Genetics Flashcards
Penetrance
(non-mendelian inheritance)
definition: % of people with the genotype exhibiting phenotype
incomplete penetrance: condition not detected in an individual with causative genotype
Achondroplasia
defect: single gene mutation in FGFR3
- AD, sporadic in 80%
genetic testing: single gene sequencing FGFR3
pathophysiology: normal FGFR3 has a negative regulatory effect on bone growth. mutation produces a constitutively active gene
incidence: 1/25,000
clinical:
- facies: macrocephaly, frontal bossing, flat midface/nasal bridge
- physical: short, rhizomelic limb shortening, trident hand, kyphosis, varus/valgus defomities, narrow spinal canal, OSA, middle ear disease
Albright hereditary osteodystrophy
(Pseudohypoparathyroidism)
genetic: AD
pathogenesis: Gs alpha subunit deficiency
clinical: pseudohypothyroidism, short stature, short 4/5th metacarpal, round face, MR
Alagille syndrome
defect: AD single gene mutation in JAG-1 gene Ch20p12
- 10% deletion, 50% point mutation
clinical:
- facies: triangle face, deep set eyes, prominent jaw
- physical: butterfly vertebrae 87%, posterior embrotoxon of eye (88%)
- cardiac: PPS (85%)
- GI: intrahepatic bile dysgenesis, chronic cholestasis (91%), deficiency fat soluble vitamins
- renal: structural abnormality/function 40%
investigations:
- serum: increased bilirubin/aminotransferases
- liver biopsy: reduced number bile ducts
Angelmans syndrome
incidence: 1/45,000
defect: 11q11-13 gene for UBE3A expressing ubiquitin ligase
- deletion maternal sequence (paternal copy imprinted)
genetic test: methylation testing 15q11.2-q13
clinical:
- physical: 20-80% hypopigmented skin/eyes, swallowing issues, prominent mandible, wide mouth, drooling, smooth palms
- cognitive: severe ID, DD, sleep disturbance, seizures, jerky movements, flapping, laughter/smiling, happy demeanour
investigations:
- EEG: high amplitude delta activity with intermittent spike and slow-wave discharges
Anticipation
definition: early onset, more severe or accelerated disease in successive generations
associations: triplet repeat disorders eg. MD, Huntington’s
pseudo-anticipation: caused by ascertainment bias
Apert syndrome
genetics: sporadic
clinical: coronal synostosis, maxillary hypoplasia, high palate, strabismus, syndacyly (mitted hands/feet)
- 66% hydrocephalus and intellectual disability
*Like Crouzon but abnormal hands
Autosomal dominant
- most gain of function
- most new mutations
- less severe
- variable expressivity/penetrance
- can skip generations
Autosomal Dominant
- Achondroplasia
- Alagille
- CHARGE
- Cornelia de Lange
- Ehler Danlos
- Marfan
- Myotonic Dystrophy
- NF1
- Noonan
- Stickler
- Tuberous sclerosis complex
Autosomal recessive
- usually lose of function
- associated consanguinity
- common to skip generations
- more severe
- less variability in families
Autosomal Recessive
- Smith-Lemli-Opitz
- Ataxia telangiectasia
- Mucopolysaccharidoses
Bardet-Biedel syndrome
genetics: autosomal dominant
mechanism: unclear
clinical: obesity, retinitis pigmentosa, polydactyly, hypogonadism, and renal failure
Beckwith-Wiedemann Syndrome
incidence: 1:13,700
defect: range of defects with abnormal imprinting 11p15 causing overactive IGF-2 gene causing an overgrowth disorder
- 85% sporadic, 15% inherited, associated IVF
genetic test: methylation studies 11p
symptoms:
- facies: macroglossia, macrosomia, ear pits/creases
- physical: hemihypertrophy, abdo wall defects (omphalocoele/hernia), visceromegally, naevus flammeus
- endocrine: hypoglycaemia (hyperinsulinaemia)
- renal abnormalities
associated cancers: Wilm’s tumour (5-10%), hepatoblastoma, rhabdomyosarcoma, NB
- abdominal US every 3 months until 8 years
- AFP every 3 months until 4 years
Brachio-oto renal syndrome
genetics: rare AR
clinical: hypoplastic/absent kidneys, ear and neck abnormalities
CHARGE syndrome
incidence: 1/10,000
genetics:
- mutations CHD7 chromosome 8 (60%)
- association: non random anomalies that occur together more often than you would expect by change
clinical:
C- coloboma, CNS anomalies
H- heart defects
A- atresia of the choanae
R- retardation growth/development
G- GU defects
E- ear anomalies/deafness
Choroideraemia
incidence: rare
genetics: mutation in CHM gene X chromosome, males only
pathophysiology: degeneration of the choroid and retina
clinical: night blindness then progressive loss of vision
