Genetics Flashcards

Question

What base is different on mRNA than DNA?

Answer 1

T is replaced with U (uracil) on mRNA | Also has ribose instead of deoxyribose

Answer 2

Exons code for protein | Introns don't code for protein

Answer 3

- Replication of a segment of DNA that forms a gene into mRNA (protein blueprint) - RNA polymerase binds to the promoter region and assembles mRNA - Copy of the DNA is made, except for T bases are replaced with U bases, and introns are cut out - The mRNA then goes to the ribosome in the cytoplasm to make a new protein

Answer 4

- Transcription = DNA -> mRNA | - Translation = mRNA -> protein

Answer 5

- Ribosomes assemble proteins from amino acids - transfer RNA brings amino acids to the ribosome and has an anticodon that complements mRNA - As ribosome moves down the mRNA, it leaves a polypeptide tail which is the growing protein - Ribosome takes fresh protein to endoplasmic reticulum

Answer 6

``` AUG = start UGA = stop ```

Answer 7

Provide start or stop codons, or code for a particular amino acid

Answer 8

DNA replication, 46 chromosomes are duplicated

Answer 9

A to T, 2 hydrogen bonds | C to G, 3 hydrogen bonds

Answer 10

Unwinds the DNA into single strands, ready for replication

Answer 11

- In DNA replication - Binds to area of single stranded DNA that has an RNA patch on it, then goes on to synthesise second strand of DNA by adding complementary nucleotides to the template strand of DNA - Moves from 3' to 5' - Leading strand and lagging strand

Answer 12

- Fragile X (X-linked dominant) - Huntington's disease (AD) - Myotonic dystrophy (AD) - Friedreich's ataxia (AR) - Juvenile myoclonic epilepsy

Answer 13

- Longest part of the cell cycle where the cell prepares to divide - G1 phase: growth 1 phase, longest phase, cell grows, organelles synthesise proteins - G1 checkpoint for DNA damage and to ensure correct proteins synthesised. If errors then enter G0 (cell repair) or apoptosis - S phase: synthesis phase where DNA replicates (still have 46 Ch). - G2 phase: growth 2 phase, duplication of organelles - G2 checkpoint: if no damage found, then cell enters mitosis

Answer 14

- DNA repair or non-dividing phase, outside cell cycle - e.g. hepatocytes rest in G0 until there is liver damage, at which point they enter G1 again - e.g. neurons, spend entire life in G0

Answer 15

- When one cell divides into two daughter cells "please make another two cells" - Prophase: chromatids condense into chromosomes, nucleolus disappears - Metaphase: nuclear membrane disintegrate, chromosomes line up along middle of cell, spindle fibres from centrosomes attach to centromere of each chromosome - Anaphase: centrosomes pull on spindle fibres to pull sister chromatids apart - Telophase: nuclear membrane reforms around each set of chromatids - Cytokinesis: cell membrane pinches in until 2 daughter cells separate

Answer 16

- Chromosome is made up of 2 chromatids joined by a centromere i.e. double the DNA - The 2 chromatids are exact copies of each other

Answer 17

- Formation of 4 haploid gametes from 1 diploid cell - Meiosis 1 + 2, each made up of prophase, metaphase, anaphase, telophase - Prophase 1 makes up 90% of meiosis: membrane disintegrates, tetrads form between homologue chromosomes and crossover events occur (so maternal and paternal DNA mixed), chromosomes start to pull away but still connected at chiasmata/crossover region - Metaphase 1: tetrads line up along metaphase plate - Anaphase 1: tetrads pulled to opposite sides of cell - Telophase 1: nuclear membrane reforms, cell pinches, 2 haploid daughter cells formed

Answer 18

- At the end of meiosis 1, cell enters interphase. However, no duplication of chromosomes at S phase - Prophase 2, metaphase 2, anaphase 2, telophase 2 occur in the same way - Resulting 2 cells contain 23 chromatids, rather than 23 chromosomes

Answer 19

To double the amount of DNA in each cycle, so there is more DNA available to analyse

Answer 20

- Allows us to look for DNA mutations and DNA repeats - Smaller pieces of DNA can move across gel faster, allowing separation of segments along the gel - Uses markers to follow alleles through crossover events in meiosis (SNPs and STRPs)

Answer 21

Autosomal dominant

Answer 22

- As an SNP array compares the polymorphisms found in individual patients, it can detect contiguous LCOH (long stretches where the same SNP is found on both alleles) - They are not in themselves disease-causing, but may be significant if an AR condition is suspected - >8% LCOH is suggestive of parents who are first cousins

Answer 23

- Maternally imprinted - Prader-Willi syndrome is caused by loss/abnormal methylation of the paternal allele of chromosome 15q11.2q13. - Paternal deletion 65-75%, maternal UPD 20-30%, imprinting defever 5%, gene mutation 0.1% and balanced translocation 0.1%.

