder (weakness, atrophy, fasciculations) of the lower motor neurons.Gynecomastia. Testicular atrophy. Mild androgen insensitivity.

Answer 230

Renal disease (progressive renal failure, haematuria, proteinuria).Hearing loss.Ocular lesions.

Answer 231

85% X-linked dominant: COL4A5 mutations.| 15% autosomal recessive (10%) and dominant (5%): COL4A3 and COL4A4

Answer 232

LoF MECP2 mutations. Usually male lethal.Progressive neurodegenerative disease. Normal development until 18 months, then regression (language and motor). Characteristic hand flapping. Gait ataxia, panic attacks, autistic features.

Answer 233

```Huntingtons.Myotonic dystrophy.CMT2A.BCR-ABL1 fusion.Spinocerebellar ataxia.Achondroplasia```

Answer 234

Cytogenetics: DiGeorge, Williams, Cri du chat.Cancer: BRCA, PTEN, TP53.Single gene disorder: Aniridia, Alagille syndrome.

Answer 235

TP53.PML-RARA fusion.Osteogenesis Imperfecta.Autosomal dominant myotonia congentia

Answer 236

Over expression: Charcot Marie Tooth type 1a/Hereditary Motor & sensory Neuropathy type 1a.Haploinsufficiency: Hereditary Neuropathy with liability of Pressure Palsies.

Answer 237

Mutation: Androgen Insensitivity Syndrome.| CAG expansion: Spinal and Bulbar Muscular Atrophy.

Answer 238

LoF mut: Hirschsprung Disease.GoF mut: MEN2 (multiple endocrine neoplasia type 2).Somatic: NSCLC, Thyroid carcinoma.

Answer 239

DNA mismatch repair genes: MLH1, MSH2, MSH6, PMS2, EPCAM.

Answer 240

PTPN11 (50%). SOS1 (13%). RAF1 (3-17%). KRAS (1%). NRAS (1%). BRAF (1%).

Answer 241

SMN1 and SMN2 (pseudo gene). There's 1-5 copies of SMN2 in tandem. 4% population have 2 copies of SMN1 in tandem.SMN1 & 2 differ by 5nt in exon 7 so exon 7 isn't transcribed from SMN2.SMN1 expresses a full length transcript. SMN2 expresses a short transcript that's non functional and rapidly degraded (it does produce a small amount of full length).

Answer 242

2% SMA patients have a de novo mutation

Answer 243

Most common autosomal recessive disorder in Caucasians.| A multi system disorder affecting: pancreatic, pulmonary, gastrointestinal, reproductive.

Answer 244

Potentiators (directly activate CFTR protein): (G551D) IVAcaftor.Correctors (promote correction of protein misfolding): (p.Phe508del) LUMAcaftor.

Answer 245

Antisense oligonucleotide treatment: corrects SMN2 splicing resulting in restored SMN expression.Quinazoline related compound: increases SMN2 promoter activity, altered SMN mRNA levels or splicing patterns leading to increased SMN protein levels.Histone deacetylase inhibitors are being looked at.

Answer 246

SMN1 exon 7 dosage analysis first (often done with exon8 for a control). If have 0 copies of exon 7 that's the result. If 1 copy: sequence looking for intragenic mutation.

Answer 247

Test using mutation panel (commercial usually) of approx 30 mutations - detects about 90% mutations.Could sequence CFTR if haven't detected mutation from panel.PolyTtract for 5T if testing for CVAD.could test for TG (12/13) repeat if 5T is detected in CVAD.

Answer 248

Neonate with meconium ileus.Neonate with elevated IRT.Positive sweat test.Features of CF.

Answer 249

Duchenne muscular dystrophy/Becker muscular dystrophy. Spinal and bulbar muscular atrophy.Androgen insensitivity syndrome.

Answer 250

Progressive and symmetrical muscle weakness often with CALF HYPERTROPHY and SEVERE JOINT CONTRACTURES.Classic feature: gowers sign.Age of onset: 2-5yrs.1st signs: impaired motor development and delayed milestones.5th affected makes have MR.Wheelchair bound by 12yrs and dies of respiratory failure/cardiomyopathy late teens/early twenties (have cardiomyopathy by 18yrs). Referral reason: delayed milestones, waddling gait, difficulty climbing.

Answer 251

Similar progression to DMD (progressive symmetrical weakness, often calf hypertrophy.Older onset to DMD: 5-15yrsSlower rate of disease progression (wheelchair bound by 16yrs).Milder phenotype: activity induced cramps, flexion contractures of elbows, preservation of neck flexor muscle.Heart failure is the most common cause of death at about 40yrs.

Answer 252

Dilated cardiomyopathy with congestive heart failure.NO skeletal involvement.Typically males 20-40yrs (females in later life). Rapid progression to death in males/ slower (over a decade) in females.

Answer 253

