Genetics Flashcards

Question

Deletions

Answer 1

= loss of chromosome material, which can be terminal (ends of chromosomes) or interstitial a. Often associated with mental retardation b. Most common deletions are distal c. Can be detected with FISH or microarray

Answer 2

= piece of chromosome is broken and incorporated into a break in another part of chromosome a. Can occur between 2 or 1 chromosome b. Insertions are RARE c. Carriers are at risk of having offspring with deletions/ duplications of the inserted segment

Answer 3

a. Ends of a chromosome are deleted + ends joined to form a ring b. Can have normal phenotype/ congenital abnormalities depending on amount loss

Answer 4

* Genotype = genetic constitution of an organism * Phenotype = physical characteristics * Locus = position of a gene on the chromosome * Allele = an alternative variant of a particular gene • Homozygous = at a particular locus there are two copies of the same allele • Heterozygous = at a particular locus there are two different alleles • Hemizygous o Only carrying one copy of a genomic region due to deletion or altered function of the corresponding region on the other chromosome o Males – a mutation in any gene on the X chromosome o Female – a mutation in any gene on the X chromosome ONLY if Turner’s syndrome • Compound heterozygote = at a particular locus there are two different mutations • Polymorphism = where there are at least two, or more, relatively common alleles of a gene in the population (>=1%) o Eg. Different alleles of genes responsible for ABO blood groups * Dominant = a phenotype is dominant if the trait can be seen in individuals who are heterozygous for an allele (ie only need one copy); NOTE: may not be inherited, can be de novo and so severe that the individual dies and does not pass on the allele * Recessive = a phenotype is recessive if the trait is seen only individuals homozygous for the disease (ie need two copies) * Codominant = a phenotype is co-dominant when the effects of both alleles are seen in the heterozygote • Penetrance = proportion of people with a genotype who develop disease (black + white) o For some disorders penetrance is 100% eg. NF-1, CF o For other disorders lower penetrance eg. BRCA1, polydactyly • Expressivity = how the phenotype is expressed in a different individual (shades of grey) o Some disorders the expressivity is similar eg. NF-1 (variable), CF (consistent), HOCM/DCM • Genetic heterogeneity = multiple genes converge on same phenotype o Allelic heterogeneity = where different mutations of the same gene exist to cause the same phenotype (eg multiple mutations of the CFTR exist, causing the phenotype of CF) o Locus heterogeneity = where multiple genes can be mutated in various ways to cause the same phenotype  Eg. LQT syndrome can result from genetic mutations in different sodium and potassium channels  Eg. ID, hearing loss, retinitis pigmentosa, epilepsy • Digenic inheritance = disease caused by co-inheritance of mutations at two distinct loci (rare) ``` • Mosaicism = more than one genotype in different cells o Point mutation or chromosomal abnormality o Germline (gonadal) vs constitutional (somatic) ```

Answer 5

Mendelian • Refers to the collection of patterns of expression of physical traits over two or more generations that follows the rules of parental-to-offspring transmission (autosomal or sex-linked, dominant or recessive), that Mendel first described • Patterns attributable to the action of single genes • Most clinically recognizable for rare, highly penetrant, monogenic diseases EG: AD, AR, XD, XR, YD Non-Mendelian • Many instances of familial clustering of rare traits but pattern of inheritance does not follow Mendel’s laws • Inheritance can appear to be non-Mendelian o Multiple genes impact on phenotype expression o Despite a disorder being monogenic additional factors impact the concordance between genotype + phenotype EG: Incomplete penetrance, Sex-limited expression, Imprinting, Multigenic inheritance, Anticipation, Mitochondrial inheritance

Answer 6

1. Key points a. Phenotype is dominant if the trait can be seen in individuals who are heterozygous for an allele b. Common to have de novo mutations – occur and can create case without FHx – E.g. Noonan’s 2. Examples = NF1, Marfan, PCKD, TS, vWD, OI, hereditary spherocytosis, familial hypercholesterolaemia, HD, myotonic dystrophy, acute intermittent porphyria, hereditary haemorrhagic telangiectasia, Noonan syndrome 3. Inheritance a. If one parent affected 50% of children will inherit 4. Pedigree a. Equal numbers of affected males and females b. Vertical transmission of phenotype (>1 generation) c. Male to male transmission occurs (this excludes X linked) + female to female transmission d. Skipped generation may be due to incomplete penetrance e. Most common form of inheritance (think: reproductive fitness) 5. Exceptions a. De novo mutations iii. The more severe the disorder, the more common de novo mutations are (those with severe disorders less likely/ never procreate – called low/zero fecundity) iv. Examples 1. Achondroplasia 80% de novo b. Gonadal mosaicism

Answer 7

1. Key points a. Phenotype is recessive if the trait is only seen in individuals who are homozygous for the allele b. Both parents need to be carriers c. More severe than autosomal dominant (unlikely to reproduce with most AR conditions) d. Less likely to be due to new mutations as need 2 new mutations of the same gene e. Fewer variables within families f. Heterozygotes typically not affected and asymptomatic but can have late effects – mild disease in adults g. Consanguinity increases risk of AR conitions 2. Examples = deafness, albinism, Wilson disease, sickle cell disease, thalassemia, haemochromatosis, PKU, alpha-1-antitrypsin deficiency (+ other IEM), CF, Friedreich ataxia, homocystinuria 4. Pedigree a. Horizontal appearance of phenotype especially among siblings b. Equal number of males and females c. Consanguinity (mating of related individuals) may be present d. Heterozygotes are carriers, and are generally healthy 5. Note a. Biallelic phenotype = 2 different mutations i. More likely if there is high prevalence in the community, usually due to low severity disease b. Pseudo-dominant conditions i. Recessive conditions in more than one generation by bad luck ii. Pedigree looks dominant but is actually AR iii. More common with common and less severe disorders (eg haemacrhomatosis)

Answer 8

o The allele and genotype frequencies in the population o p2 + 2pq + q2 = 1 o Represents frequency of alleles in population in one gene  P = incidence of one allele  Q = incidence of second allele  p2 = number of unaffected individuals in a population (assume 1 for rare AR condition) = homozygous for allele 1  q2 = incidence of disorder = homozygous for allele 2  2pq = carriers = heterozygous for the 2 alleles ``` o Example = If the incidence of Tay Sachs in 1 in 10,000  Q2 = 1/10,000  Q = 1/100  P2 = 1  P = 1  2pq = 2 x 1 x 1/100 = 2/100 = 1/50  Therefore carrier frequency is 1/50 ```

Answer 9

1. Key points a. Common to have de novo mutation b. Female carriers may have mild phenotype OR be completely healthy i. 50% of females with fragile X have ID 2. Examples = DMD, Fragile X, haemophilia A, adrenoleukodystrophy, X-linked hypohidrotic ectodermal dysplasia, G6PD, Fabry disease, ocular albinism, colour blindness, CGD 3. Inheritance a. Male with disorder i. All female daughters are carriers ii. None of sons inherit b. Female carriers i. 1/4 chance of having an affected child ii. Males – 50% affected (ie. 25% chance of having affected male) iii. Females – 50% carrier 4. Pedigree a. Absence of father-son transmission b. Affected males much more common; all their daughters are obligate carriers Ratio of affected/hemizygous males to carrier/heterozygous females 2:1 Lyonisation and skewed X inactivation can lead to symptoms in female - rare, and usually more mild Female dystrinopathy - DMD/similar phenotype in females to males is RARE - female dystrinopathies occur d/t: 1. Turner XO 2. Translocations b/w X and autosomal chromosomes 3. Skewed X inactivation 4. Homozygous mutations in dystrophin gene

Answer 10

1. Key points a. Less common clinically b. Phenotype consistently in females and males i. If not lethal for males – males will have the more severe phenotype ii. If lethal for males – only females will be affected c. Common to have de novo mutations 2. Examples = X-linked hypophosphataemic rickets, incontentia pigmenti (males lost as miscarriages) 3. Inheritance a. Affected males i. 100% daughters affected ii. 0% sons affected b. Affected females i. 50% sons affected ii. 50% daughters affected – less severe 4. Pedigree a. As common in females and males HOWEVER often lethal in males

Answer 11

1. Key points a. Terms that describe how the disease genotype correlates with clinical phenotype b. Alterations in penetrance or expressivity can make monogenic traits appear to be transmitted in a non-Mendelian pattern 2. Penetrance a. Penetrance = proportion of individuals who carry the causative genotype who manifest disease (0-1) b. For most disorders, complete penetrance is the exception and not the rule c. Classification i. Full penetrance = genotype status predicts development of disease; can be reliably used for genetic counselling (HD, TaySachs) ii. Incomplete penetrance = penetrance values of <1, in which expression of disease NOT always observed among individuals who carry the disease associated genotype iii. Variable penetrance = penetrance levels that change across ethnic groups of within families (BRCA1) 3. Expressivity a. Expressivity refers to clinical or phenotypic differences of disease manifestation when the condition is present b. Common among diseases which effect multiple organ symptoms