Answer 24

- There are currently over 14 genes that have been associated with Noonan syndrome and conditions on the Ras-Mpk pathway - PTPN11 is the most commonly associated gene, but only accounts for approximately 50% of cases

Answer 25

- Coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies - 15-20% also have tracheoesophageal fistula

Answer 26

- Vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities

Answer 27

- Altered codon produces amino acid substitution (single base pair substitution might not change AA)

Answer 28

- Altered codon becomes a stop codon and produces a truncated protein (mRNA terminates at that point)

Answer 29

- Prader-Willi = absent paternal expression = microdeletion of paternally derived gene or maternal uniparental disomy - Angelman = absent maternal expression = microdeletion of maternally derived gene or paternal uniparental disomy

Answer 30

Microdeletion on 7q11.23

Answer 31

33% chance of recurrence

Answer 32

- X-linked - Overgrowth, organomegaly - Coarse facial appearance, hypertelorism, large mouth and tongue - Congenital heart disease - Polydactyly - Wilms tumour (7.5%)

Answer 33

- Overgrowth syndrome, associate cognitive abnormalities - Known as cerebral gigantism - 2-3% risk of WIlms tumour

Answer 34

- Overgrowth syndrome - Fetal gigantism, visceromegaly, unusual facies - Renal issues including WIlms

Answer 35

Amplified DNA | RNA is northern plot, protein is Western plot

Answer 36

Male to male transmission

Answer 37

- DMD caused by deletion or mutation | - BMD caused by in-frame mutation which leads to a short protein with some preservation of function

Answer 38

- Mitochondrial disorder | - Autosomal dominant with paternal imprinting

Answer 39

Divide the frequency by 4, then take the square root. | E.g. if frequency is 1 in 1,000,000. Then carrier frequency = 500

Answer 40

NF 2, often present earlier than schwannomas

Answer 41

< 50 - normal 55-200 - carrier/pre-mutation >200 - Fragile X (ID in males, females variably affected) Pre-mutations: - Premature ovarian failure, shy personality (females) - Cerebellar tremor/ataxia syndrome (males>females)

Answer 42

Noonan's syndrome

Answer 43

22,000 genes, separated by non-coding DNA

Answer 44

37 genes, no introns, 93% of mitochondrial genome is coding DNA (c.f. nuclear = ~2%)

Answer 45

Angelman's syndrome

Answer 46

- Superior = Marfan's | - Inferior = homocystinuria

Answer 47

Microduplications and deletions

Answer 48

6% (normal population = 3%) (note incest = 50%)

Answer 49

- Fathers can't pass on to sons, all daughters are carriers | - Mothers pass on to 50% sons (affected), 50% daughters (carriers)

Answer 50

- Fathers can't pass on to sons, all daughter are affected | - Mothers pass on to 50% sons and 50% daughters (affected)

Answer 51

Homozygous Connexin 26 mutation

Answer 52

Double-stranded DNA macromolecule wrapped around histone proteins

Answer 53

Protein-coding genes, only make up 1-2% of genome. Rest is non-coding DNA

Answer 54

Aneuploidy

Answer 55

64 combinations = 61 specify 20 amino acids + 3 specify stop signals

Answer 56

- Alter the reading frame, leading to a completely different set of amino acids - Can result in a premature stop codon

Answer 57

- Reduction by about half in amount of protein - Usually due to a whole gene deletion - Can occur secondary to a frameshift mutation or nonsense mutation

Answer 58

Where there are at least two, or more, relatively common alleles of a gene in the population (>1%) e.g. different alleles in ABO blood groups. These are not mutations, just variations

Answer 59

Different mutations in the same gene causing different conditions

Answer 60

Mutations in different genes can cause the same condition e.g hearing loss, ID, epilepsy

Answer 61

Translocation between two acrocentric chromosomes (short-arm chromosomes) = 13, 14, 15, 21, 22

Answer 62

- 47, XXY, nondisjunction during mitotic division - Testing: karyotype, microarray, FISH - Most common cause of primary male hypogonadism - Low testosterone - hypogonadotropic hypogonadism - Infertility, incomplete virilisation, small testes, gynaecomastia - Euchnoid body habitus, tall stature, truncal obesity - Mild learning difficulties, emotionally immature, shy - Increased rates ASD, depression, anxiety - Inc rates diabetes, hypothyroidism, osteoporosis, breast cancer, mediastinal germ cell tumour

Answer 63

- Molecular karyotype = microarray - Look for microduplications or deletions - Below the resolution of a conventional karyotype - Increasing number of human diseases recognised to be due to copy number variants in non-coding DNA

Answer 64

Still have the genotype, but don't express the phenotype. Black and white.

Answer 65

Still have the genotype and the phenotype, but have varied spectrum of disease e.g. NF1, may just have some cafe au lait, or may have all the features. Shades of grey.