caused by DMDmut that affects muscle promotor and associated with exon 1 only which results in no dystrophin transcripts produced in cardiac muscle.

Answer 254

DMD Xq21 dystrophin.2.4Mb. 79 exons.Expression controlled by 3 independently regulated promoters (B- brain, M-muscle, P-purkinje).```2 deletion hotspots: (screening 19 exons account for 98% all deletions)Central Region (exon 44-53) (80% del/ 20% dup).5' region (exon2-20) (20% del/80%dup)```

Answer 255

90%cases:Out-of-frame mutation : DMD.In-frame mutation : BMD.single point mutation/ small in/del: 25% DMD and 10-20% BMD.

Answer 256

Not curative.Aims to alleviate symptoms with steroids, physio, anticongestives.```Dystrophin restoration approaches:Stop codon read through (GENTAMICIN).Exon skipping (MORPHOLINO OLIGONUCLEOTIDE).```

Answer 257

DMD: lack dystrophin protein.BMD: reduction in amount of protein, alteration in size of protein.Lack of dystrophin protein causes progressive fibre damage and membrane leakage.

Answer 258

One of the major roles of dystrophin is a glycoprotein complex where it stabilises sarcolemma and protects muscle fibres from long term contraction induced damage and necrosis.

Answer 259

Non random X inactivation.X-auto some translocation. UPD of X chromosome. Deletion involving other X / compound heterozygote of two DMD pathogenic variants

Answer 260

60-65% are large insertions or deletions that cause a frameshift.40% are point mutations or small frameshift rearrangements including pure intron deletions.

Answer 261

Most widely used method now is MLPA.Analyse all exons which increases mutation detection rate. It'll detect whole exon deletions and duplications and will characterise breakpoints to an exon level and can be used for female carriers.

Answer 262

The principle factor is the reading frame.Severity of clinical symptoms does vary according to which exons and how many are involved.

Answer 263

Congenital bilateral absence of the vas deferens.OBSTRUCTIVE AZOOSPERMIA.1-2% of all infertility. Caused by mucus clogging the vas deferens as they're for wing leading to deterioration before birth.CFTR: mutated in 70-90% cases.88%: 1 severe mutation (p.Phe508del, R117H) and 1 mild mutation (5T polyT tract allele).12%: 2 mild mutations.Using standard CF mutation detection methods only 47% CBAVD must will be detected.

Answer 264

FXTAS: fragile X associated tremor-ataxia syndrome.FXPOI: fragile X associated premature ovarian insufficiency.

Answer 265

Endocrine disorder. So reduced tLevels of GnRH- hypogonadotrophic hypogonadism: undeveloped gonads and incomplete secondary sexual maturation.Males: undeveloped testes/ lack second sex charc/ infertile.Females: little or no breast development/ primary amenorrhea.Gens: KAL1: Xp22.33. FGFR1 (8p21 (AD)). GnRHreceptor (4q13.2 (AR)).

Answer 266

Males: uni and bi-lateral cryptorchidism (77%) resulting in azoospermia/oligospermia.Female: normally fertile.

Answer 267

Progressive androgen insensitivity. Severe oligospermia. Infertility. Testicular atrophy.

Answer 268

Progressive neurodegenerative disorder.Motor symptoms. Cognitive impairment. Psychiatric disturbances.First symptoms manifest: 35-60yrs. Disease duration: 15-20yrs.

Answer 269

It's ubiquitously expressed and required for normal development. 2 alternatively polyadenylated forms: larger 13.7Kb expressed in adult and fetal brain; smaller 10.3Kb s widely expressed.Expansion causes of gain of function: acquires a deleterious effect casting neuronal dysfunction and degeneration.

Answer 270

CAG expansionLess than 27 rpts: normal.27-35 rpts: intermediate (family at increased risk)36-39 rpts: incomplete penetrance (diagnosis confirmed) (family at increased risk)40 and over: pathogenic (diagnosis confirmed) (family at increased risk)Repeat expansion are usually paternal (risk of offspring developing HD is highest in dads carrying intermediate rpts and over 35yrs old).

Answer 271

Increase in disease severity/reduction image of onset is observed in successive generations.Repeat numbers correlate inversely with mean age of onset. Longer repeats= earlier onset.```Very large expansions (>60) present with juvenile HD - before 20yrs.Shorter expansions (36-39) can be asymptomatic..```Number of repeats accounts for about 70% of variance in age of onset

Answer 272

Genotype to establish of real.Consider age of onset (large expansion: Southern blot).STR allele analysis (check for two allele).Polymorphism under biding site