Answer 12

1. Pleiotropy = ability of variants in a single gene to produce more than one or multiple phenotypic effects, often in different tissues or organs a. Distinct from variable expressivity, which describes how two individuals with the same pathogenic variant (or combination of variants) can manifest different phenotypic effects or different degrees of disease expression despite identical genotypes 2. Example = Marfan syndrome - pathogenic FBN1 variants can cause cardiac manifestations (aortic dilatation and rupture), ocular manifestations (ectopia lentis and severe myopia), and connective tissue findings (joint hyperextensibility and arachnodactyly)

Answer 13

1. Key points a. Anticipation = phenomenon in which successive generations display accelerated, earlier-onset, or more severe disease manifestations b. Often first recognized in the most severely affected offspring – milder disease forms in parents/grandparents 2. Examples a. Trinucleotide repeat expansion b. Short telomere syndrome eg. dyskeratosis congenita

Answer 14

1. Key points a. Mosaicism = state of having two populations of genetically distinct cells in an individual who arose from a single fertilized egg b. Occurs due to several mechanisms in the developing blastocyst or embryo c. Usually caused by mitotic non-disjunction d. Events that occur later during development affect a smaller proportion of cells and a more limited number of cell lineages e. Classic feature is hypomelanosis of Ito (Blaskhoid hypomelanosis) i. Congenital skin disorder affected M+F ii. Associated with chromosomal mosaicism + translocation iii. Patterned, hypopigmented macules over the body surface in demarcated whorls, streaks and patches iv. Often associated with: ID, seizures, microcephaly, muscular hypotonia 2. Inheritance a. Individuals with mosaicism can only transmit the variant to the next generation if it is present in the gametes. 3. Diagnosis – can be made on microarray + next generation sequencing 4. NOTE a. Chimerism = uncommon state of having two or more populations of genetically distinct cells due to fusion of two or more fertilized egg

Answer 15

1. Key points a. Mitochondrial inheritance = traits due to genetic variation in the mtDNA rather than the nuclear genome 2. Mitochondrial inheritance a. Exclusively inherited through maternal line (ie. from egg) b. Heteroplasmy = more than one type of mitochondria (affected or unaffected by the variant) in each cell c. Females with a mitochondrial variant who exhibit heteroplasmy will pass on varying numbers of affected or unaffected mitochondria to their eggs -> substantial variation in the contribution of the mitochondrial variant to each offspring 3. Mitochondrial diseases a. 1000-2000 mitochondrial cell b. Mitochondrial failure -> cell injury c. Disease commonly affects brain, heart, liver, muscle, renal, endocrine, respiratory 4. Pedigree a. All a mother’s children affected b. No descendants of an affected male have the disease 5. Mitochondrial vs X linked a. No male to male in either b. X linked = males affected exclusively (or more severely) than females c. Mitochondrial = males and females affected to the same extent d. Mitochondrial = no descendants of an affected male have the disease, whereas this can happen in X linked conditions

Answer 16

• The expression of some traits, regardless of their chromosomal location, can be restricted to one sex, likely due to critical physiologic, anatomic, or hormonal differences • Examples o Male pattern baldness – can be inherited as AD trait o Familial male precocious puberty – variants of GNAS1 gene o Juvenile hypertrophy of breast – limited to females

Answer 17

1. Key points a. Caused by the combined effects of >1 gene – multigenic or complex disease 2. Classification a. Digenic i. Pathogenic variants at two distinct loci required for disease to manifest ii. Many exhibit classic AR inheritance pattern iii. Example = digenic form of retinitis pigmentosa, Usher syndrome b. Triallelic i. Rare type of inheritance that requires three gene variants for disease to manifest 1. Two pathogenic variants at one locus and one additional variant at a different locus 2. Example = Bardet-Biedl a. Most individuals homozygous or compound heterozygotes for a pathogenic variant in one gene consistent with AR b. Families described in which three variants in two genes segretgate with the disease phenotype

Answer 18

1. Key points a. Characterised by familial clustering, but non-Mendelian patterns b. Due to multiple genes with small effects d. Examples = DM, CVS disease, asthma, MS etc 2. Characteristics a. Similar rate of recurrence among all first-degree relatives b. Identical twin risk is not 100%, but is more than sibling risk c. Often susceptibility alleles in non-coding regions (SNPs) 3. SNPs a. Occur every 1/300 base pairs b. Most common type of genetic variation c. Each individual has 10 million SNPs d. Usually in non-coding regions f. Often used in association studies – Genome Wide Association Study (GWAS)

Answer 19

* May be inherited from a carrier or appear de novo * Carriers of a reciprocal translocation are phenotypically normal, with an increased risk for miscarriage and bearing affected children ``` • Pedigree o Males = females o Multiple miscarriages o Parents unaffected o Offspring  2/6 normal (50% carrier)  1/6 unbalanced = affected  3/6 non-viable = miscarriage ```

Answer 20

1. Definitions a. Epigenetics = alteration of gene expression (rather than DNA itself) i. Transcribed genes need to be accessed by transcription factors, and so the chromatin is more open ii. Methylation of cytosines in promoter region contributes to ‘silencing’ of genes b. Imprinting = epigenetic marking of a gene based on its parental origin and results in monoallelic expression i. For imprinted genes, expression is determined by the parent of origin of the chromosome ii. Exception NOT the rule – 1% genome is imprinted c. Mechanism of imprinting is usually due to parental specific methylation of CpG-rich domains AND modification of histone proteins d. This is reset during gamete formation i. Genetic imprinting occurs early in the formation of eggs/sperm ii. Imprinting then occurs again in the next generation when that person produces his/her own eggs/sperm ie. maternal or paternal imprint is sex specific in relation to the parent the allele is inherited from NOT the offspring iv. Father passes on paternally imprinted genes v. Mother passes on maternally imprinted genes 4. Imprinting disorders a. Imprinting disorders occur when there are INAPPROPRIATELY two active copies or two inactive copies of the imprinted gene (ie. group of disorders based on inappropriate gene dosage) i. Eg. normal maternal imprinting – you are relying on the paternal copy to work – therefore if something goes wrong with the paternal copy there is a problem c. Maternal vs paternal imprinting i. Maternal imprinting = maternal gene silencing (and paternal gene expression) – a maternally imprinted gene means that when inherited from the mother it is NOT expressed, and vice versa d. Imprinting silences one gene a. Imprinting = DNA sequence will be normal, but the relevant allele is switched off  methylation testing required

Answer 21

= both genes are inherited from the one parent (maternal UDP = two maternal copies) i. Is the presence of two chromosomes/ two alleles inherited from one parent ii. Effect of this varies, can result in: 1. An imprinting type disorder 2. Uncovering of autosomal recessive disorder iii. Is usually maternal, due to non-disjunction during meiosis 1. Error in meiosis I  two copies of material from the same grandparent (uniparental isodisomy) 2. Error in meiosis II  one copy of material from each maternal grandparent (uniparental heterodisomy) iv. This means the maternal gamete has an extra set of chromosomes, with uniparental disomy arising due to fertilization with nullisomic gamete OR trisomic rescue (most common) v. Note that the terminology is the opposite to imprinting: 1. Maternal UPD = two copies of maternal chromosomes, absence of paternal genes 2. Paternal UPD = two copies of paternal chromosomes, absence of maternal genes c. Uniparental disomy = FISH or SNP array i. NOTE: SNP detects some but not all UPD ii. Can do specific UPD studies

Answer 22

* PWS and Angelman syndrome occur due to absence of monoallelic expression of key genes at 15q12 * Some genes in this location are only active on the paternal copy, and some on the maternal copy * Absence of PATERNALLY functioning genes * Deletion on paternal 15 – OR both 15s are maternal • Mechanism o 70% paternally derived deletion of 15q12 o 25% maternal UDP 15 - increasing due to increasing maternal age o <1% imprinting defect  Paternal imprinting = silencing ``` • Key features o Floppy baby (hypotonia) o Voracious appetite (hyperphagia) - most common syndromic form of obesity o Obesity, short stature o Moderate ID o Hypogonadism, cryptorchidism - hypopigmentation vi. Depigmentation of the skin or eyes relative to familial background in 30-50% - small hands and feet ``` Other features: - neuro/psych: OCD, epilepsy (25%) - facies: almond shaped eyes i. Premature adrenarche (pubic and axillary hair), but other secondary sexual characteristics are delayed or incomplete 5. Investigations a. Methylation analysis: detects all cases b. Microarray abnormal in deletions + and some UPD c. Deletions can also be detected via FISH d. In practice, PWS panels will perform karyotype, methylation studies FISH + microsatellite probes for maternal uniparental disomy 6. Treatment a. Growth hormone i. Does not require formal GH deficiency testing ii. Subsidized in genetically confirmed PWS until the age of 18 years v. Require sleep study prior to use vi. Contraindications: uncontrolled DM, respiratory compromise, severe sleep apnoea (IGF-1 stimulates adenotonsillar hypertrophy) vii. Series of increased fatality seen initially within commencement of GH treatment, usually related to severe OSA + intercurrent URTI 7. Prognosis a. Mortality up to 3%, average age of death is 33.2

