Genetics Flashcards

Question

Chromosome 3 disorders

Answer 1

**Von Hippel Lindau** - AD - benign/malignant tumours: haemangioblastomas, RCC, retina, phaeochromocytoma, pacreatic, middle ear

Answer 2

**Achondroplasia** - _FGFR-3 gene_: gain of negative function - _AD:_ 80% new mutations - _incidence:_ most common non lethal skeletal dysplasia - _clinical:_ short limbs, low nasal bridge, coarse features, midface hypoplasia, caudal narrow SC, delayed motor milestones, OSA, trident hand

Answer 3

**Spinal muscular atrophy** - SMN1 gene - AR carrier frequency 1/80 - most common NMD after DMD - _type 1 (infantile):_ frog leg, areflexia, tongue atrophy, fasciculations, swallowing/resp difficultires - _type 2 (3m-15yrs):_ proximal weakness, decreased/absent reflexes, survival 30yrs - _type 3 (5-15yrs):_ hip girdle weakness, calf hypertrophy, walk to 40s **Adenomatous polyposis coli** - APC tumour suppressor gene 5q21 - AD - _clinical:_ polyposis 10yrs, 100% risk colorectal cancer, assoc duodenal ampullary/thyroid/hepatoblastoma/gastric/medulloblastoma

Answer 4

**Williams syndrome** - deletion long arm (7q11) \>25 genes for protein elastin - sporadic - _clinical:_ supravalvular AS, peripheral PS, hypercalcaemia, serrated teeth, carp mouth, hypertelorism, small upturned nose, puffy eyes, chattery, stellate iris, MR, elfin facies

Answer 5

**Hereditary spherocytosis** - AD - deficiency of RBC membrane structural protein spectrin

Answer 6

**Tuberous sclerosis** - TSC1 protein encoding harmatin (complexes with tuberin): both tumour suppressor genes - 2/3 new mutations, 1/3 AD - _clinical:_ brain (seizures, MR, tubers, tumours (eyes, heart, lung, skin, liver, muscle) **Fredrich's ataxia** - trinucleotide repeat of GAA encoding frataxin - deficiency of frataxin leads to Fe accummulation in mitochondria - AR - _clinical (5-15yrs):_ dorsal columns (loss DTR/sensory changes), lateral CS tract (spasticity, upgoing plantars), spinocerebellar tracts (ataxia), cardiomyopathy, scoliosis, optic atrophy

Answer 7

**incidence:** \>8% globally **associations:** congenital/genetic disorders x2 shared genes: - 1st degree: 1/2 genes - 2nd degree: 1/4 genes - 3rd degree: 1/8 genes (progeny homozygous at 1/16 loci, 6% chance severe abnormality)

Answer 8

**cause:** abnormality of 2 or more genes located next to each other **pathogenesis**: microdeletions or microduplications of chromosome segments **examples:** - DiGeorge 22q11 - WAGR syndrome 13q14.11 - PWS/Angelman syndrome

Answer 9

**incidence:** 1/10,000 **defect:** single gene mutation in cohesion complex - 60% gene NIPBL on chromosome 5, SMC1A, SMC3 - most sporadic _genetic testing_: single gene sequencing **clinical:** - _facies_: short nose, long philtrum, synophrys (unibrow), arched eyebrows, long lashes, microcephaly - _physical:_ hirsutism, ulnar-ray defect, GORD - IUGR, severe ID, obesity

Answer 10

**assoc:** advanced maternal age **clinical:** tall flat forehead, proptosis, midface hypoplasis - like Alpert's but normal hands

Answer 11

**4 nucleobases** _purines:_ Adenine (A), Guanine (G) _pyrimidines:_ Thymine (T), Cytosine (C) **A-T:** 2 hydrogen bonds **C-G:** 3 hydrogen bonds

Answer 12

**DNA to RNA (transcription)** **nucleus** - RNA polymerase binds promoter sequence 3' and unwinds the helix - DNA/RNA form H bond and DNA read 3' to 5' - RNA strand formed 5' to 3' - with bond breakage at terminator sequence **RNA to protein (translation) ER in cytoplasm** - movement 3' to 5' through tRNA from anti-codon side to AA binding side

Answer 13

**incidence:** 1/3500 **genetics:** X-linked recessive Xp21 gene, BOYS **pathophysiology:** - mutation in gene dystrophin - excess Ca penetrates sarcolemma causing rupture, oxidative stress, cell death, necrosis **clinical**: - onset symptoms age 2-3years - progressive proximal muscle weakness of legs/pelvis (Gower's sugn) - spreads to arms/neck - early pseudohypertrophy, low endurance, difficulty standing/stairs - _LATER_: cardiomyopathy, dysaarhythmias, scoliosis, respiratory disorders **prognosis:** - wheelchair dependent age 12 - life expectancy 25 **diagnosis:** - CK, EMG, genetics, muscle biopsy **treatment:** steroids, beta2agonists