Answer 66

2/3rds/ 66%

Answer 67

- X-linked hypophosphatemic rickets (Vit-D resistant rickets), incontinentia pigmenti, Rett syndrome, most cases of Alport syndrome, Fragile X - X-linked dominant disorders are often lethal in males (survivors are mosaic)

Answer 68

- Increased instability with larger repeat sizes - Milder symptoms may be noted in those with intermediate range expansions - Gender of transmitting parents may affect stability .e.g myotonic dystrophy, HD, Fragile-X maternal copy more likely to be unstable, Huntington's paternal copy - Anticipation: phenotype worsens in subsequent generations - e.g. Fragile X, myotonic dystrophy, HD, spinocerebellar ataxia

Answer 69

- "above the gene" - Alterations in the way a gene is expressed - Gene regulation is affected by: DNA methylation, histone modification/conformation of chromatin (how open/closed chromatin is), non-coding RNA

Answer 70

- Prader-Willi - loss of paternal allele (paternal deletion 70% or maternal UPD 25% or imprinting defect <1%) - Angelman - loss of maternal allele (maternal deletion 70%, or paternal UPD 5%, UBE3A mutation 5-10%, imprinting defects 3%, unknown 10-20%)

Answer 71

- Arises from non-disjunction | - Either fertilisation with a nullisomic gamete, or trisomic rescue (kick out wrong copy)

Answer 72

- Visually analyses whole chromosomes - Detects aneuploidy, large chromosomal imbalances, balanced and unbalanced translocations - Cells arrested in metaphase (chromosomes maximally condensed and visible) - Google maps: looking at world from outer space - Takes up to 10 days - Cannot detect: microdeletions/duplications, DNA sequence changes

Answer 73

- Fluorescent labelled DNA probes for specific target - Need to know what you are looking for - Detect presence/absence of specific DNA sequences on chromosomes - E.g. 22q11, Williams, trisomies/monosomies - Replaced by chromosomal microarray but still used for localisation and looking for balanced rearrangements, and rapid testing (24-48hrs) - Google maps: satellite image highlighting specific cities

Answer 74

- Test of dosage - too much or too little - Test DNA (red) compared to control DNA (green). More green = deletion, more red = duplication - Can detect: microdeletions/duplications, monosomies and trisomies e.g. T21, 22q11, Williams - Cannot detect: balanced chromosomal changes/rearrangements - Google maps: world is a jigsaw puzzle, looking for missing/duplicated bits

Answer 75

- Can detect variation in a single nucleotide at a specific locus (copy number variation) and allelic imbalance (are 2 copies of allele the same or different e.g. UPD) - Genome-wide test of chromosomal dosage, or SNP at specific locus - Can go to submicroscopic level - Cannot detect: balanced rearrangements, triple repeats, sequence changes, methylation changes, whole/partial gene deletions - Good for T21, 22qq11, UPD - Google maps: individual houses on both sides of the street, microarray = every street on the map

Answer 76

- Chimerism - UPD (as can detect allelic imbalance) - Long continuous stretches of homozygosity - Mosaicism to approx 7%

Answer 77

- Microdeletions and microduplications - Trisomy - Some single gene disorders - CGH mosaicism to approx 15%

Answer 78

- Balanced rearrangements (as looks for copy number variation) - Methylation changes - Sequence changes - Triplet repeat expansion disorders

Answer 79

- Copy number variances of unknown significance - LCSH - not related to reason you did test, risk of unmasking recessive disease - Unable to detected balanced rearrangements - Incidental findings e.g. BRACA1 gene in a child

Answer 80

- Used to determine the exact sequence of bases "spelling of DNA" - e.g, sequencing the Marfan gene (FBN1) or NF1 gene (NF1), Noonans gene (PTPN11) - Can detect single gene mutations - Need to know what you are looking for - Cannot detect exonic deletions or duplications - Struggles with larger than 100 triple repeats (which is usually a pre-mutation size) - Google maps: down the street we are labelling houses 4 diff colours (A, T, C, G)

Answer 81

- Indirect method of looking at genes - Genes that are close together are inherited together, therefore looking at markers around a gene of interest - e.g. if you know the parent have a genetic mutation and want to find out if offspring have it but direct mutation analysis not possible - Google maps: if you see a McDonalds, you know there will be a Burger King close by

Answer 82

- PCR to look at number of triplet repeats - PCR can only detect up to certain number of repeats, then need Southern Blot (which can size the full range of expansion) - Southern blot: large pieces move slowly through the gel, small pieces move quickly - Southern blot: DNA, Western blot: protein (e.g. dystrophin in DMD/BMD)

Answer 83

- Tests for deletions and duplications below the resolution of a microarray - Separates each amplification product by its unique length, therefore know if any are missing or duplicated - Similar to FISH but looking at a much smaller level - Looks for microdeletion/microduplication in a specific gene (c.f. microarray is in the whole genome) - e.g. DMD, SMA (SMN1 gene) - Cannot detect sequence changes, or large copy number changes - Need to know exactly which gene to look at - Google maps: in each town on the map the streets have different lengths