Answer 23

* PWS and Angelman syndrome occur due to absence of monoallelic expression of key genes at 15q12 * Some genes in this location are only active on the paternal copy, and some on the maternal copy * Absence of MATERNALLY functioning genes (UBE3A) * Deletion on maternal 15 – OR both 15 are paternal ``` • Mechanism o 70% maternally-derived deletion of 15q12 o 5-10% UBE3A mutation o 5% patUDP15 o 3% imprinting defect o 10-20% unknown ``` • Key features o Severe ID o Lack speech + inappropriate laughter - behavioural "happy puppet" o Unsteady gait/ataxia o Epilepsy - postnatal microcephaly, delayed and disproportionate - hand flapping - seizures in 80%, and abnormal EEG even in absence of seizures 3. Investigations a. Methylation testing of 15q11.2-13 (will pick up 70%) b. UBE3A single gene sequencing (will pick up 10%)

Answer 24

* BWS and Russel-Silver syndrome are caused by the same gene (11p15) – location of IGF-2 (paternally expressed growth factor) * Usually only the paternal copy is active * Loss of maternal copy (eg. paternal UDP) = paternal over-expression = BWS (big) * Loss of paternal copy eg. imprinting defect, both copies maternal imprint = paternal under-expression = Russel silver (small)

Answer 25

* Absence of MATERNAL gene * Disrupting imprinting of 2 neighbouring domains on 11p15 (paternal allele growth promoting, maternal allele growth suppressing) 1. Key point = association with IVF (loss of IC2 methylation) c. Overactivity of IGF-2 (growth factor) d. Imprinted genes = IGF2, gene H19 (involved in IGF2 suppression), WT1 (Wilms tumour gene), many others • Mechanism o 50% loss of methylation at mat IC2 on 11p o 20% paternal UPD 11 o 5% gain of methylation at mat IC1 on 11p o 5-10% CDKN1C mutation ``` • Key features o Overgrowth disorder o Macrosomia, neonatal hypoglycaemia o Hemihypertrophy o Macroglossia, visceromegaly o Predisposition to embryonal malignancies (Wilms, hepatoblastoma, neuroblastoma) - screening every 3mo - exomphalos - ear creases/pits - naevus flammeus - cognitively can be normal, mild-mod ID ``` 6. Investigations a. Methylation testing – diagnostic b. SNP array is abnormal in rare microdeletions/duplications and some patUDP11 1. Prognosis a. Generally good prognosis if survive past infancy i. Apnoea/cyanosis may occur -> 21% infant mortality b. Follow-up tumours with USS and AFP i. Nowadays JUST do USS every 3/12 until age 8 years

Answer 26

• Absence of PATERNAL gene • Mechanism o 50-60% 11p methylation defect o <10% maternal UPD7 o Rest unknown • Key features o Short stature o IUGR o Asymmetry o Triangular face (prominent forehead, pointed chin) o Macrocephaly (preserved HC despite IUGR) - hemihypertrophy as well - clinodactyly (bending/curving of finger) 4. Investigations a. Methylation testing 11p b. UPD7 studies (DNA from parents) c. May detect UPD7 on SNP array 5. Treatment a. GH treatment effective

Answer 27

* For imprinting it is the gender of the parent of origin of the gene that matters – NOT the gender of the child * Equal number of males and females • Key points o No affected children from the gender that is imprinted (no affected children from females if maternal imprinting, no affected children from males if paternal imprinting) o Imprinting is reset when passed to the next generation o If a pedigree shows a disorder inherited from both male and female parents, it cannot be an imprinting disorder • Maternal imprinting = genes inherited from the mother are switched off o Mutation in a maternally imprinted gene will result in the condition in  HALF of the children of a male with a mutation  NONE of the children of a female with the mutation (mutation imprinted) • Paternal imprinting = genes inherited from the father are switched off o Mutation in paternally imprinted gene will result in the condition in:  HALF of the children of a female with the mutation  NONE of the children of a male with the mutation

Answer 28

b. Classification i. Normal range (stable range in mitosis and meiosis) ii. Intermediate (mutable) range / permutation repeat size is unstable but does not result in a phenotype iii. Full mutation c. Allele expansion often dependent on gender of transmitting parent i. Maternal = myotonic dystrophy, FRAX, Friedreich ataxia (lager repeats) ii. Paternal = CAG repeat disorders such as HD, SCA (smaller repeats) ii. CANNOT use the repeat size to predict phenotype with accuracy eg. myotonic dystrophy prenatal, HD predictive test 2. Classification a. Repeat Codon CAG (glutamine) = polyglutamine, e.g. HD, SMA b. Non-CAG, e.g. FRAX, FA, myotonic dystrophy

Answer 29

• Linkage = the use of ‘markers’ to follow gene/mutation through a family o Marker is generally polymorphic section of DNA in/near a gene • Polymorphic = section of DNA that differs in different people o SNP = single nucleotide polymorphism o Short tandem repeats • Linkage disequilibrium o Tendency for alleles of genes or genetic markers to be inherited together in a non-random fashion o Occurs when two genes or genetic markers are in close chromosomal position – particular patterns of markers are unlikely to be separated by the random assorting of chromosomes by cross-overs at meiosis o The closer together two genes or genetic markers the higher the linkage disequilibrium

Answer 30

i. Sequence = pattern of structural defects caused by a single problem in morphogenesis (eg Pierre Robin) ii. Syndrome = pattern of multiple defects due to a known cause, e.g. Down syndrome = T21 iii. Association = pattern of structural defects that are statistically related, not due to a known sequence or syndrome (eg VACTERL) i.e. cause unknown

Answer 31

iii. Palpebral = line from inner to outer canthus 1. Normal: 1:1 with inner canthus 2. Upslant – T21 3. Downslant – Noonan 4. Short – fetal alcohol syndrome

Answer 32

= a fold of skin coming from upper eyelid, in front of medial canthus

Answer 33

= below level of inner canthus 1. Noonan, OAVS, 22q11, T21 2. Posteriorly rotated – Noonan

Answer 34

Midline abnormality – think holoprosencephaly

Answer 35

May have associated muscular defect in soft palate

Answer 36

i. Clinodactyly = medial or lateral curve to toe or finger (usually 5th) due to hypoplasia of middle phalanx 1. Down syndrome, Russell-Silver, Klinefelter’s ii. Syndactyly = incomplete separation of fingers (usually 3rd/4th) or toes (2nd/3rd) 1. Apert’s – mitten syndactyly, Carpenter’s, Cornelia de Lange, trisomies, Smith-Lemli-Opitz iii. Camptodactyly = abnormal persistent flexion of fingers or toes iv. Polydactyly = extra finger or toe (usually 5th)- simple or complex, family history common 1. Carpenter syndrome, trisomy 13, Rubenstein-Taybi, Smith-Lemli Opitz, Bardet-Biedl vi. Trident hand = achondroplasia

Answer 37

Carbamazepine HLA-B1502 Risk of SJS More frequent in patients of Han Chinese, Thai and Malay background Testing prior to patients of Asian ethnicity ``` Warfarin Cytochrome P450 (CYP2C9) Affects warfarin dose requirements Variable evidence for clinical utility of genotype guided vs. clinical dosing ``` Azathioprine TPMT polymorphism Risk of drug accumulation and severe myelosuppression if low functional enzyme activity Can measure enzyme activity or via genotyping Tested prior to prescribing ``` Tamoxifen Cytochrome P450 (CYP2D6) Variants may influence efficacy, as the active metabolite of tamoxifen (endoxifen) is generated by genetic metabolism ```

Answer 38

• Cytogenetics o Karyotype • Molecular cytogenetics o FISH = fluorescent tagged DNA probes to visualize particular areas o MLPA = targeted probes to detect copy number changes at the exomic level o Molecular karyotype (microarray) = virtual karyotype from array of many thousand tagged DNA probes

Answer 39

a. Identifies i. Aneuploidy ii. Large chromosomal imbalances (5 Mb or greater) iii. Balanced AND unbalanced translocations b. Does NOT identify i. Microdeletions/ duplications ii. Single gene mutations iii. Triplet repeat expansion iv. Imprinting disorders Level of analysis Chromosomes ``` Examples T21 Klinefelter Turner Balanced translocation ```

Answer 40

a. Identifies i. Presence/ absence of specific DNA sequences on chromosomes ii. Now good for localization + looking for balanced rearrangement iii. Resolution up to a few Mb (50-200 b of DNA) (1 megabase = 1,000,000 bases) b. Does NOT identify i. Unknown mutation - must use specific prob 2. Method a. RAPID result b. DNA probes made for a specific target c. Probes bind to specific target and are fluorescent labelled 3. Note a. Often used for rapid diagnosis of trisomies and prenatal diagnosis (<24 hours) Level of analysis Chromosomes to submicroscopic chromosomal ``` Examples Whole chromosome (trisomy) Microduplications/ deletions (eg. 22q, Williams) ```

Answer 41

1. Standard MLPA a. Modified PCR amplification b. Each amplification product has a unique length c. Amplification products separated by electrophoresis d. Reflects the relative copy number of target sequences (eg. duplications/ deletions) e. Cannot detect sequence changes or large copy number changes f. NOTE: outdated, not commonly used, largely replaced by microarray 2. Methylation sensitive MLPA a. Can detect methylation – uses an enzyme that only amplifies targets that are unmethylated b. Used for imprinting disorders Examples Duplication/ deletion of any gene