Answer 14

**incidence:** 1/20,000 **genetics:** most AD type-V collagen via gene COL5A1/COL5A2/COL1A1 - also mutations in other fibrous proteins and enzymes **pathophysiology:** altered structure, production, or processing of collagen/proteins **clinical:** - msk: hyperflexible joints, thoracic outlet syndrome, tearing tendons/muscle, myalgia, scoliosis - skin: fragile, livedo reticularis - CVS: arterial rupture, MVP, dilated aorta, Raynaud's, cardiac conduction disorders - hiatus hernia, GORD, anal prolapse

Answer 15

**definition:** how the DNA is read and manifested **gene regulation:** - _histone modification:_ alters DNA conformation/transcription - _DNA methylation:_ can silence promotors - _non coding RNA:_ mediate gene regulation

Answer 16

**incidence:** 1/130,000, Ashkenazi Jews **defect:** AR mutations in both copies of DNA repair genes (17 FA genes) **pathophysiology:** defect in proteins responsible for DNA repair **clinical:** - _physical_: congenital defects (75%), microcephaly, short, hypo/hyperpigmentation (CAL, freckles), radial ray abnormalities - _organs:_ renal anomalies, GI atresia, BM failure (1st decade, pancytopaenia, 90%) - _cognitive_: DD - endocrine issues 75%

Answer 17

**clinical:** **F**ace: short palpebral fissues, flat philtrum, thin upper lip **A**bnormal learning: jittery infants, learning disability, DD, seizures **S**hort: IUGR, microcephaly, short stature **criteria for diagnosis:** - all 3 facial abnormalities + growth deficit + CNS abnormality

Answer 18

**method:** fluorescent probes to bind parts of chromosome **use:** specific for chromosome or region eg. Cri Du Chat **benefits:** fast

Answer 19

**defect:** expansion of CGG trinucleotide repeat affecting the FMR1 gene on X chromosome **genetic test:** size triplet repeat (PCR/southern blot) **pathophysiology:** reduced function FMR protein **premutation allele:** _55-200 repeats_ - late onset tremor/ataxia, learning difficulties, social anxiety - females 21% have early menopause **full mutation:** _\>200 repeats_ - _facies:_ long face, large ears, strabismus - _physical_: high palate, hyperextensible joints, flat feet, hypotonia, macroorchidism - _cognitive_: ID mild to severe, ADHD (most), \>50% autism \* females with full mutation can have a full or milder phenotype

Answer 20

**parental karyotype:** inversions, translocations **coagulopathies:** antiphospholipid sx/thrombophilia **endocrine issues:** DM, thyroid **gynae:** PCOS, uterine abnormalities

Answer 21

**point mutation:** need gene sequencing **insertions/deletions:** one or more nucleotides **DNA sequence variation:** affects single base **silent mutation:** change in base with no change AA **nonsense mutation:** substitution that changes codon for AA to stop codon **missense mutation:** substitution changes codon for one AA to another AA **splice site mutation:** region between intron/exon, alters normal pre mRNA splicing (intron retention) **regulatory polymorphism:** substitution alters binding affinity of transcript related proteins and protein production

Answer 22

**definition:** differential expression of genetic information depending on maternal or paternal inheritance **examples:** - PWS/Angelman's

Answer 23

**defect:** sporadic cause unknown **pathophysiology:** 1st/2nd branchial arch maldevelopment **clinical:** - hemifacial microsomia - confuctive deafness - visual field defect - vertebral defects

Answer 24

**defect:** AR single gene mutation in CBS gene **pathophysiology:** cystathione beta synthase deficiency - inability to convert homocysteine to cystathionine - homocysteine accumulates damaging, CT/muscles/CNS **test:** plasma total homocysteine **clinical:** tall, stiff, ID, ectopia lentis (downwards), myopia **treatment:** methionine restricted diet, folate/B12 supplementation **complications:** thrombi, CVA, seizures

Answer 25

**genetics:** XLR (only one that only affects males) **incidence:** RARE, 2000 worldwide **pathophysiology:** mucopolycsaccharidosis II - lysosomal storage disease caused by deficient enzyme iduronate-2-sulfatase - accumulation of substrated heparan sulfate and dermatan sulfate **clinical:** macrocephaly, DD, short, abnormal skeletal development, hepatosplenomegally, inguinal hernia, NO CORNEAL OPACITY

Answer 26

**genetics:** Huntingtin gene (HTT) chromosome 4 - encoding protein Huntingtin (HTT) - gene contains trinucleotide repeat (CAG) usually \<36 copies - 36-39 reduced penetrance, 40+ full penetrance **inheritance:** autosomal dominant - new expansions as CAG repeats 28+ are unstable - increases in repeat no. cause anticipation **clinical:** onset 35 to 44 years - personality: anxiety, depression, blunted affect, aggression - cognition: executive function, memory - physical: chorea

Answer 27

**definition:** MPS-1 lysosomal storage disease (most severe) genetics: AR **defect:** genes encoding lysosomal enzymes needed to degrade glycosaminoglycans (GAG) (formerly iknown as mucopolysaccharides) causing accummulation in cells, blood, CT **clinical**:severe, progressive mental/physical decline with death by 10 yrs - onset 6-24 mths with characteristic features - coarse facial features,large tongue, prominent forehead, short stature - corneal clouding, hearing loss * -* hepatosplenomegaly, cardiomyopathy - skeletal dysplasia: dysostosis multiplex, joint stiffness **diagnosis:** radiographs, urinary GAG excretion, enzyme assays **treatment:** BMT, enzyme replacement.