Answer 84

- Used for imprinting disorders - Prader Willi, Angelman, Beckwith Wiedemann, Russell Silver - MLPA probes only identify methylated targets, then looks at whether pattern is normal or abnormal - Google map: there is an ASB ATM located on only some streets

Answer 85

- DNA sequencing of a whole genome/exome - Analyse multiple genes simultaneously - Used for genetically heterogeneous conditions - Cannot detect triplet repeats or methylation defects - Need to give lab lots of information so they know what you are looking for - High diagnostic yield, fast and accurate, allows re-analysis, good for ultra-rare diagnoses, but get unexpected diagnoses

Answer 86

- Looks for mutations (spelling changes) within a set number of genes at once - Good for genetically heterogeneous conditions e.g. arrhythmias, cardiomyopathy, Noonan's - Only good for single-system diseases - Serial panel testing is not cost effective - do exome sequencing instead - Cannot detect: copy number changes, methylation abnormalities, changes in genes not included in panel

Answer 87

FGFR3 mutations = achondroplasia group = thanatophoric dysplasia, achondroplasia, hypochondroplasia

Answer 88

Mutation on the X-chromosome in a male (or a female with Turner's)

Answer 89

Marfans, osteogenesis imperfecta, Noonans, vWD, NF1, tuberous sclerosis, myotonic dystrophy, Huntingtons, ADPKD, hereditary spherocytosis, familial hypercholesterolaemia

Answer 90

- De novo mutations - Incomplete penetrance - Variable expressivity - Gonadal mosaicism

Answer 91

- More than one genotype in different cells - Can be a point mutation or chromosomal abnormality - Constitutional (somatic) vs germline (gonadal)

Answer 92

- Common: AD and X-linked - Rare: AR - The more severe the disorder, the more common de novo mutation is (severe disorders are less likely to procereate - low/zero fecundity)

Answer 93

Deafness (some), albinism, Wilson disease, sickle cell, thalassaemia, CF, Friedreich ataxia, haemochromatosis, PKU, a1aT deficiency, homocystinuria

Answer 94

- The allele and genotype frequencies in the population will remain constant in the absence of other evolutionary influences (mate choice, new mutations, selection etc) - p2 + 2pq + q2 = 1

Answer 95

100% identical twin 50% parents/sibling 25% 2nd degree relative = uncle/aunt/niece/grandparent 12.5% 3rd degree relative = cousin Number of unbroken lines = degree of relative

Answer 96

Recessive conditions in more than one generation by bad luck. Pedigree looks dominant but is in fact recessive

Answer 97

Fragile X, haemophilia, G6PD, ocular albinism, testicular feminisation, CGD, Rett syndrome (X-linked dom, males die at birth), colour blindness, DMD, hypophosphatemic rickets

Answer 98

- Loss of paternal genes 15q12 | - Floppy baby (hypotonia), large appetite (hyperphagia), obesity, short stature, moderate ID, hypogonadism

Answer 99

- Loss of maternal genes (UBE3A) 15q11-13 - Severe intellectual disability, lack speech, spontaneous laughter, happy puppets with hand flapping, love water, poor sleep, ataxia - Unsteady gait, epilepsy - Microcephaly, large mouth and chin - Monitor for obesity

Answer 100

- Loss of maternal genes 11p15 - Overgrowth disorder - Macrosomia, neonatal hypoglycaemia - Hemihypertrophy - Macroglossia, visceromegaly - Inc risk Wilms, hepatoblastoma

Answer 101

- Loss of paternal genes 11p15 (or Chr 7) - methylation defect in 60%, maternal UPD7 10%, rest unknown - Short stature, IUGR, macrocephaly, asymmetry, cafe au lait, clinodactyly - Triangular face - Test: methylation studies, if normal then UPD7 studies (can do SNP) and DNA from parents - Usually normal IQ, can use growth hormone, risk fasting hypoglycaemia in infancy

Answer 102

11p15 Excess expression = BWS (loss of maternal allele) Lack of expression = RSS (loss of paternal allele)

Answer 103

- Maternal imprinting - no affected children from females (mothers with mutation silence it when passed on). All affected persons inherit mutated gene from father - Paternal imprinting - no affected children from males (fathers with mutation silence it when passed on). All affected persons inherit mutated gene from their mother. - If pedigree shows affected offspring from both males and females then can't be imprinted

Answer 104

- Some mitochondria have the mutation and others don't, and not all mitochondria are replicated to daughter cells during oogenesis - Therefore not all children of a mother with mitochondrial disorder will be affected, and mother can be asymptomatic but have profoundly affected child

Answer 105

The closer together two genes or genetic markers, the higher the linkage disequilibrium i.e. the tendency for alleles of genes to be inherited together in a non-random fashion

Answer 106

- 11-15 weeks - Needle into placenta - 1:500 miscarriage risk

Answer 107

- 15-20 weeks - Needle into uterus - 1:1000 miscarriage risk