Answer 42

1. Key points a. Identifies differences in the amount of genetic material – gains or losses b. Copy number variation (CNV) = difference in the number of copies of one or more sections of DNA that result from DNA gains or losses c. Variations of unknown significance = VOUS 2. Method a. CGH array i. Compare DNA (genome) from two sources – test sample (green) and patient (red) - green = loss of material, red = gain, yellow = equal Detects Microdeletions + microduplications Monosomies + trisomies Variations that may not be clinically significant b. SNP array i. Identifies variation in a single nucleotide at a specific locus iv. Detects whether the 2 allelic copies of a single base pair are homozygous (same) or heterozygous (different) 1. Loss of heterozygosity eg. UPD in Angelman/ BWS 2. Mutated copy of tumour suppressor gene i. Better, higher resolution test than CGH ii. Get some sequence information – not just dosage (cf. CGH) iii. Identifies consanguinity (loss of heterozygosity), some cases of UDP, mosaicism Detects Copy number neutral variation with genotype abnormalities Allelic imbalance (are 2 copies of allele the same or different) b. Cannot detect i. Balanced karyotypes – translocations, inversions ii. Point mutations (Marfan syndrome, N, Fragile X iii. Triplet repeat expansion disorders - Fragile X, Myotonic dystrophy iv. Spatially localise chromosomal rearrangements v. Methylation changes – BWS, RSS, PWS/AS vi. Small deletions

Answer 43

1. Key points a. DNA sequencing technologies used to analyse multiple genes b. Multiple reactions take place quickly and simultaneously c. Allows rapid and inexpensive DNA sequencing of whole genome/ exome d. High throughput – more economical than Sanger sequencing of genes individually and sequentially 2. Method a. Break DNA of the genome into multiple fragments b. Massive parallel sequencing of DNA fragments c. Computer reassembles sequence, and reads for changes 3. Types a. Whole genome = exon + intron i. Gold standard of sequencing ii. Expensive b. Whole exome sequencing = exon only i. Majority of what is done in clinical practice ii. Sequences 1-2% of genome iii. Clinically there are targeted exome panels – eg for cardiomyopathy, arrhythmias, SCD 4. Utility a. Missing DNA or sequence changes in multiple genes b. Useful for genetically heterogenous conditions c. Cannot detect triplet repeats or methylation defects

Answer 44

1. Utility a. Trinucleotide repeat disorders b. Examples = Fragile X, Huntington Disease, spinocerebellar ataxia, Friederich Ataxia, myotonic dystrophy 2. Method - PCR then Southern Blot

Answer 45

Method of transferring DNA/RNA/protein onto specific membrane then visualised with specific probes DNA/protein denatured -> gel electrophoresis -> label added Southern = DNA (Dandenong is south) Northern = RNA Western = protein (Perth is west) - e.g. DMD/BMD

Answer 46

1. Key points a. Not commonly used now we can sequence genes b. Indirect method – relies on the fact that genes that are close together are inherited together (chromosome exchange occurs at meiosis) c. Does not assess gene of interest but markers around it – usually SNP or short tandem repeat 2. Utility a. Know the disease, and want to find position of the disease gene (gene discovery in population) b. Know the parents have the genetic mutation, and want to find out if the offspring have inherited the abnormal haplotype (direct mutation analysis not always possible) 3. Linkage disequilibrium a. The tendency for alleles of genes/ genetic markers to be inherited together in a non-random fashion b. Occurs when two genes or genetic markers are close in chromosomal position  unlikely to be separated by random assorting of chromosomes / crossovers at meiosis if they are close c. The closer together two genes or genetic markers, the higher the linkage disequilibrium d. Working out linkage equilibrium of two polymorphisms = % polymorphism 1x % polymorphism 2  if higher than this number, unlikely to be present due to chance

Answer 47

1. Methods a. CVS i. 11-15 weeks ii. Needle into placenta iii. 1/500 miscarriage risk iv. Diagnose = chromosomal abnormalities, DNA studies, biochemical studies b. Amniocentesis i. 15-20 weeks ii. Needle into uterus iii. Take 15ml sample of fluid iv. 1/1000 miscarriage risk v. Diagnose = chromosomal abnormalities, DNA studies, biochemical studies c. Maternal blood = NIPT i. Available from 10 weeks gestation ii. Fragments of placental DNA extracted from maternal blood iii. Diagnose = aneuploidy, sex chromosomes, deletion syndromes 2. Testing a. Karyotype b. FISH c. Microarray – from CVS/ amniocentesis 3. Pre-implantation Genetic Diagnosis a. Performed in context of IVF b. Testing by embryo biopsy c. Can detect chromosomal abnormalities, single gene disorders d. No apparent increase in birth defects i. 97% diagnostic accuracy ii. 20% pregnancy rate per cycle iii. CF the most common indication

Answer 48

1. Key points a. Presymptomatic genetic testing is for children who have a family history of a heritable condition but no signs or symptoms of the condition – that they will certainly develop if they have the mutation i. Examples include FAP, Huntington, spinocerebellar ataxia b. Predictive testing is where a person with the mutated gene has an inherited predisposition to the condition (but may never develop). i. E.g. BRCA1/BRCA2 2. Indications a. Conditions for which there is potential medical benefit in the immediate future i. E.g. surveillance for FAP b. Testing for a condition that has its onset before adolescence 3. Contraindications a. There are no treatments to alter the natural history of the condition i. E.g. Huntington b. Potential benefits do not occur until adulthood - testing should be delayed until adulthood to allow the child to make their own decision