Answer 28

**definition:** genetic phenomenon occurs in SOME chromosomes **method:** genes marked as maternal/paternal origin - eg. DNA methylation (turns off), histone modifications - some genes behave differently if they're from mother/father **imprinted chromosomes:** 7, 11, 15 **imprinting disorders:** PWS, Angelman, BWS, RSS **methylation studies:** look methylation profile maternal/paternal genes

Answer 29

**genetics:** AR - mutations in KCNE1 and KCNQ1 genes which form potassium channels **incidence:** 1/1 million **clinical:** bilateral SNHL, long QT

Answer 30

**incidence:** 1/32,000 **defect:** AD loss of function mutation KMT2D chromosome 12 **clinical:** - _facies:_ wide eyes, arched interrupted eyebrows, broad nose, cleft/high arched palate, large/low ears - _physical_: hearing loss, short stature, short fingers, loose joints - _cognitive_: ID

Answer 31

**incidence:** 1:10,000 M\>F **gene:** chromosome X KAL1 gene **clinical:** - GnRH deficiency/gonadotropin deficiency - failure of puberty - hypogonadism - disorders of olfaction - cleft palate - skeletal defects - renal issues

Answer 32

**method:** direct visualisation chromosomes **use:** large changes, translocations

Answer 33

**aneuploidy**: abnormal no. of chromosomes within a cell **compound heterozygote:** 2 mutations same gene leading AR phenotype **epigenetic change:** alteration of phenotype w/o changing genotype **epistasis:** gene/gene interaction producing different phenotype **euploidy:** multiple of the monoploid no. **expressivity:** variable phenotype individuals same genotype **linkage:** tendency of genes close to be inherited together **polymorphism:** genetic region more than one allele present \>1% (mutation is

Answer 34

**incidence:** 1:1,000 **genetics:** non dysjunction sex chromosomes in meiosis (47 XXY), 20% mosaicism **genetic test:** karyotype, microarray **clinical:** - _physical:_ weak, tall, poor coordination, less hair, small genitals, breast growth - _cognitive_: low IQ, impulsive, poor attention/judgement/insight - _fertility:_ primary gonadal failure (normal age onset of puberty but no secondary sexual changes), less interest in sex **investigations:** high FSH/LH, low testosterone (testosterone may be normal to mid-puberty) **comorbidities:** breast cancer **treatment:** androgen treatment age 11-12, aromatase inhibitors for gynaecomastia

Answer 35

**genetics:** 2 genes PTPN11 and RAF1 **clinical: Noonan syndrome with multiple lentigines** **L**entigines: reddish/brown macules to skin (80%) **E**CG abnormalities ie axis devations, hypertrophy, conduction defects, BBB **O**cular hypertelorism **P**ulmonary stenosis **A**bnormal genitals **R**etarded growth **D**eafness (SNHL)

Answer 36

deficiency hypoxanthine-guanine phosphoribosyltransferase (enzyme brain) HPRT gene increased purine synthesis X-linked 1:200,000 normal at birth but hypotonia, vomiting hyperuricaemia, ID, dystonic movements, choreoathetosis, dysarthric speech, self-biting MRI: reduced size basal ganglia treat allopurinol, dental extraction

Answer 37

**incidence:** 1/5,000 **genetics:** AD single gene mutation of FBN1 on chromosome 15q21.1 encoding fibrillin-1 (glycoprotein in ECM) - 25% sporadic **clinical:** - _cardiac_: aortic root disease (dilation, aortic regurg, dissection), MVP - _eyes_: ectopic lens (up and outwards) 80%, myopia - _msk_: tall/thin, hypermobile joints (Steinberg thumb sign/Walker-Murdoch wrist sign), decreased elbow extension, arachnodactyly, pectus deformity, scoliosis, decreased upper/lower ratio, ductal ectasia, hindfoot valgus - _skin_: striae _NORMAL IQ_ **ghent criteria positive if:** - ARD + ectopia lentis - ARD + FBN1 - ARD + systemic score \>7 (in absence of FHx) **treatment:** beta blockers/ARBs (slow aortic dilatation)

Answer 38

**genetics:** somatic mutation ch 20 - G protein mutation stimulated cAMP forming oncoprotein causing gland hyperfunction **DIAGNOSIS (2 of 3):** 1. Cafe au lait spots (Coast of Maine) - rarely cross midline 2. Peripheral precocious puberty 3. Polyostotic fibrous dysplasia **also:** hypophosphatemic rickets, GH excess, Cushing's thyrotoxicosis, arrhythmias, cholestasis