Answer 108

- Huntington CAG - Fragile-X CGG - Myotonic dystrophy CTG

Answer 109

- AD - 30-50% are new mutations - Mutation in NF1 gene (tumour suppressor gene, codes for neurofibromin) - Virtually 100% penetrant by 5 years - Large gene, many possible mutations, therefore diagnosis is clinical

Answer 110

- Lisch - brown, NF1 | - Brushfield - grey-brown, T21

Answer 111

- Unidentified bright objects on T2 MRI - inc in size until age 10 then often disappear, benign - Seizures 5% - Learning difficult approx 50%, ID approx 5% - CNS tumours - optic nerve glioma + meningiomas, astrocytomas (5 x more common than average) - Malignant peripheral nerve sheath tumours - neurofibrosarcoma, highly malignant - Spinal neurofibromas - in spinal canal, can be extensive and cause pain - Scoliosis 5% - Short stature 10-15% - Macrocephaly - Hypertension 6% (essential HTN, renal artery stenosis, pheochromocytoma) - Mortality - mean M 54y, F 59y

Answer 112

- Children - yearly follow up - Learning evaluation, psychometric testing occ. - Neuro assessment - BP - Scoliosis - Yearly ophthalmology until age 8 (optic glioma more common when younger)

Answer 113

- AD, up to 50% are new mutations (lower fecundity) - Mutation in NF2 gene - Tumour suppressor gene that codes for merlin (links membrane proteins/cell cytoskeleton) - Nonsense/frameshift leads to severe disease - Missense often milder

Answer 114

One of: - Bilateral vestibular schwannoma - almost all will have by 30 years - 1st degree relative with NF2 AND unilateral VS or any two of meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities - Multiple meningiomas AND unilateral VS and any two of schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities

Answer 115

- Eye lesions - cataracts 60-80%, retinal hamartomas - Multiple CNS tumours - Unilateral hearing loss 35% - Focal weakness 12% - Tinnitus, bilateral hearing loss 10% - Balance dysfunction - Seizures 8% - Diagnosis due to family history - Focal sensory deficit - Visual loss

Answer 116

- Nastier than NF1 - Death ~36y (15y from onset first symptoms) - Annual MRI scans and early surgical treatment of VS to preserve hearing - Monitor vision and treat cataracts - New med: avastin (bevacizuman) shrinks VS

Answer 117

- Multiple benign hamartomas of multiple organs | - Epilepsy and cognitive impairment common

Answer 118

- AD, 2/3rds have new mutations - TSC1 - hamartin (9q34) - 20% - TSC2 - tuberin (16p13.3) - 50% - Highly variable expression, broad phenotypic changes - Assess parents: skin exam, MRI brain, RUSS, opthal

Answer 119

- Pathogenic mutation in TSC1 or TSC2 genes - Clinical: 2 major or 1 major + 2 minor = definite, 1 major + 1 minor = probable, 1 major or 2 minor = possible - Major: - Skin: facial angiomas/adenoma sabaceum or forehead plaque, periungal fibroma, >3 ash-leaf (Woods lamp), shagreen patch, retinal nodular hamartomas - Brain: cortical tubers, subependymal nodules, SEGA - Other: renal angiomyolipoma (often bilateral, 80%), cardiac rhabdomyoma (benign, regress spont), lymphangioleiomyomatosis - Minor: - Skin: confetti skin lesions, dental enamel pits, gingival fibromas, retinal achromic patch - Brain: cerebral white matter migration lines - Other: non-renal hamartomas, bone cysts, hamartomatous rectal polyps, multiple renal cysts

Answer 120

- 85% have CNS complications - Seizures 75% including infantile spasms, myoclonic, partial, GTCS - Intellectual disability 50%, 30% profound - Behaviour - ADHD, autistic-like, sleep issues - CNS changes and tumours - tubers, subependymal glial nodules, SEGA (highest risk adolescence) - Opthal: mulberry lesions - Resp: dilated lymphatics, cystic lung disease, pneumothorax

Answer 121

- mTOR inhibitors (mTOR pathway activated by mutations in TSC1 and 2) - Sirolimus- des angiomyolipomas, improved PFTs - Everolimus - decr size SEGA, decr seizure frequency - Topical rapamycin - facial angiofibromas

Answer 122

- AR hereditary ataxia - GAA repeat expansion in intron 1 of FXN, affected if >56 reepats - Onset 10-15 years, death 37 years - Progressive neurological dysfunction: cerebellum and dorsal root ganglia - Gait and limb ataxia - Absent LL reflexes but upgoing plantars - Posterior column dysfunction (vibration/proprioception_ - HCOM, diabetes mellitus

Answer 123

- Often asymptomatic until puberty - Intellectual disability - Elongated face, large protruding ears, high arched palate, double-jointed thumbs - Large testes, flat feet, low muscle tone - Flapping hand movements, shyness, poor eye contact, may meet criteria for ASD - ADHD - Seizures up to 20% - Strabismus, refractory errors 30% - Mitral valve prolapse, aortic root dilation

Answer 124

- Inherited progressive neurodegenerative disorder - Chorea, dementia, psychiatric symptoms - Onset until death 18yrs - Usual onset age 40, can present in childhood <20 years with dystonia - Due to CAG repeat in HTT Huntington gene exon 1 - AD with anticipation, fully penetrant if >40 repeats

Answer 125