Answer 49

``` Proportionate • Turners • Noonan • Fanconi anaemia • Williams, 22q and other CNVs ``` Disproportionate • Russel Silver • Achondroplasia and other skeletal dysplasias

Answer 50

* Marfan syndrome = joint laxity, superior lens dislocation, normal IQ * Homocystinuria = joint contractures, inferior lens dislocation, low IQ, stroke risk * Klinefelter = non-dysmorphic, eunuchoid habitus, mild learning difficulties, pubertal delay, infertility * Sotos = macrocephaly, not Marfanoid habitus, dysmorphism, advanced bone age * BWS = coarse facial features, abdominal wall defect, hypoglycaemia, asymmetry

Answer 51

* Prader Willi = hypotonia, hyperphagia, obesity, undescended testes, dev delay * Bardet Biedl = polydactyly, renal anomalies

Answer 52

* T21 = dysmorphism, congenital cardiac lesion * Prader Willi = undescended testes, micrognathia * Myotonic dystrophy = hypotonia, maternal percussion myotonus over thenar eminence * SMA = alert and interactive infant with profound hypotonia and weakness * Peroxisomal disorders (eg. Zellweger) = tall forehead, abnormal brain (screen VLCFA) * Congenital disorders of glycosylation (screen with transferrin isoforms)

Answer 53

* Turner = short, non-dysmorphic (heart shaped face), web neck, shield chest, wide nipples, normal IQ * Klinefelter = tall non-dysmorphic male, eunuchoid habitus, small testes, low IQ, impulsive behaviour • Syndromes with short stature often cause pubertal delay

Answer 54

* Fanconi * Thrombocytopenia and absent radius (TAR syndrome) = absent radius, normal thumb * VACTERL * Blackfan Diamond (anaemia) = thumb abnormal, triphalangeal thumb * Goldenhar (OAVS) * Holt Oram

Answer 55

External ear normal • Waardenburg = iris heterochromia, white forelock • Jervell-Lange-Nielson = long QT • Usher = retinitis pigmentosa • Pendred = hypothyroidism • Alport = haematuria, anterior chamber eye abnormalities • NF2 = later onset deafness, CAL patches, caracts • T21/multi organ syndrome External ear abnormal • Goldenhar = microtia, epibulbar dermoid, vertebral abnormalities • Treacher-Collins = bilateral microtia, hypoplastic zygoma • Brachio-oto-renal Non-syndromic • GJB2 gene (=Cx26) = commonest cause, AR 1/30 carrier frequency • CMV

Answer 56

* 22q11 = cleft palate ONLY * Stickler * Pierre Robin * T13 = CL and CP * Kabuki

Answer 57

Coloboma • Cat eye syndrome (del 22) = inverted duplication of part of chromosome 22 • CHARGE (Coloboma, heart, atresia choanae, retardation of growth, genitourinary, ear) • Teacher Collins ``` Cataracts • T21 • Smith Lemli Optiz = 7 dehydrocholesterol, cataracts, dysmorphic features, organ malformation • NF-2 • Cockayne syndrome ``` Lens dislocation • Marfan’s = Upwards • Homocystinuria = Downwards

Answer 58

* NF1 = short with big head, neurofibromas, Lisch nodules, axillary/inguinal freckling, learning difficulties, optic gliomas * NF2 = less common * Fanconi anaemia = short with small head * McCune-Albright = skeletal polyostotic fibrous dysplasia, coast of Maine CAL, endocrine hyperfunction/precocious puberty * Legius syndrome * LEOPARD syndrome * Bloom syndrome * Watson syndrome * Russel-Silver syndrome

Answer 59

* VACTERL | * Alagille’s

Answer 60

1. Epidemiology a. Prevalence in liveborn infants is 1/5000 2. Genetics a. Trisomy 13 b. Mechanism = non-disjunction, rarely translocation (e.g. Robertsonian with 13 and 14) 3. Clinical presentation a. Severe, multiple congenital anomalies – midline defects b. Normally grown (cf. T18) Key features - micro/anophthalmia - cleft lip/palate - postaxial polydactyly - heart abnormalities - scalp defects (absent hair/skin) 5. Prognosis a. Median survival 10 days b. 80% die by 3 months c. 92% die by 1 year d. Profound intellectual disability in survivors

Answer 61

1. Genetics a. Trisomy 18 i. Meiotic nondisjunction ii. Translocation involving chromosome 18 b. Second most common trisomy observed in live births after T21 3. Clinical presentation a. Prenatal i. IUGR ii. Low estradiol, PAPP-A, bHCG, increased inhibin A = same as T21 b. Birth with IUGR, dysmorphism + multiple anomalies Key features - affects any organ system - majority die in utero or w/i 48 hours - 5-10% survive beyond 1 year - Rockerbottom foot - fisted hand - wizened features - cardiac malformations - IUGR - GIT in 75% (Meckels, malrotation, omphalocele) 5. Prognosis a. Death within first 2 weeks = 50% b. Death within first 3 months = 80% c. Death within first 12 months = 90% d. 5-10 % survive the first year, have severe ID

Answer 62

1. Epidemiology a. 1/800 b. Most common cause of intellectual disability c. Increased prevalence with increasing maternal age 2. Genetics a. Trisomy 95% i. Extra from Mum 96% meiotic nondisjunction (recurrence rate 1% for aneuploidy, age effect) b. Translocation 2.5% i. Most common 14;21 c. Mosaic 2.5% 3. Clinical presentation a. Prenatal i. Increased or absent nasal bone on SS ii. Combined screening b. Birth = hypotonia, dysmorphism, malformation Key features - dysmorphism (upslanting palpebral fissures, epicanthal folds, low ears, short neck with excess nuchal skin, sandal gap, simian crease) - grimace when crying - low IQ (avg 45) - hypotonia - hearing and vision impairment - CHD (AVSD) - autoimmune disease (thyroid, coeliac, T1DM) g. Haematological i. Transient leukaemia (normal Hb and platelets) ii. AMKL (acute megakaryoblastic leukaemia) – 1/50-200 children DS (500x risk general population) iii. ALL / AML – (10-20x risk general population) 5. Investigations a. FISH – quickest result b. Microarray/ Karyotype – important to determine if cause is translocation (microarray won't detect balanced translocations)

Answer 63

2. Possible indications a. Offered to all b. Maternal age >35years (considered risk of invasive diagnostic procedures equal to risk of DS) c. Previously affected pregnancy d. Known chromosomal translocation/inversion/aneupliody in parents e. Anomalies on structural scanning 3. First trimester combined screening a. 9-13weeks gestation b. US – nuchal translucency + gestational age (crown-rump length) c. Serum markers – Pregnancy associated plasma protein A (PAPP-A down) or bHCG (up) 4. Second trimester integrated test a. For neutral tube defects and trisomy 21 b. US 10-13weeks– nuchal translucency c. Serum markers 15-18weeks – PAPP-A (down), AFP (down trisomy, up NTD), unconjugated estriol (down), inhibin A (up) d. Highest detection rate 85-95% 5. Used to determine probability of Trisomy 21 (and usually 18) in pregnancy b. First trimester screening – means can have CVS (higher risk fetal loss but earlier option termination) offered to those high risk (>1/50) c. Second trimester screening – means amniocentesis for diagnosis – FISH for chromosomes 13, 18, 21, X and Y 6. Screening results a. Negative – risk <1/250, doesn’t exclude b. Positive – risk >1/250

Answer 64

Alpha fetoprotein Synthesized in yolk sac, GIT and liver of fetus, Peak 10-13weeks, then decline ``` Elevated: Neural tube defect Congenital skin defects (abdominal wall) GI defects (obstruction) ``` Depressed: Chromosomal trisomy

Answer 65

beta human chorionic gonadotropin Released by syncytiotrophopblast after implantation Rapid risk to 8/40, then decreased until 20/40 Elevated: Trisomy 21 Twin pregnancy Molar pregnancy Depressed: Trisomy 18

Answer 66

1. Hypothyroidism a. 13-63% prevalence i. Congenital hypothyroidism 1. 28x population risk (1.5-6.1% prevalence) 2. ↑TSH ↓ T4 b. Hypoplasia most common cause; Dyshormogenesis is NOT common ii. Subclinical hypothyroidism 1. High prevalence 7-40% 2. Mildly ↑TSH normal T4 3. Asymptomatic iii. Auto-immune hypothyroidism 1. 2-28% 2. TPO-Ab appear from 8 years onwards – increase with time iv. Autoimmune hyperthyroidism 2. Coeliac disease a. Celiac disease more common in T21 – prevalence 3-18% (vs. 1% in general population) f. Diagnosis = IgA-tTG preferred single test g. Screening i. HLA typing first line – if negative no serological testing ii. If positive 2-3 yearly serological testing 3. OSA b. Prevalence = up to 100% c. Associations i. Pulmonary hypertension ii. Reduced verbal IQ iii. Reduced executive functioning d. Screening i. PSG in all children over 4 years e. Treatment i. Tonsillectomy resolved 30-50% of OSA ii. 50-75% had persistent OSA iii. Early use of CPAP recommended 4. Atlanto-axial instability c. Incidence i. 1-2% of children with DS develop symptomatic AAI – features consistent with cervical myelopathy and/or cervical instability (torticollis, decreased neck ROM) ii. 10-30% of DS have asymptomatic AAI on screening d. Screening i. Flexion/extension X-rays = demonstrates excessive movement of C1 relative to C2 implying instability f. Guidelines i. New guidelines suggest NO routine screening

Answer 67

1. Key points a. Klinefelter syndrome (KS) = chromosomal disorders in which there is >=1 extra X chromosome b. Undiagnosed in most males c. Most common cause of primary male hypogonadism c. The greater the number of X chromosomes, the greater the phenotypic consequences 3. Clinical presentation a. Normal phenotype and go unrecognized for life b. Learning difficulty in childhood (but most have normal IQ) c. Delayed puberty at adolescence (primary hypogonadism - hypogonadotrophic) d. Infertility as adult (atrophy of seminiferous tubules) Key features - eunochoid body habitus (tall, slim and underweight, with long legs and long arms) - gynaecomastia - small testes - IQ decreased - behavioural phenotypte 5. Investigations = karyotype, microarray 6. Management a. Testosterone, LH and FSH levels – check at age 11-12 years i. Replacement therapy with testosterone therapy once LH and FSH begin to rise above normal b. Aromatase inhibitors – treatment for gynacomastia c. Screening for complications i. Fasting glucose, lipids HbA1c – at risk of metabolic syndrome ii. DEXA 7. Prognosis a. Increased morbidity in later life from pulmonary diseases, cancers (including breast), diabetes, SLE (extra X chromosome)

Answer 68