Answer 39

**genetics:** autosomal recessive, MKKS gene mutation **population:** Amish **clinical:** polydactyly, cardiac abnormalities, GU issues - similiar to Bardet-Biedel but no visual loss of MR

Answer 40

**inheritance:** X-linked recessive **gene:** chromosome Xp13 ATP7A gene **defect:** error copper transporting ATPase protein **clinical:** - progressive neurodegeneration/severe MR - seizures, hypotonia, feeding difficulties, optic atrophy - colourless hair, kinky, fragile - chubby red cheeks - death \<3yrs **investigations:** - hair shaft: trichorrhexis nodosa, pili torti, monilethrix - serum: copper/caerulosplasmin low **management:** - copper-histidine subcutaneously

Answer 41

**method:** molecular karyotype - patients blood and control blood is labelled and mixed together - spread across bored and discolouration if unbalanced expression of DNA region **use:** 1st line investigation, detects deletion/duplications **negatives:** will detect variance of unknown significant, will NOT detect balanced translocations/point mutations

Answer 42

**definition:** short segments of repetitive DNA bases scattered throughout genome in non-coding DNA **pathophysiology:** propenisity to develop changes in no. of repeats due to DNA repair errors during replication **examples:** colorectal, endometrial, ovarian and gastric cancers

Answer 43

**M**itochondria=**M**other ## Footnote - sperm bring very little mitochondria to embryo - mito genome= mtDNA - mitochondrial DNA replicates autonomously with high mutation rate - ALL offspring mother affected - all eggs have different degrees of mutation

Answer 44

**genetics:** maternal inheritance **pathophysiology:** - ragged red changes to muscle **clinical:** muscle weakness, neurological issues, hearing loss

Answer 45

**Mitosis:** somatic cells - results in 2 diploid cells **Meiosis:** germline cells - results in 4 sister gametes (haploid cells)

Answer 46

**incidence:** 2:1,000,000 **pathogenesis:** underdevelopment CN VI/VII caused by distruption of blood flow in prenatal development **characteristics:** - facial paralysis - inability to move eyes vertically or close eyes - upper lip retraction - limb/chest wall anomalies

Answer 47

**incidence:** 1/200,000 most common MPS (type IV) **defect:** - type I: deficient galactosamine-6-sulfatase - type II: deficient beta-galactosidase pathophysiology: excess GAGs cause organ damage **clinical:** - macrocephaly - hypermobile joints - short stature - abnormal development bones: scoliosis, bell-shaped chest - coarse facies, wide spaced teeth

Answer 48

**definition:** occurence of cells that differ in their genetic component from other cells in the body **germline:** affecting ova/sperm **somatic:** affecting cells other than germline **mixed:** germline/somatic

Answer 49

**definition:** neuromuscular channelopathy **genetics:** CLCN1 gene **pathogenesis:** CIC forms Cl- channel causing delayed relaxation of skeletal muscle fibers **clinical:** prolonged muscle contractions mainly LL - worse with inactivity **types:** Becker (later/more severe), Thomson

Answer 50

**genetics:** trinucleotide repeat disorder DM1: DMPK gene chromosome 19 CTG repeat DM2: ZNF9 gene on chromosome 3 CCTG repeat **inheritance:** autosomal dominant **clinical:** DM1: severe congenital + milder childhood forms - facial muscles, distal muscles forearm, respiratory failure and death DM2: severe congenital + adult - rarer, proximal myotonic myopathy

Answer 51

**incidence:** 1/25,000 **defect:** NF2 gene on Ch22q1.11 **diagnosis with 1 of 4:** 1. Bilateral vestibular schwannomas 2. 1st degree relative NF2 + uni vestibular schwannoma _OR_ any 2 other tumours (meningioma, schwannoma, glioma, neurofibroma, posterior subscapular lenticular opacities) 3. Uni vestibular schwannomas + 2 other tumours 4. Multiple meningiomas and uni vestibular schwannoma _OR_ 2 other tumours **diagnosis:** clinical **prognosis:** 40% medical problem, 50% learning problem, 6% ID, 5% morbidity

Answer 52

**definition:** tumour disorder **incidence:** 1/100,000, no assoc sex/race **defect:** AD mutation NF1 gene on chomosome 17 encoding neurofibromin - 1/3 are new mutations - 100% penetrance by 5 years **diagnosis (at least 2 of the following):** _1. \>5 CAL macules_ - \>5 mm in diameter prepubertal/\>15 mm postpubertal - 100% NF1 have CAL _2. \>1 neurofibroma or 1 plexiform neurofibroma_ _3. freckling axillary/inguinal regions_ - 80% by 6 yrs _4. \>1 Lisch nodule_ - 40% by 4 years, 100% adults _5. optic glioma (low grade astrocytoma)_ _6. distinctive bony lesion_ - sphenoid dysplasia, thickening of long bone cortex, pseudoarthrosis _7. 1st degree relative with NF1_ **associations:** macrocephaly, learning difficulties 30%, seizures 8%, scoliosis 10%, HTN, malignant malformations 3%, aqueductal stenosis, precocious puberty **investigations:** _MRI:_ unidentified bright objects (disappear by 30 yrs)