- X-linked, 1:4000 (1:30,000 BMD) - Due to mutation in dystrophin gene which codes for dystrophin protein - 60% deletion, 8% duplications, others point mutations - DMD: disrupts the reading frame and therefore no functioning protein - BMD: "in frame" mutation, resulting in a shortened and semi-functional protein/milder phenotype - High gonadal mosaicism rate, therefore always need prenatal genetic counselling

Answer 126

- Proximal muscle weakness, onset ~age 3 - Delayed motor milestones - Broad, waddling gait, falls - Gower sign, trouble with stairs - Calf pseudohypertrophy (muscle replaced with fat and connective tissue) - Wheelchair age 12, loss of UL muscles age 16, death 20y - Mild IQ impairment - Cardiomyopathy

Answer 127

- CK, genetic testing, muscle biopsy with stain for dystrophin - Management: maintain mobility, prevent contractures, steroids, genetic counselling (confirm if mother is a carrier), palliation - Emerging drug therapies: skip gene, make dystrophin

Answer 128

- Trisomy 21 - 95% nondisjunction trisomy - 1% recurrence risk, higher if Mother >40yo. Maternal ND 90%, paternal ND 10% - 2-3% translocation - 33% recurrence risk in siblings. Seen on karyotype, not microarray or FISH. Carrier has 45 chromosomes. Most commonly Ch 14 + 21 - If mother carrier = 12% risk recurrence - If father carrier = 1% risk recurrence - 2% mosaic (due to trisomy rescue or non-disjunction early after conception) - Ix: karyotype, microarray, FISH - Antenatal screening: decr PAPPA+AFP, increased bHCG - Increased nuchal/absent nasal bone on USS

Answer 129

- Upslanting palpebral fissures, epicanthic folds, small low set ears, flat nasal bridge, large tongue, sandal gap, curved 5th finger, brushfield spots - Mild-mod ID, 5-8yrs equivalent - Hypotonia, hyperflexible joints - 75% develop Alzheimer's by age 60 (APP gene on Ch21) - CHD: VSD > AVSD > PDA > ASD > ToF, MVP in adolescent - Hypothyroidism 30%, coeliac - Duodenal atresia, TOF, Hirschsprung, imperforate anus - Leukaemia (AML = ALL) 1:300 (10-20x inc risk), but lower rates solid tumours. TMPD (10%) -> 20% of these will develop AML, polycythaemia, macrocytosis. Children with T21 and AML respond better to treatment. - Low immunity, recurrent low-grade infections e.g. viral - Occipito-atlanto-axial instability 15% - screening controversial. Can lead to subluxation and spinal cord injury. Hip issues. - OSA (anatomical + hypotonia) 50-70% - Hearing (conductive) and vision (refractory, cataracts) issues 60-70% - Short height, microcephalic, often obese by age 3-4y - Fertility: male infertile, females severely reduced (1/2 children with have T21)

Answer 130

- Trisomy 21 is most common genetic cause of ID | - Fragile-X is most common cause of inherited ID

Answer 131

- Single gene disorder, FBN1 mutation (can do Sanger sequencing) - AD, broad phenotype - 1:4000 - Diagnosis in absence of FHx: aortic root enlargement (Z score >2) + one of: ectopia lentis, pathogenic FBN1 variant, systemic score >7 - Diagnosis with FHx: 1st degree relative + ectopia lentis, systemic score >7, aortic root enlargement >3 if <20yo

Answer 132

- Connective tissue disorder - tall and stretchy - Tall, long limbs, thin stature (increased LS and arm span ratios) - Joint hypermobility - CVS: aortic dilation/dissection, AR/MR - Pectus carinatum or excavatum - Superior lens dislocation - Wrist and thumb sign

Answer 133

- 250 times greater risk of dissection than normal population - Tx: prophylactic beta-blockers or ARBs to slow progress - Surgical repair

Answer 134

- 45XO in 50% - Mosaic 45XO/46XX in 25% - 25% other karyotype with X chromosome structural abnormalities - Vast majority of 45XO miscarry, therefore do survivors have another cell line? - Diagnosis: karyotype, microarray, FISH

Answer 135

- Short stature (average 20cm shorter than sisters) - require growth hormone - Gonadal dysgenesis, streak ovaries - primary amenorrhea, pubertal delay. May need oestrogen - Dysmorphology - webbed neck, shield chest, widely spaced nipples - Generally normal IQ, but defects in visuospatial functions. Verbal IQ > performance IQ - Urinary tract malformations in 30%, horseshoe kidney - Cardiac anomalies in 30% - aortic dilation, coarctation > bicuspid aortic valve > aortic stenosis, cardiomyopathy - Endocrine: hypo/hyperthyroid, diabetes, osteoporosis, coeliac - HTN - Congenital lymphoedema: puffy hands/feet at birth

Answer 136

- Trisomy 13 - Midline defects: holoprosencephaly, cleft lip/palate, heart abnormalities (VSD, PDA), scalp defect - Microcephaly, visual loss, polydactyly, low-set ears, cyclopia, rocker-bottom feet - Often multiple malformations in neonatal period - Genetics: nondisjunction event, rarely translocation - Test: karyotype, microarray, FISH - Median survival 10 days, 92% die by 1 year - Profound ID in long-term survivors

Answer 137

- Trisomy 18 - IUGR, wizened features (small palpebral fissures, microstomia), prominent occiput, overlapping fingers, rocker-bottom feet, multiple malformations, microcephaly - VSD/ASD - Present with IUGR or abnormal maternal serum screening (low oestradial, PAPPA, beta HCG, AFP) - Genetics: nondisjunction event - Test: karyotype, microarray, FISH - Median survival 14 days, 92% die by 1 year

Answer 138