1. Epidemiology a. Occurs in 1/5000, most spontaneously abort (95-99%) 2. Genetics + pathogenesis a. 45,X (monosomy X) = 45% i. X chromosome is derived from mother in 2/3 b. 45,X mosaicism = 50% i. Examples – 45X/46XX or 45X/47XXX ii. Results from sex chromosome non-disjunction during post-zygotic cell division iii. Presence and degree of mosaicism differs among different tissues iv. Normal karyotype on peripheral blood sample does NOT preclude mosaicism in other tissues 3. Clinical presentation a. Congenital lymphedema (puffy hands and feet at birth) Key features - short stature (95-100%) - growth failure - ovarian dysgenesis (streak gonads) and infertility (95%) - ovarian failure (90%) - delayed puberty (only 1/3 spontaneous) - increased upper:lower segment - defective dental development - recurrent otits media (50-70%) - SNHL (50% by adulthood) - cardiac malformations (50%) (arch abnormalities, elongated, coarctation, bicuspid aortic valve) - renal anomalies (Horseshoe kidney, collecting system abnormality) - generally normal IQ 5. Investigations a. Standard karyotype i. Peripheral blood mononuclear cells 1. To detect mosaicism minimum of 30 cells in metaphase should be scored ii. If negative and high suspicion – perform using a different tissue such as skin fibroblasts or buccal mucosal cells 6. Management a. Growth i. GH – should be started when height < 5th centile: increase rate of growth without increasing bone age iv. Commencement of oestrogen leads to growth plate closure b. Puberty i. Oestrogen should be commenced for 2/3 who do not enter spontaneous puberty between 12-14 age 7. Complications a. ↑ risk of autoimmune problems (hypothyroidism, coeliac disease) b. ↑ risk of aortic dissection

Answer 69

* Tall stature * Mild delay in motor and language * Normal puberty + fertility * NO increase in aggression

Answer 70

* Most common sex chromosome abnormality in females * Usually incidental diagnosis * May have slightly lower IQ 15-30 than siblings

Answer 71

* Most common sex chromosome mosaicism diagnosed by amniocentesis + prenatal karyotype * Mild clinical features of Turner syndrome * Many women undergo spontaneous puberty and are fertile

Answer 72

1. Genetics a. Heterozygous micro‐deletion 7q11.23 c. AD – most cases are de novo, very rarely transmitted 2. Clinical presentation a. Irritable infant b. Child with short stature and developmental delay c. Specific behavioural profile – overfriendliness, social disinhibition, excessive empathy, attention problems, non-social anxiety Key features - Elfin-like facies (periorbital fullness of SC tissue i.e. puffy eyes, long flat philtrum) - CHD (supravalvular AS, peripheral PS, RAS, HTN) - endocrine (hypercalcaemia) - neuro and behaviour (as above, mild-mod ID, cocktail party personality) 4. Investigations a. Microarray OR FISH OR duplication/deletion testing 5. Treatment a. Nothing specific

Answer 73

= DiGeorge syndrome = Velocardiofacial Syndrome 1. Epidemiology a. 1/4000 2. Genetics a. Continugous gene deletion syndrome b. Deletion i. Heterozygous 22q11 deletion c. AD – 93% de novo, 7% inherited d. DiGeorge syndrome = neonates with thymic hypoplasia and hypocalcaemia e. 3rd and 4th pharyngeal POUCH fail to develop 3. Clinical presentation a. Neonate with congenital abnormalities b. Older child with developmental delay or short stature Key features = catch 22 - C: cardiac (conotruncal anomalies, truncus arteriosus is pathognomonic, TOF, interrupted arch, VSD) - A: abnormal facies (cleft palate but NOT lip, bifid uvula) - T: thymic hypoplasia (impaired T cell function) - C: cleft palate - H: hypocalcaemia (parathyroid hypoplasia) - 22: 22q11.2 deletion Other features - cognitive impairment - psychiatric e.g. schizophrenia 5. Investigations a. FBE - lymphocytes b. CMP – calcium c. CXR - thymus, cardiomegaly d. Renal USS e. Echocardiogram f. FISH / microarray for diagnosis i. Test parents g. NOTE: must assess for immunodeficiency prior to live vaccine 6. Prognosis a. Mean IQ is 75: 30% have intellectual disability, 75% have learning difficulties, nonverbal IQ < verbal IQ b. 20% have ASD c. 60% have a psychiatric illness (25% schizophrenia)

Answer 74

1. Genetics a. Single gene mutation i. Usually de novo (pts do not reproduce) ii. Risk to siblings 1.5% due to possible germline mutation 2. Clinical manifestations a. Severe intellectual disability + microcephaly b. Growth retardation a. Dysmorphism i. Unibrown (synophrys), arched eye brows ii. Long eyelashes iii. Hirsutism b. Musculoskeletal i. Ulnar ray defects c. Other i. Severe GOR iii. Infertility 3. Investigations a. Single gene sequencing (cannot do microarray) b. Whole exome 4. Treatment a. Developmental b. Monitoring – GOR, cardiac, developmental, hearing, vision

Answer 75

1. Genetics a. AD – 2/3 de novo mutation 1. Complications a. Face b. Physical features i. Short stature ii. Broad or webbed neck iii. Widely spaced nipples c. Congenital heart disease i. Pulmonary valve stenosis d. Other i. Cryptorchidism in males ii. Developmental delay 3. Investigations a. PTPN11 gene sequencing b. Noonan gene panel c. Whole exome 4. Management a. Coags – risk of bleeding (d/t coag defect as part of syndrome) b. No screening recommended for leukaemia

Answer 76

Noonan with multiple lentigines ``` L = lentigines (Lentigines, or liver spots, are benign lesions that occur on the sun-exposed areas of the body) E = ECG conduction defects / HOCM O = occular hypertelorism P = pulmonary stenosis A = abnormalities of genitalia R = retarded growth D = deafness ```

Answer 77

1. Clinical manifestations a. FTT = due to severe postnatal feeding difficulties b. Developmental delay or ID c. Physical features i. Loose, soft skin with deep palmar and plantar creases ii. Papillomata of face and perianal region d. Musculoskeletal i. Diffuse hypotonia and joint laxity ii. Hold hand in ulnar deviated position e. Cardiac f. Malignancy i. 10-15% tumour risk 1. Rhabdomyosarcoma 2. Ganglioneuroblastoma 3. Bladder carcinoma ii. Screen with 3/12 USS until 6-8 years of age

Answer 78

1. Clinical manifestations a. Prolonged feeding abnormality  FTT b. Developmental delay c. Seizures d. Facies e. Cutaneous i. Xerosis ii. Hyperkeratosis iii. Dystrophic nails f. Cardiac i. HOCM > PS g. Malignancies i. ALL

Answer 79

1. Genetics a. NSD1 mutation - >95% de novo b. If neither parent have the mutation – risk to siblings is <1% 1. Clinical manifestations a. Facial features i. Broad and prominent forehead + large head ii. Sparse frontotemporal hair (high anterior + temporal hair line) b. Learning disability c. Overgrowth i. Height and/or head circumference >2 SD above the mean ii. Height may normalize in adulthood iii. Macrocephaly usually present in all ages 3. Diagnostic criteria a. Overgrowth – height and or HC >2 SD above the mean typically prenatal onset b. Facial gestalt – high bossed forehead, sparse frontotemporal hair, long narrow face, downslanting palpebral fissures, prominent jaw c. Learning disability – mild to severe 4. Investigations a. Microarray (10%) b. Single gene NSD1 sequencing (90%) c. Overgrowth ‘panel’ via clinical exome

Answer 80

1. Genetics a. AD b. FBN1 gene (chromosome 15q21.1) – 75% have one affected parent, 25% de novo mutation c. Defective fibrillin, component of connective tissue 1. Clinical manifestations a. Ocular i. Ectopia lentis – 50-80% (UPWARD) b. Cardiac Dilatation of aortic root predisposing to aortic tear and rupture, enlargement of proximal PA ii. MVP +/- MR, Tricuspid valve prolapse c. Skeletal i. Bone overgrowth, arm span > height ii. Arachnodactyly iii. Joint laxity – see scoring system Chest wall deformity d. Other i. IQ normal ii. Spontaneous pneumothorax 3. Investigations a. FBN1 gene sequencing 5. Treatment a. Cardiology i. Aggressive control of blood pressure – ARB/ACE-I/ beta blocker ii. Usually started if any evidence of aortic dilatation iii. Annual echocardiogram to monitor for aortic root dilatation b. Opthal = annual examination c. Orthopaedic surgeon = evaluation for scoliosis and management of lax joints

Answer 81

4. Diagnosis = Ghent criteria a. In presence of family history (first degree relative), one of the following diagnostic: i. Lens ectopia ii. Systemic score >=7 (points to a number of clinical features) iii. Aortic root enlargement (Z score >2.0 in those >20 years, or >=3 in those <20 years) b. In absence of family history, one of the following: i. Aortic root enlargement (Z score >2.0) + ectopic lens ii. Aortic root enlargement (Z score >2.0) + systemic score >7 iii. Aortic root enlargement (Z score >2.0) + causal FBN1 mutation found iv. Ectopic lens + causal FBN1 mutation found Systemic Score - 3 points: wrist and thumb sign - 2 points: pectus carinatum, hind food deformity, pneumothorax, dural ectasia, protrusion acetabula - 1 point: reduced upper segment lower segment ratio and increased arm span height ratio, scoliosis/kyphosis, reduced elbow extension, facial features, skin striae, myopia, mitral valve prolapse

Answer 82

1. Genetics a. CBS mutation b. AR c. Cystathionine beta-synthase (CBS) deficiency d. Homocysteine is an intermediary amino acid, formed by conversion of methionine → cysteine 2. Classification a. B6 responsive  milder phenotype b. B6 non-responsive 1. Clinical manifestations a. Ocular i. Ectopia lentis – downward dislocation b. Skeletal system i. Excessive height ii. Long limbs d. CNS i. Developmental delay, ID e. Other i. Seizures 4. Investigations a. Plasma total homocysteine and methionine = markedly elevated (do NOT test urine) b. Most detected on newborn screening c. CBS gene sequencing 5. Treatment a. Vitamin B6 if responsive (CBS enzyme is pyridoxine dependent) b. Methionine restricted diet c. Folate + B12

Answer 83

Homocystinuria = downward dislocation + down IQ (low IQ) + stiff Marfan syndrome = upward dislocation + up IQ (high IQ) + stretchy Marfan - AD - FBN1 mutation – chromosome 15 - IQ: Normal - Hyperextensible joints - Upward dislocation of ocular lens (ectopia lentis) - Aortic root dilation/dissection - Valvular insufficieny - GHENT criteria - Beta blockers for aneurysm +/- Surgery Homocystinuria - AR - CBS mutation – chromosome 21 - Intellectual disability - Rigid joints - Downward dislocation of ocular lens (ectopia lentis) - Vaso-occlusive disease - High plasma/urine levels of homocysteine and methionine - Treat with high dose vitamin B6 (if responsive)