Answer 53

**incidence:** 1/1000, both sexes **defect:** AD, 60% mutation PTPN1 chromosome 12q24.1 encoding tyrosine phosphatase SHP-2 **gene testing:** single gene sequencing, of PTPN11 and 11 other Noonan genes **clinical:** - _cardiac:_ PS, LVH, HOCM 20% - _neuro:_ ID, DD - _haem:_ bleeding disorders, small risk leukaemia - _physical:_ downslanting palpebral fissures, hypertelorism, low set ears, webbed neck, chest wall deformity - _gonads:_ delayed puberty, cryptorchidism **diagnosis:** - ECG: LAD and dominant S wave over precordial leads

Answer 54

**method:** Southern blot but RNA instead of DNA **use:** to determine size of mRNA/total RNA fragment produced by specific gene

Answer 55

**incidence:** 1/20,000 **defect:** mutations COL1A1 (most) and COL1A2 encoding type 1 collagen - most AD **genetic testing:** OI gene panel or sequencing **pathophysiology:** - type I: insufficient quantity collagen, mild disease - type II: insuffiency quality/quantity, severe/lethal perinatal period - type III: collagen defective, progressive deformity - type IV: decrease quality/quantity, deformed mesh like bones **clinical:** - _physical:_ short, blue sclerae, hearing loss, fractures - _neuro:_ communication hydrocephalus, basilar invagination, seizures **treatment:** bisphosphonate

Answer 56

**mechanism:** amplify DNA fragment between two primers **method:** select DNA, increase temp to separate strands, add primer, add polymerase **use:** - selective DNA isolation eg. ecoli, paternity - amplification/quantification DNA to analyse small amounts DNA eg. ancient DNA - disease diagnosis eg. infections, cancer

Answer 57

**genetics:** AR, SLC26A4 gene encoding pendrin protein chromosome 7 **pathophysiology:** SLC26A4 in the cochlea, thyroid, kidney and participate in the excretion of bicarbonate **clinical:** congenital SNHL, goitre 75% (euthyroid/hypothyroid)

Answer 58

**incidence:** 1/25,000 **genetics:** AD STK11 gene **clinical:** - hyperpigmented macules to lips/oral mucosa (melanosis) - GI hamartomatous polyps - bowel obstruction due to intussusception age 6-18yrs - 70% cancer: colorectal, stomach, small bowel, pancreas **management:** - bowel radiography every 2 yrs - colonoscopy every 2 years - CT/MRI pancreas yearly

Answer 59

**clinical:** midface hypoplasia, broad thumbs, variable syndactyly, proptosis **types:** - type 1: mildest, normal IQ - type 2: clover leaf skull, severe proptosis - type 3: as for 2 without clover head

Answer 60

**_NOT A SYNDROME_** **pathogenesis:** underdevelopmet of jaw causes abnormal placement of tongue causing cleft palate and resp obstruction **clinical:** micrognathia, airway obstruction, CP **association:** Stickler syndrome is the commonest associated syndrome - cleft palate, bifid uvula, ocular defects, HF hearing loss, muskuloskeletal issues (scoliosis, femoral head failure, OA)

Answer 61

**definition:** multiple phenotypes caused by single mutation

Answer 62

**definition:** disease results from combination of multiple genes **examples:** most non pathological eg. eye colour, height **different sex threshold:** risk of disease different between sex _eg._ if mother CAD higher risk in children than father, if mother pyloric stenosis then lower risk

Answer 63

**incidence:** 1:10,000 **defect:** 15q11-q13 encoding SNRPN/necdin genes - deletion paternal sequence (20% uniparental) (maternal copy imprinted) - 99% sporadic **genetic test:** methylation testing 15q **clinical:** - _triad H₂O_: hypotonia, hyperphagia, obesity - _facies_: almond eyes, strabismus, thin upper lip - _physical_ acromicria (small hands/feet), obesity, insatiable appetite (high ghrelin), hypogonadism, undescended testes, hypopigmentation - _cognitive:_ developmental delay, mild ID, psych issues **treatment:** GH injections

Answer 64

**CVS:** from 11 weeks, placenta sampling, MS 1/100 **Amnio:** from 15 wks, amniotic fluid, MC 1/200 **PGD:** DNA extraction embryo and mutation detection testing **Non-invasive prenatal testing:** FISH for common variations

Answer 65

**genetic:** very rare, unknown mutation **clinical:** overgrowth skin, bones, muscle, fatty tissues, blood, lymphatics - tumours of skin, bone, ovaries, testical, meningioma, parotid glands as they age