- Cardiac - conotruncal, aortic arch defects, TA, ToF, AVSD - Abnormal facies - low set and rotated ears, hypertelorism, high nasal bridge, micrognathia - Thymic hypoplasia - variable levels of T cell function, complete with SCID in only 1% - Cleft palate (not cleft lip) - Hypocalcaemia - abnormal parathyroid glands - Up to 5% have a 10p13 microdeletion - Developmental delay, cognitive impairment 75% - Psychiatric illness in 60% - Test: microarray, FISH, need to check parents - Critical genes; TBX1 (cardiac), COMT (behaiour/psych). More than 35 genes involved in common deletion

Answer 139

- Elfin facies, blue eyes, coarse facial features as age, periorbital puffiness, wide mouth - Supravalvular aortic stenosis - Long philtrum, upturned nose, widely spaced teeth - Short stature and developmental delay - Over-friendly, cocktail personality, non social anxiety - Heterozygous microdeletion on 7q11.23 - Test: microarray or FISH - Mild ID, hypothyroid, hypercalcaemia, joint laxity, hypertension later

Answer 140

- Neonatal hypotonia, undescended testes, poor suck and weak cry - Hyperphagia and obesity after infancy - Intellectual disability, skin picking - Hypopigmentation, small hands and feet - 15q, loss of paternal allele - Microarray picks up deletions and some UPD, methylation testing - Often require growth hormone

Answer 141

- IUGR, hirsutism, ulnar ray defects, severe GOR, severe intellectual disability, autistic traits - Short nose, long philtrum, unibrow (synophrys), arched eyebrows - Single gene disorder, mutations in NIPBL 75% - Test via single gene sequencing

Answer 142

- Overgrowth, advanced bone age, high anterior and temporal hairline, frontal bossing, long narrow face, pointed chin, tall stature, large head - Mild-severe ID - NSD1 mutations (90% point mutations, 10% deletions) - test via microarray or single gene sequencing, or "overgrowth" panel - Adult height variable

Answer 143

- Tall and stiff, tall stature with long limbs, ID, ectopia lentis down, severe myopia - AR metabolic condition - Test plasma total homocysteine (not urine), detected on newborn screening - Can't process certain amino acids, accumulate homocysteine - Need protein restriction, folate/B12 supps, methionine-restricted diet - Can get thrombus (CVA), seizures

Answer 144

- Brittle bone disease, short long bones, multiple fractures - Dental abnormalities, hearing loss, blue sclera, osteoporosis, wormian bones - Short stature and scoliosis - Single gene disorders of gene encoding collagen proteins COL1A1/ COL1A2, most AD, if de novo then gonadal mosaicism risk 3-4% - Broad phenotypic severity - OI gene panel or single gene sequencing - Tx: bisphosphonates - 1 mild, 2 severe, 3 progressive and deforming

Answer 145

- Short stature, disproportionate short limbs - Hypotonia and gross motor delay, normal IQ - Macrocephaly, flat nasal bridge, trident hand, normal trunk with rhizomelic (proximal) limb shortening - AD, FGFR3 mutations - Single gene sequencing, skeletal survey is diagnostic test - Complications: stenotic spinal canal (can cause hydrocephalus and foramen magnum compression), OSA, middle ear disease - International rial of vosoritide (inc growth velocity)

Answer 146

- Short palpebral fissures, flat philtrum, thin lip - Jittery, learning disability, DD - IUGR, microcephaly, short stature - May have seizures

Answer 147

Proprotionate: - Turners - Noonans - Fanconi anaemia - Williams Disproportionate: - Russell Silver - Achondroplasia/skeletal dysplasias

Answer 148

- AR, mutations in DNA repair genes - susceptibility to cancer - Test: chromosomal breakage studies, Fanconi panel - Short stature, microcephaly, developmental delay - Abnormal thumb/radius, renal anomalies, GI atresias - Freckles, cafe au lait - Bone marrow failure, pancytopenia (may not present with all cell lines) in 1st decade

Answer 149

- Klinefelter - Marfan - Homocystinuria - Sotos - Beckwith-Wiedemann

Answer 150

- Prader-Willi | - Bardet-Biedl

Answer 151

- Prader-Willi - Myotonic dystrophy - SMA - Peroxisomal disorder (Zellweger) - Congenital disorders of glycosylation (hypotonia, big ears, abnormal fat pads over iliac crest)

Answer 152

- Severe hypotonia, tall forehead, abnormal brain MRI - AR - Abnormal VLCFAs

Answer 153

- Turner - streak ovaries - Klinefelter - hypogonadism - Any syndrome associated with short stature often causes pubertal delay

Answer 154

- Williams - SVAS | - Storage disorders (MPS) - AS

Answer 155

- Noonans - Williams - Alagille (supravalvular pulmonary artery stenosis) - Tuners - Downs

Answer 156

- T21 - 22q11 - Fetal alcohol syndrome

Answer 157

- Turners | - Kabuki (short stature, cleft, CHD, interrupted eyebrows, dysmorphism)

Answer 158

- Marfans (also MVP, MR, AR) - Ehlers Danlos - connective tissue - Loeys Dietz - Marfan-like, bifid uvula - Turners

Answer 159

- Fanconi anaemia - TAR - thrombocytopenia with absent radius (thumb normal) - VACTERL - Blackfan diamond - thumb abnormal - Goldenhar

Answer 160