Answer 84

1. Genetics a. Classic EDS = AD b. 50% de novo mutations c. Common mutations – COL5A1, COL5A2 Multiple types: Classic (EDS I, EDS II) = skin+joint Hypermobility (EDS III) = joint+ANS dysfunction Vascular (EDS IV) = vessel/viscous rupture Kyphoscoliosis (EDS VI) = hypotonia, joint laxity, kyphoscoliosis Arthrochalasia (EDS VIIA, EDS VIIB) = short+contractures+fractures+hypotonia Dermatosparaxis (EDS VIIC) = saggy skin+hernias+blue sclerae 3. Clinical manifestations a. Skin i. Poor healing ii. Easy bruising and fragility iii. Soft, douching skin iv. Abnormal scar formation – hypertrophic v. Translucency vi. Skin spheroids vii. Stretchy – defined >4cm from neutral site until feeling resistance b. Joints i. Hypermobility – (Beighton hypermobility scale) ii. Multiple dislocations – shoulder, patella, TMJ c. Marfanoid phenotype i. Pes planus ii. Pectus excavatum iii. High arched palate d. Eye i. Myopia ii. Lens dislocation e. Cardiac / vascular i. MVP ii. Aortic root dilation iii. In vascular form – prone to arterial rupture (spleen, iliac, renal), prone to viscus rupture f. Prolapses i. Hernias ii. Cervical insufficiency iii. Uterine prolapse iv. GIT/bladder diverticulae g. ANS dysfunction i. Delayed gastric emptying / IBS ii. POTS

Answer 85

1. Key points a. Spectrum from perinatal lethality -> severe skeletal deformities -> mild predisposition to fractures with normal stature lifespan 2. Genetics a. AD – most, mostly de novo, COL1A1 and COL1A2 3. Pathogenesis a. Collagen forms extracellular matrix of most tissues (teeth, sclera, ligaments, blood vessels, skin) and organic part of bone 4. Clinical presentation a. Prenatal – short long bones b. Childhood – multiple fractures a. Triad i. Fractures with minimal or absent trauma – any bone, most common extremities ii. Variable dentogenesis imperfecta (DI) – grey or brown teeth that may appear translucent iii. Hearing loss (adulthood) Key features: fractures, dental anomalies, hearing loss, blue sclerae, osteoporosis, Wormian bones 6. Classification a. Type I: classic non-deforming OI with blue sclerae b. Type II: perinatally lethal OI c. Type III: progressively deforming OI d. Type IV: common variable OI with normal sclerae e. Type V-8: uncommon 1. Investigations a. Antenatal (Severe forms) b. Radiographic i. Fractures of varying ages and stages of healing Wormian bones = sutural bones which are 6x4mm (in diameter) or larger, in excess of 10 in number, with a tendency to arrange in a mosaic pattern iii. Osteopaenia iv. Spine: Scoliosis, “Codfish” vertebrae (result from spinal compression fractures), Compression fractures v. Chest = Pectus excavatum or carinatum c. Molecular genetic testing i. OI gene panel ii. COL1A1 and COL1A2 sequencing d. Biochemical - vitamin D, CMP, ALP typically normal i. May have elevated ALP or hypercalciuria as a marker of increased bone turnover 1. Treatment a. Non-pharmacological i. Bracing of limbs ii. Orthotics to stabilise lax joints Physical + OT b. Surgical = correction of deformity and fracture c. Medical i. Bisphosphonates 2. IV pamidronate most commonly used

Answer 86

Blue sclerae are characteristic of a number of conditions, particularly connective tissue disorders. Osteogenesis imperfecta Ehlers Danlos syndrome Scleritis Marfans

Answer 87

1. Epidemiology a. The most common form of short limbed dwarfism: 1/15000-1/40,000 2. Genetics + pathogenesis a. Mutation in FGFR3 - fibroblast growth factor 3 receptor (FGFR3) b. AD - however 80% de novo c. Gain of function mutation: leads to activation of the receptor in the absence of FGF d. Homozygous mutations are usually lethal in the newborn period 3. Clinical presentation a. Prenatal (late) or neonatal presentation (most common) b. First year of life with short long bones, hypotonia + gross motor delay but normal IQ 4. Clinical manifestations a. Short stature i. Rhizomelia (short arms and legs, proximal limbs more involved) ii. Note birth length can be low-normal/ slightly less than normal iii. Hyperextensible joints (extension restricted at the elbow) iv. Delayed motor milestones with hypotonia b. Midface hypoplasia c. Macrocephaly d. Intelligence is normal 5. Diagnosis a. Skeletal survey b. Genetic testing NOT used for diagnosis 6. Investigations a. X-ray b. Genetic = sequencing of FGFR3 1. Complications a. Spinal cord stenosis = compression at foramen magnum, hydrocephalus, lumbar canal stenosis b. Sleep apnoea = hypoxemia during sleep c. Restrictive pulmonary disease ( < 5%) d. Middle ear disease 2. Prognosis a. Normal life span b. Some have tried surgical limb lengthening / growth hormone → controversial

Answer 88

1. Genetics a. Single gene disorder i. JAG1 = 90% 1. Point mutation 90% ii. NOTCHC2 = 1-2% b. 30-50% inherited, 50-70% de novo c. AD 2. Clinical presentation a. Neonate with cholestatic jaundice, bile duct paucity b. Structural/ functional renal abnormality Key features - dysmorphic facies - hepatic: intrahepatic biliary dysgenesis -> cholestasis - vertebral: butterfly vertebra - heart: pulmonary stenosis (peripheral) - eye: posterior embryotoxin (a corneal abnormality) 4. Investigations a. Microarray – detects deletion (10%) b. JAG1 sequencing c. NOTCH2 sequencing 5. Treatment a. MDT management b. Ursodeoxycholic acid c. Other medications for pruritis – cholestyramine, rifampicin 6. Prognosis a. Good prognosis = 10% mortality – vascular accident, cardiac disease + liver disease result in death b. Patients likely to have pruritis, xanthomas with markedly elevated serum cholesterol, neurological complications of vitamin E deficiency if untreated

Answer 89

1. Genetics a. CHD7 gene mutation – encodes chromodomain helicase DNA binding protein b. AD – most de novo mutation 2. Clinical manifestations - Coloboma - Heart defect - choanal Atresia - Retarded growth/development - Genital (e.g. cryptorchidism, hypogonadism - Ear anomalies - Other: cranial nerve anomalies, swallowing difficulty

Answer 90

d. Abnormality of the 1st/2nd brachial arches 1. Clinical manifestations a. Ear i. Deafness (conductive, sensorineural, mixed) ii. Preauricular pits/tags iii. Auricular deformity b. Brachial fistulae/cysts c. Renal malformations i. Range from hypoplasia to bilateral renal agenesis

Answer 91

1. Clinical manifestations a. Cone-rod dystrophy i. Visual impairment ii. Photophobia b. Obesity c. Progressive SNHL d. Dilated or restrictive cardiomyopathy e. Insulin resistance syndrome

Answer 92

1. Clinical manifestations a. Rode-cone dystrophy i. Night blindness by 7-8 years ii. Legal blindness by 15 years b. Truncal obesity c. Postaxial polydactyly d. Cognitive impairment + learning disability e. Urogenital - hypogonadotropic hypogonadism a. Poor prognosis

Answer 93

1. Genetics + pathogenesis a. AR b. BLM gene mutation - encodes RECQl3 c. Results in genome instability – defects in the recognition and/or repair of damage to DNA 2. Clinical manifestations a. Growth i. Severe pre- and post-natal growth deficiency b. Cutaneous i. Erythematous skin ii. Sun sensitive - malar distribution iii. Telangiectasias, café au lait spots c. Malignancy risk i. 50% develop cancer by the age of 25 years d. Facies e. Normal IQ f. Endocrinology i. Primary hypogonadism ii. Diabetes iii. Infertility in men, severely reduced in female g. Immunodeficiency i. Recurrent sinuopulmonary infections

Answer 94

1. Genetics + pathogenesis a. CBFA1 gene – responsible for initial differentiation of osteoblasts to form skeletal structures 2. Clinical manifestations a. Bones i. Defective bone formation ii. Clavicles - hypoplastic/aplastic iii. Large head with delayed suture closure iv. Narrow pelvis v. Spinal abnormalities b. Short stature c. Dental i. Supernumerary teeth 3. Treatment a. Extraction of supernumerary teeth

Answer 95

1. Clinical manifestations a. Skeletal malformations i. Upper extremity malformation – involve radial, thenar or carpal bones 1. Thumb - absent, hypoplastic or triphalangeal 2. Radius - absent or hypoplastic ii. Syndactyly between 1st and 2nd fingers b. Cardiac defect i. Ostium secundum ASD ii. VSD iii. Cardiac conduction disease

Answer 96

1. Genetics + pathogenesis a. AR b. Disorder of cholesterol synthesis 2. Clinical manifestations a. Growth retardation i. Microcephaly = 80-85% b. Dysmorphic features i. 2-3 toe syndactyly ii. Post-axial polydactyly c. Cardiac d. Intellectual + behaviour = severe to mild e. Congenital cataract f. Genital abnormality i. Hypospadias and/or cryptorchidism ii. 46, XY sex reversal iii. 46, XX bicornuate uterus 3. Investigations a. Raised 7-dehydrocholsterol (7-DHC) b. NOT DIAGNOSED genetically 4. Treatment a. Cholesterol supplementation

Answer 97

* Weeks 2-6 of gestation – brachial arch develops * Neck is hollow tube with arches, between which are clefts and pouches * Clefts are on outside – ectoderm * Pouches are on inside - endoderm * Arches are neural crest in origin First - Cleft: External auditory canal - Arch: Mandible, Muscles of mastication - Pouch: Eustachian tube Second - Cleft: Sinus of His - Arch: Muscles of facial expression, Malleus and incus, Hyoid bone - Pouch: Palatine tonsil, Supratonsillar fossa Third - Cleft: Sinus of His - Arch: Hyoid bone, Stylopharyngeus muscle - Pouch: Inferior parathyroid glands, Thymus Fourth - Cleft: Sinus of His - Arch: Epiglottis, Thyroid cartilage, Pharyngeal muscles, Aortic arch - Pouch: Superior parathyroid glands

Answer 98

2. Included phenotypes a. Hemifacial microsomia b. Oculo-auriculo-vertebral spectrum c. Goldenhar syndrome d. First and second branchial arch syndrome e. Otomandibular dysostosis f. Facio-auriculo-vertebral syndrome g. Lateral facial dysplasia 3. Clinical manifestations a. Spectrum of malformations primarily involving structures derived from the 1st and 2nd branchial arches b. Facial asymmetry = results from maxillary and/or mandibular hypoplasia c. Pre-auricular or facial tags d. Ear malformations i. Microtia = hypoplasia of external ear ii. Anotia = absence of external ear iii. Aural atresia = absence of external ear canal iv. Hearing loss e. Cleft lip and/or palate f. Non-craniofacial malformation = vertebral, renal, cardiac, limb

Answer 99