Answer 66

**genetics:** AR **pathophysiology:** peroxisomal disorder with impaired alpha oxidation of branched chain FAs resulting in buildup of phytanic acid in tissues - caused by PHYH mutations **clinical:** onset in childhood/adolescence - neurological damage: cerebellar dysfunction, PN

Answer 67

**big repeats:** worse from mother (eg. MD) **small repeats:** worse from father (HD) **characteristics:** unstable between generations, assoc anticipation, repeat size doesn't accurately predict phenotype **triplet repeat disorders:** Frederich ataxia, MD, Fragile X, HD

Answer 68

**etiology:** syndromic or non-syndromic (1/4000) **genetics:** most inheretic forms of retinal degeneration - multiple genes and inheritance **syndromes:** Usher (deafness), Kearns-Sayre (opthalmoplegia, dysphagia, ataxia), abetalipoproteinaemia (retardation, PN, ataxia, stearorrhoea), Bardet Biedel (DD, hypogonadism) **pathophysiology:** progressive degeneration of the rod photoreceptor in the retina **clinical:** onset infancy to adulthood - tunnel vision eventually extending into central field, night blindness (nyctalopia), and accumulation of bone spicules in the fundus

Answer 69

5' upstream, 3' downstream **E**xons: sense portion (**E**ssential) **I**ntrons: non-sense portions that need to be removed pre-translation by slicing (**I**diots) **Codons:** 3 units in mRNA encode specific AAs - 3 stop/start codons, 61 AA codons (only 20 AAs)

Answer 70

**mRNA** (messenger): mirror image of DNA with uracil instead of thiamine **tRNA** (transfer): brings AA back to ribosomes **rRNA** (ribosomal): make up the ribosome with enzymes

Answer 71

**genetics:** microdeletion syndrome in 16p13.3 encoding the CREBBP gene **clinical:** - short, ID, short/broad thumbs, hairy, cryptoorchodism - facies: beaked nose, high palate, downward palpebral fissues, broad nasal bridge \*risk with anaesthesia

Answer 72

**incidence:** 1/50,000 **defect:** 11p methylation defect resulting in decrease IGF-2 production **genetic test:** methylation testing 11p **clinical:** - _neonatal:_ SGA, feeding issues, hypoglycaemia, wide/late closing fontanelle, GORD - _physical:_ macrocephaly, triangle face, cafe au laie spots, blue sclerae, clinodactyly, body asymmetry, precocious puberty, low subcutaneous fat - NORMAL IQ **treatment:** growth hormone

Answer 73

- some genes expressed only in 1 sex eg. male pattern baldness

Answer 74

**genetic:** AR, mutation in gene chromosome 10 encoding neuroaminidase **pathogenesis:** deficiency of neuraminidase causing accumulation of oligosaccharides; storage in liver, BM, brain **clinical:** _type I_: presents 2^nd decade with myoclonus and cherry red spots _type II:_ congenital/ infantile/ juvenile - congenital: hydrops, ascites, HSM, stippling epiphyses, periosteal cloaking, stillbirth - infantile: dysostosi multiplex, moderate MR, visceromegaly, corneal clouding, cherry red spot, seizures - juvenille: edema, ascites, skeletal dysplasia, cherry red spot, dysostosis multiplex, visceromegaly, MR, dysmorphism, corneal clouding, neurological impairment, cherry red spots

Answer 75

**defect:** AR mutation in DHCR7 causing inborn error of cholesterol synthesis **clinical:** - _facies:_ low/rotated ears, cleft lip/palate - _physical:_ cerebellar hypoplasia, agenesis CC, polydactyly hands/feet, short thumb, syndactyly 1/2 toes, ambiguous genitals - CHD, renal/pulmonary/eye abnormalities

Answer 76

**defect:** NSD1 gene mutation (95% sporadic) **clinical:** - _facies:_ high hairline, high bossed forehead, long face, pointed chin - _physical:_ overgrowth prenatal/postnatal, advanced bone age, hypotonia, premature tooth eruption - _cardiac:_ PDA, ASD - _cognitive_: mild-severe ID **investigations:** - MRI: dilated ventricles, cortical atrophy, abnormal corpus callosum

Answer 77

**method:** transfer of electrophoresis separated DNA fragments to a filter membrane and subsequent fragment detection by probe hybridization **use:** linkage to a DNA polymorphism Old method uncommon now

Answer 78

**genetics:** AR, gene SMN1 **clinical:** wasting or proximal muscles and lung - progressive muscular wasting and mobility issues

Answer 79

**genetics:** AD, COL2A1 gene **pathophysiology:** subtype of collagenopathy affecting type II and XI **clinical:** - flattened facial appearance - ocular: high myopia, retinal detachment, glaucoma - hearing loss - joint problems: hypermobile, arthritis