External ear normal: - Waardenburg - iris heterochromia, white forelock - Alports - haematuria - Jervell-Lange-Nielsen - long QT - Pendred - hypothyroidism - NF2 - late onset deafness - T21 External ear abnormal: - Goldenhar - microtia, fatty eye lumps, vertebral abnorm - Treacher-Collins - bilateral microtia, hypoplastic zygoma

Answer 161

- Heterochromia iridis, white forelock, sensorineural hearing loss, bright blue eyes - AD, single gene disorder PAX3 and SOX10 - Test: gene sequencing panel

Answer 162

- Oculo-auriculo-vertebral dysplasia (OAVD) - 1st and 2nd branchial arch maldevelopment - Hemifacial microsomia, conductive deafness, vertebral defects, sporadic/cause unknown - Fatty eye lumps (epibulbar dermoid), microtia

Answer 163

- Single gene disorder - Symmetrical mandibulofacial dysostosis - Sloping eyes, lower lid coloboma, small midface, microtia - Conductive hearing loss - Normal IQ - Single gene sequencing TCOF1 gene

Answer 164

- 22q11.2 - palate only - Stickler syndrome - severe myopia and retinal detachment - Pierre Robin sequence - cleft palate secondary to mandibular hypoplasia - Trisomy 13 - lip and palate - Kabuki syndrome - coarctation

Answer 165

- Coloboma - cat eye syndrome, CHARGE, treacher collins - Lens dislocation - Marfans (up), homocystinuria (down) - Cataracts - T21, Smith-Lemli-Opitz

Answer 166

- Red cells: Fanconi (pancytopenia), Diamond-Blackfan (BMF, triphalangeal thumbs) - White cells: 22q11 (thymus, T-cell), CHARGE (leukopenia) - Platelets: TAR, Wiskott Aldrich

Answer 167

- T21 (AML, ALL, transient myeloproliferative disease) - Ataxia telangiectasia (leukaemia, lymphoma, sensitive to x-rays) - Fanconi anaemia - Noonans

Answer 168

- NF1 - McCune-Albright - coast of Maine - Fanconi anaemia

Answer 169

- Malformation: organ abnormality caused by intrinsically abnormal development - Syndrome: recognisable pattern of malformations

Answer 170

- Coloboma, clefts, hypotelorism, absent olfactory lobes, solitary central incisor

Answer 171

- Pattern of multiple abnormalities derived from a single known anomaly or mechanical factor - Describes the pathogenesis, not the cause e.g. prune-belly sequence, Pierre-Robin sequence

Answer 172

- Commeest syndrome associated with Pierre-Robin sequence - Cleft palate/submucosal cleft/bifid uvula - Myopia, retinal detachment, staring eyes - High frequency hearing loss - Femoral head failure, scoliosis, osteoarthritis

Answer 173

- Nonrandom occurrence of multiple anomalies not known to be a sequence or syndrome - e.g VACTERL (note CHARGE thought to be association until gene discovered, not it is a syndrome)

Answer 174

Lateral displacement of the inner canthi - look they are hyperteloric but aren't. Can't see white of eye in medial aspect.

Answer 175

- Up = Down syndrome | - Down = Noonans

Answer 176

Fetal alcohol syndrome

Answer 177

- Rhizomelia - short proximal segment - achondroplasia, skeletal dysplasia - Mesomelia - short middle segment - Achromela - short distal segment (hands and feet) - Requires skeletal survey

Answer 178

Autosomal dominant

Answer 179

- AD, usually de novo - Infantile FTT, loose skin, papillomata - Severe feeding difficulties, look emaciated - Ulnar deviation of wrist - HOCM, arrhythmia, valve abnormalities - 10-15% tumour risk: rhabdo, bladder carcinoma

Answer 180

- In the Ras/MPK signal transduction pathway - Noonans generally least severe - Costello syndrome, cardiofaciocutaneous syndrome - NF1 - Legius syndrome

Answer 181

CHARGE syndrome (CHD7 gene)

Answer 182

- Allelic heterogeneity: many different types of mutations in a gene can result in the same condition - Locus heterogeneity: mutations in many different genes can result in the same disorder

Answer 183

Ch 16 - all abort 2nd trimester

Answer 184

- AD, also called heart-hand syndrome - ASD, VSD, heart blocks - Absent radius, often thumb abnormalities - Mutation in TBX-5 gene

Answer 185

- AD, usually de novo as don't reproduce - Cardiac: HCMO>PS - Face: tall forehead, low ears, nasal bridge, curly sparse and brittle hair, dry skin - Prolonged feeding abnormality -> failure to thrive. - Developmental delay and seizures - Pectus excavatum. - Gene defect in RASMAPK pathway (same as Noonans and Costello)

Answer 186

- AR - Short stature & obesity - Type 2 diabetes - Dilated cardiomyopathy - Hearing impairment - Cone-rod ocular dystrophy

Answer 187

- Autosomal recessive– chr 15 = DNA fragility - Chromosome breakage disorder, inc cancer risk (lymphoma, leukaemia, carcinoma, Wilms) - Short stature (usually only feature present at birth) - Telangiectatic erythema of the face (malar rash), photosensitive -> butterfly distribution then limbs - Microcephaly, prominent ears, malar hypoplasia, abnormal dentition, contractures of hands & feet, acanthosis nigricans/ café au lait/ ichthyosis, polydactyly - IgM and IgA -> immunodeficiency in all patients.

Answer 188

- AD, defect in CBFA 1 gene - Responsible for differentiation of osteoblasts to form skeletal structures - Defective bone formation, hypoplastic clavicles, large head, delayed suture closure, narrow pelvis, spine abnormalities - Short stature - Supernumerary teeth, defective cementum formation - Think: photo with shoulder dislocated forward