``` • Sporadic – cause unknown • 1st and 2nd branchial arch maldevelopment • Clinical manifestations o Hemifacial microsomia o Ear anomalies – microtia, accessory preauricular tags/ pits/ middle ear defects  Conduction hearing deafness o Mandibular abnormalities o Can be associated with cleft palate o Vertebral defects ```

Answer 100

1. Genetics a. TCOF1 (Treacher Collins-Franschetti Syndrome 1) mutation – chromosome 5 (most common) b. Abnormal 1st and 2nd branchial arches c. AD d. Variable penetrance 2. Clinical manifestations a. Face i. Hypoplasia of zygomatic bones and mandible – mandibulofacial dysostosis ii. Malar hypoplasia – small midface b. Ear i. External ear abnormalities, microtia c. Eye i. Coloboma (notching) of the lower eyelid d. Other i. +/- cleft palate ii. Normal IQ 3. Diagnosis a. Clinical b. Can do genetic testing – TCOF1 sequencing ``` NOTE Nagar syndrome is similar: 2. Clinical manifestations a. Similar to Treacher Collins - distinguished from TSC by absence of eyelid colobomas b. Severe clef palate ALWAYS present c. Short stature d. Normal intelligence ```

Answer 101

1. Key points a. Due to mandibular hypoplasia (occurs < 9 weeks of development) c. SEQUENCE – underdeveloped lower jaw begins a sequence of events, which leads to the abnormal placement of the tongue, resulting in the clef palate and respiratory obstruction 2. Clinical manifestations a. Triad i. Micrognathia ii. Glossoptosis iii. Cleft palate b. Consequences i. Airway obstruction = tongue prolapse backward ii. Feeding difficulties c. Often isolated abnormality but 1/3 have associated anomalies, Stickler syndrome, VCFS - get eye examined 3. Natural history a. Major initial post-natal concern is airway obstruction i. Posterior prolapse of the tongue (during inspiration) may cause life-threatening airway obstruction b. There should be sufficient mandibular growth by 3-12 months of age to protect the airway c. By age 4-6 of life, there has generally been sufficient mandibular growth to resemble a normal profile 4. Treatment a. Prone positioning b. Nasopharyngeal airway c. Positive pressure ventilation (if required) d. Surgical airway e. Glossopexy (tong-lip adhesion) – tongue anchored to lower lib and mandible to relieve obstruction in infants with Pierre Robin sequence f. Mandibular distraction (normally 9-18 months of age, unless airway concerns)

Answer 102

1. Key points a. Commonest syndrome associated with Pierre Robbin Sequence 2. Genetics a. Pathogenic variants in genes that encode type 2 collagen ii. Type II collagen is a major component of cartilage, vitreous, nucleus pulposus 1. Clinical manifestations (eyes, ears, face, bones) a. Ocular i. Myopia ii. Cataract iii. Retinal detachment b. Auditory i. Hearing loss – high frequency ii. Conductive and sensorineural c. Craniofacial abnormality i. Midfacial underdevelopment ii. Cleft palate, submucous cleft, bifid uvula d. Skeletal i. SUFE or Perthes-like disease ii. Scoliosis, spondylolisthesis, or Scheuermann-like kyphotic deformity iii. Osteoarthritis <40 years e. Other i. MVP 2. Note a. Marshall syndrome is a related CT disorder with overlapping characteristics

Answer 103

1. Spectrum a. Fragile X syndrome b. Fragile X-associated tremor/ataxia (FXTAS) c. FMR-1 related primary ovarian insufficiency 2. Epidemiology a. Most common form of inherited intellectual disability (accounts for 5% of males with ID) 3. Genetics a. X linked disorder – X linked dominant (females can have symptoms) b. Loss of function of FMR1 gene - CGG repeats + aberrant methylation c. Classification i. < 55 = normal, no risk for offspring ii. 55-200 = premutation iii. > 200 = full mutation 4. Clinical presentation a. Typically present with developmental delay at 2-4 years b. ID = IQ 30-50 c. Behaviour = ADHD, autistic traits, impulsive, anxious, shy 5. Clinical manifestations a. Fragile X - key features: large ears, macro-orchidism (POST PUBERTAL), long face and prominent jaw (post pubertal), ID, ASD (eye avoidant) - behavioural abnormalities are a/the key presentation in pre-pubertal boys b. Fragile X-associated tremor/ataxia (FXTAS) i. Occurs in males (and some females) with FMR1 premutation ii. Characterised by late-onset progressive cerebellar ataxia and intention tremor iii. Males (45%), females (17%) c. FMR-1 related primary ovarian insufficiency i. Cessation of menses <40 years ii. Occurs in 20% of females with FMR1 premutation iii. About 5-10% of women with POI will conceive 6. Investigations a. Triplet repeat analysis i. Sizing of triplet repeat – PCR/Southern Blot b. NOT DETECTED ON MICROARRAY/SEQUENCING

Answer 104

1. Genetics + pathogenesis a. AD b. CAG repeats c. Huntingtin gene (HTT) = exon 1 HTT d. Displays anticipation e. Larger repeat = earlier onset disease f. Fully penetrant if >=40 repeats 2. Clinical manifestations a. Progressive disorder of motor, cognitive and psychiatric disturbance b. Mean age of onset 35-45 years – median survival time 15-18 ears after onset 3. Treatment a. No treatment available

Answer 105

1. Key points a. MACROdeletion syndrome 2. Genetics a. Partial deletion of the short arm of chromosome 5 = 80% b. Translocation involving 5p = 5% 3. Clinical manifestations a. High-pitched, cat like crying b. Dysmorphic facies i. Hypertelorism ii. Round face iii. Downslanting palpebral fissures iv. Broad nasal bridge v. Low set and/or malformed ears c. Low birth weight d. FTT e. Hypotonia f. Psychomotor delay g. ID h. Microcephaly

Answer 106

1. Key points a. Leading preventable cause of birth defects and developmental disabilities 2. Pathogenesis a. Alcohol is a teratogen with irreversible CNS effects b. Results in reduced brain volume (specifically frontal lobe, striatum, caudate nucleus, thalamus + cerebellum) thinning of corpus callosum, and abnormal functioning of amygdala c. “Safe” threshold has not been identified d. Alcohol eliminated from fetal compartment at 3-4% of the maternal rate e. Much of alcohol excreted by the fetus into the amniotic fluid is ‘recycled’ through fetal swallowing f. Deleterious at all ages of gestation 3. Diagnostic criteria ("FAS" = face, abnormal learning, short) a. Traditional criteria = all of the following i. All 3 facial abnormalities = smooth philtrum, thin vermillion border, small palpaberal fissures ii. Documentation of growth deficits iii. Documentation of CNS abnormality (structural or fuctional) b. More recent criteria = combination of scoring in 3 areas i. Prenatal alcohol exposure ii. Neurodevleopmental domains iii. Sentinel facial features

Answer 107

1. Key points a. Group of birth defects which tend to co-occur b. Association – NOT syndrome c. No pathogenic cause to explain grouped inheritance 2. Clinical manifestations a. Vertebral = 80% i. Hypoplastic vertebrae or hemifertebrae ii. May result in scoliosis b. Anal = 55% i. Imperforate anus c. Cardiac = 75% i. VSD, ASD, TOF most common ii. Truncus, TGA less common d. Tracheo-esophageal fistula = 70% i. More likely to have cardiac anomaly e. Renal = 50% i. 35% have a single umbilical artery ii. Incomplete formation of one or both kidneys f. Limb = 70% i. Displaced or hypoplastic thumb ii. Polydactyly iii. Syndactyly iv. Radial aplasia g. Extension i. Single umbilical artery ii. Ambiguous genitalia iii. Abdominal wall defects iv. Diaphragmatic hernia h. Growth i. Difficult to gain weight

Genetics Flashcards

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