Answer 80

**definition:** lysosomal enzyme disorder **incidence:** AR, 1:25 carrier in Ashkenazi jews **pathophysiology:** mutation in HEXA gene Ch15 encodes hexoaminidase A a lysosomal enzyme **clinical:** - initially normal development - hypotonia by 4-6 months - rapid regression by age 1 with spasticity/paralysis/MR/seizures - progressive blindness/deafness - macrocephaly - death by 5 yrs **diagnosis:** decreased B-hexosaminidase A activity

Answer 81

**unbalanced:** a trisomy with the extra chromosome attached to a difference chromosone **balanced:** disomy but 1 of the chromosomes stuck to another chromosome (normal phenotype) **robertsonian translocation:** balanced translocation between short arms (p) - chromosomes 13, 14, 15, 21, 22 have very short p arms that only code ribosomal RNA - short arms break away and attach another chromosome and long arms fuse - results in 45 instead of 46 chromosomes - risk of unbalanced translocation in an offspring **insertional translocation:** integration of donor segment into another chromosome **reciprocal translocations:** non-homologous chromosomes swap parts **inversions:** 2 breaks with segment flipped - normal phenotype but can mave miscarriages

Answer 82

**incidence: 1/50,000** **defect:** AD single gene disorder in TCOF1 **clinical:** - _facies_: mandibulofacial dysostosis, sloping eyes, lower eyelid coloboma, malar hypoplasia, microtia - conductive hearing loss

Answer 83

**definition:** repeated sequence expands in successive generations leadomg tp abnormal phenotypes **examples:** myotonic dystrophy, huntington's disease

Answer 84

**defect:** 3 copies of chromosome 13 - usually nondysjunction and rarely translocation **genetic test:** karyotype, microarray, FISH **clinical:** holoprosencephaly, cleft lip/palate, heart abnormalities, scalp defect, ID **prognosis:** mean survival 10 days - 80% die by 3 months and 92% by 1 yr _NOT LETHAL BUT HIGH MORBIDITY/MORTALITY_

Answer 85

**defect:** 3 copies chromosome 18 mostly nondysjunction **genetic test:** karyotype, microarray, FISH **clinical:** IUGR, wizened appearance, prominent occiput, _overlapping fingers_, _rockerbottom feet_, multiple malformations **prognosis:** FDIU, death in first year most common - mean survival 14 days - 80% die by 3 months, 92% by 1 year

Answer 86

**defect:** 3 copies chromosome 21 - dysjunction (95%), translocation (4%), mosaic (1%) **genetic test:** karyotype, microarray, FISH **clinical:** - _facies:_ upslanting palpebral fissures, epicanthal folds, flat nasal bridge, brachycephalic head, small mouth, large tongue - _CHD (50%)_: TOF, AVSD, PDA - _GI_: duodenal atresia (12%), hirschsprungs (\<1%) - _hypothyroid_: congenital (1%), lifetime (15%) - deafness (75%), visual problems (60%) - OSA (50-75%) _other_: low IQ, AML, atlanto-axial instability, dementia, sandle gap

Answer 87

**incidence:** 1/6,000 **genetics:** AD mutation TSC1/TSC2 encoding hamartin/tuberin that form tumour suppressor complex - 2/3 sporadic **clinical:** CNS involvement is the hallmark **diagnosis:** 2 major or 1 major and 2 minor criteria (see table) **others:** seizures (20% of infantile spasms), autism, behavioural issues, low IQ, increased malginancy (RCC, giant cell astrocytoma), lymphangiomyomatosis

Answer 88

**incidence:** 1:5,000 (only 8% live births) **genetics:** 45, X (50% mosaic) - maternal X retained in 66% SHOX **clinical:** - _physical:_ short stature, shield chest, wide spaced nipples, wide carrying angle, high arched palate, hearing problems - _eyes:_ amblyopia/strabismus/ptosis/hypertelorism - _CHD_ (30%): bicuspid aortic valve 15%, coarctation of the aorta 10%, aortic dissection, HTN - _renal anomalies_ (50%): kidney dysplasia (horseshoe, abnormal vasc supply, uteropelvic obstruction) - _fertility:_ amenorrhoea (30% enter puberty spontaneously), gonadal failure (infertile), gonadoblastoma, osteoporosis - _AI:_ hypothyroidism (30%), ceoliac (10%), IBD), insulin resistance _treatment:_ GH injections, hormone replacements age 12 _prognosis:_ mortality x3 normal pop

Answer 89

**incidence:** 1/40,000 - associated maternal DM but usually sporadic **cause:** unknown, not syndrome but association **clinical:** _**V**ertebral defects:_ small hypoplastic vertebrae/hemivertebrae _**A**nal atresia 55%_: atresia or imperforate anus _**C**ardiac defects 75%_: VSD/ASD/TOF _**T**racheooesophageal fistula_ 70% _**E**sophageal atresia_ _**R**enal 50%/Radial abnormalities_ _**L**imb defects 70%:_ hypoplastic thumb, polydactyly, syndactyly, radial aplasia