Answer 273

Excess of FMRI mRNA causes a toxic build up- gain of function phenotype.

Answer 274

CCG repeat in the first untranslated exon of FMR1

Answer 275

Normal: 6-45 rpt. Stable allele (98% popn: model number: 30rpts).Intermediate: 46-58 rpt: less than 50: likely stable; 50-58: may show instability. Premutation: 59-200rpt UNMETHYLATED: distinction between pre and full is methylation status..Full mutation: 200-1000 rpts METHYLATED: 20% full muts are mosaic

Answer 276

Stability of intermediate expansion correlates to the presence of two or more AGG interspersions.Unstable repeats tend to late AGG or have only one. Therefor it's assumed it's the presence of these that maintain the stability.

Answer 277

FXTAS: 16.5% women; 45,0.5% men. FXPOI: 20% women.

Answer 278

Variable: 50% apparently normal- 50% moderate mental and social impairmentDue to differences in proportions of active and inactive normal and mutation X chromosome in relevant tissues.

Answer 279

Amenorrhea before 40yrs for over 4 months in association with FSH level in menopausal range.Varying degree of ovarian function seen in 50% women.

Answer 280

Late onset neurodegenerative disorder. Late onset cerebellar ataxia and intention tremor.Severity of symptoms and reduction in age of onset proportional to increase number of repeats.Clinical symptoms less severe in females

Answer 281

Most common: fluorescent PCR across CGG repeat. Southern blotting. Long range PCR.

Answer 282

commonest monogenic disorders worldwidedisorders caused by pathogenic sequence variants in the genes that direct synthesis of the globin chains of Haemoglobin (Hb).

Answer 283

the most widely distributed of all globin disorderscaused by a deficit in Œ± globin chain production. four loci of alpha-globin (2 on each Chr 16: HBA1 and HBA2.).Deletion of one (- Œ±) or both (- -) Œ±-genes is the most frequent cause of Œ±-thalassemia (~90 %), however point mutations in Œ±2 (Œ±+Œ±) or Œ±1 (Œ±Œ±+) also occur (~10 %).

Answer 284

One deletion: Silent CarrierTwo deletions: Alpha-thalassemia Minor

Answer 285

Three alpha-globin deletions: shortage of alpha-globin. cells produce an abnormal form of haemoglobin called haemoglobin H (HbH) consisting of Œ≤4 tetramers. abnormal haemoglobin cannot effectively carry oxygen to the body's tissues. Most patients survive to adult life and only become transfusion-dependent in their later years. compound heterozygotes or homozygotes

Answer 286

Deletion of all four alpha-globin chainsseverest form of Œ±-thal) and is incompatible with post natal life

Answer 287

16p del encompassing HBA1 and HBA2. microcephaly, short stature: variable; low IQ. distinctive Facial features; talipes, hypospadias and cryptorchidism in males

Answer 288

reduced or absent beta globin chain synthesis which in turn results in reduced Hb in RBCs, decreased RBC production and anaemia. 11p: contains the beta globin gene, delta globin gene, the embryonic epsilon gene, the fetal A-gamma and G-gamma genes, and a pseudogene (œàB1).

Answer 289

heterogeneous at the molecular level; >280 mutations: single nucleotide substitutions, deletions, insertions or frameshift mutations. Gross gene deletions are rare

Answer 290

(the most severe form of thalassaemia) severe anaemia and hepatosplenomegaly. affects infants from approx 6 months of age. They are transfusion dependent within 2 years of life.

Answer 291

present later than beta-thalassemia major and present usually with mild anaemia. need occasional transfusions

Answer 292

autosomal recessive disorder which shows overdominance (heterozygote advantage). RBCs: abnormal rigid sickle shape when viewed microscopically caused by point mutations in HBB. conditions of low Oxygen (hypoxia), acidity and cellular dehydration polymerisation of HbS within red blood cells leads to their deformation into the sickle shape.

Answer 293

p.Glu6Val mutation in HBB, known as HbS. Affected individuals are homozygous for this mutation (HbSS

Answer 294

Newborn screening Antenatal screening:All women in England are offered screening by 10+0 week If a woman is identified as a carrier, the baby‚Äôs father is also offered screening.

General Constitutional genetics Flashcards

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