Answer 90

**incidence:** 1/4000 **gene:** AD 22q11.2 deletion (most common microdeletion syndrome involving 3 megabases of DNA with 30 genes) **AKA:** DiGeorge syndrome, velocardiofacial syndrome **genetic test:** FISH, microarray **pathophysiology:** abnormal development 3rd and 4th branchial arches **clinical:**'CATCH' _**C**ardiac 40%_: conotruncal/aortic arch defects - interrupted AA, truncus arteriosus (34%), TOF, VSD _**A**bnormal facies:_ low set/rotated ears, hypertelorism, high nasal bridge, micrognathia, short upward palpebral fissues _**T**hymic aplasia:_ variable level of T cell dysfunction, only 1% SCID _**C**left palate 50%:_ full or submucosal cleft, _NO LIP_ _**H**ypocalcaemia/hypoparathyroidism:_ abnormal PT gland formation **ALSO**: seizures, **_psychosis (60%)_**, autism (20%), renal anomalies, ID (30%), learning difficulties (70%), hearing loss, facies (tubulara nose, large ears, small mouth)

Answer 91

**incidence:** 1/50,000 **genetics:** AD, sporadic, mutations in variable genes **variance:** types I-V **characteristics:** - deafness - pigmentation anomalies: heterchromia, poliosis, patches hypopigmenation - defects of structures from neural crest: telecanthus, cleft lip/palate, spinal defects, hirschsprung's

Answer 92

**W**ilm's tumour **A**niridia **G**enitourinary abnormalities **R**etardation

Answer 93

**method:** protein from cell extract separated by gel electrophoresis, placed on membrane, washed with Ab to protein, then washed 2nd Ab with dye **use:** obtain information about size/amount of mutant protein of particular disorders

Answer 94

**incidence:** 1/20,000 **defect:** heterozygous microdeletion on 7 due to misalignment in meiosis **genetic test:** microarray, FISH **clinical:** _facial features:_ widely spaced teeth, long philtrum, flattened nasal bridge, stellate eyes, puffy eyes _physical:_ short stature, developmental delay _cardiac:_ supravalvular aortic stenosis _endocrine:_ hypercalcaemia, hypothyroidism _gastic:_ colic, diverticulitis _neuro:_ low IQ, very talkative, social disinhibition, attention problems _behavioural:_ noctural enuresis

Answer 95

**incidence:** rare X-linked WASp gene, 1:25000 **clinical:** eczema, thrombocytopaenia, immune deficiency, blood diarrhoea, **investigations:** low IgM, normal IgE/IgA, high IgG **treatment:** avoid NSAIDs, BMT

Answer 96

**Rett syndrome** - deletion methyl-CpG-binding protein 2 (MeCP2) - lethal to males inutero - _female:_ normal development/HC then regression **Fragile X** - CGG repeat in FMR-1 gene - males more severe - _clinical:_ autism, MR, long face, protruding jaw, big ears **Menke Kinky Hair disease** - copper transporting ATPase gene - defective copper absorption - _clinical:_ neurodegeneration 1st months, seizures, rosy cheeks, kinky hair **Adrenoleucodystrophy** - ABCD-1 gene: prevents transport VLCFA into peroxisomes - _clinical:_ 4-8 yrs, learning difficulties, behaviour issues, neurological degeneration **Duchenne muscular dystrophy** - Xp21 deletion: dystrophin gene (1% X chromosome) - 1/3 sporadic - _clinical:_ boys, onset 18m, weakness, cardiomyopathy, resp muscle weakness, contractures, scoliosis, MR

Answer 97

**Recessive** - Fragile X - Haemophilia - DMD/BMD **Dominant** - Incontinentia Pigmenti

Answer 98

**genetics:** aneuploidy of sex chromosomes due to error in separation during anaphase II meiosis ie nondysjunction **clinical:** increase growth velocity, increase height, normal sex development/fertility, 50% learning disability/speech + language delay **investigations:** normal testosterone

Answer 99

**defect:** AR defect in protein require for assembly of peroxisomes (PEX genes) **pathophysiology:** reduced function peroxisomes and accumulation of VLCFAs normally degrades in peroxisomes **clinical:** hypotonia, tall forehead, midface hypoplasia, hepatomegally, eye abnormalities, renal cysts **investigations:** abnormal MRI, elevated VLCFAs **prognosis:** fatal by 12 months

Answer 100

1. Usher syndrome: hearing then RP 2. Bardet Biedel: polydactyly, obesity, renal, MR 3. Nephronopthisis

Answer 101

**clinical:** - mesomelic shortening - curved radius/ulna (Madelung deformity) - short 4th MC - muscular hypertrophy **genetic:** AD SHOX gene mutation

Answer 102

**genetics:** 1:20,000, X linked dominant gene MeCP2 - fatal in males **clinical:** onset 5-48 months - decreased head growth - loss of purposeful hand skills and social interests - stereotyped hand movements - gait disorder - seizures

Answer 103

**incidence:** 1/100,000 **genetics:** AR 11 genes **clinical:** retinitis pigmentosa, SNHL