Chromosome 11 disorders
Ataxia telangiectasia
- ATM gene
- AR
- clinical: B/T cell defects, low Ig, ataxia, oculocutaneous telangiectasia, MR, FTT, DM, secondary cancers, raised AFP/CEA
Beckwith-Wiedemann
- 11p15: abnormal methylation, uniparental disomy
- sporadic
- clinical: macrosomia, macroglossia, exomphalos, organomegally, hyperinsulinaemia, MR, ear creases/puts, hemihypertrophy, Wilm’s
Chromosome 12 disorders
Noonan’s syndrome
- PTPN 11 (protein tyrosine phosphatase)
- AD
- clinical: PS, septal defects, HCM, webbed/short neck, pectus excavatum, wide nipples, cubitus valgus, short, ptosis, low ears, small genitals, coag defects, MR
Chromosome 13 disorders
Retinoblastoma
- RB1 gene, hereditary or somatic
- AR 90% penetrance
- clinical: retinoblastoma, 25% of cases bilateral (always hereditary), also increased risk osteogenic sarcoma
Chromosome 15 disorders
Prader Willi
- 15q deletion: 70% paternal deletion, 25% UPD maternal
- clinical: severe hypotonia, obesity, short, small hands/feet, hypogonadism, MR
Angelmann’s
- 15q deletion: most maternal deletion (lower UPD)
- clinical: hypotonia, fair hair, midface hypoplasia, seizures, prognathism, ataxic movement, laughter, MR
Chromosome 17 disorders
Neurofibromatosis 1
- neurofibromin protein (tumour suppressor)
- 1/2 sporadic, AD
- clinical: skin/eyes neurofibromas, bone, brain tumours, RAS, macrocephally
Charcot Marie Tooth
- 17q11.2 gene producing myelin protein P22
- AD
- clinical: motor, sensory, autonomic neuropathy
Chromosome 19 disorders
myotonic dystrophy
- CTG repeat
- AD with anticipation
- clinical: weakness, heart conduction defects, DM, cataracts, testicular failure, MR
Chromosome 20 disorders
Alagille syndrome
- JAG1 gene: microdeletion 20p12
- AD
- clinical: peripheral PA stenosis, liver disease, decreased intrahepatic intralobular bile ducts, high cholesterol, butterfly vertebrae, short, FTT, high voice, deep eyes, broad forehead, hypertelorism, pointed chin
Chromosome 22 disorders
Di George
- 22q11.2 delection
- 95% sporadic, AD
- clinical: CATCH
Chromosome 3 disorders
Von Hippel Lindau
- AD
- benign/malignant tumours: haemangioblastomas, RCC, retina, phaeochromocytoma, pacreatic, middle ear
Chromosome 4 disorders
Achondroplasia
- FGFR-3 gene: gain of negative function
- AD: 80% new mutations
- incidence: most common non lethal skeletal dysplasia
- clinical: short limbs, low nasal bridge, coarse features, midface hypoplasia, caudal narrow SC, delayed motor milestones, OSA, trident hand
Chromosome 5 disorders
Spinal muscular atrophy
- SMN1 gene
- AR carrier frequency 1/80
- most common NMD after DMD
- type 1 (infantile): frog leg, areflexia, tongue atrophy, fasciculations, swallowing/resp difficultires
- type 2 (3m-15yrs): proximal weakness, decreased/absent reflexes, survival 30yrs
- type 3 (5-15yrs): hip girdle weakness, calf hypertrophy, walk to 40s
Adenomatous polyposis coli
- APC tumour suppressor gene 5q21
- AD
- clinical: polyposis 10yrs, 100% risk colorectal cancer, assoc duodenal ampullary/thyroid/hepatoblastoma/gastric/medulloblastoma
Chromosome 7 disorders
Williams syndrome
- deletion long arm (7q11) >25 genes for protein elastin
- sporadic
- clinical: supravalvular AS, peripheral PS, hypercalcaemia, serrated teeth, carp mouth, hypertelorism, small upturned nose, puffy eyes, chattery, stellate iris, MR, elfin facies
Chromosome 8 disorder
Hereditary spherocytosis
- AD
- deficiency of RBC membrane structural protein spectrin
Chromosome 9 disorders
Tuberous sclerosis
- TSC1 protein encoding harmatin (complexes with tuberin): both tumour suppressor genes
- 2/3 new mutations, 1/3 AD
- clinical: brain (seizures, MR, tubers, tumours (eyes, heart, lung, skin, liver, muscle)
Fredrich’s ataxia
- trinucleotide repeat of GAA encoding frataxin
- deficiency of frataxin leads to Fe accummulation in mitochondria
- AR
- clinical (5-15yrs): dorsal columns (loss DTR/sensory changes), lateral CS tract (spasticity, upgoing plantars), spinocerebellar tracts (ataxia), cardiomyopathy, scoliosis, optic atrophy
Consanguinity
incidence: >8% globally
associations: congenital/genetic disorders x2
shared genes:
- 1st degree: 1/2 genes
- 2nd degree: 1/4 genes
- 3rd degree: 1/8 genes (progeny homozygous at 1/16 loci, 6% chance severe abnormality)
Contiguous gene syndrome
cause: abnormality of 2 or more genes located next to each other
pathogenesis: microdeletions or microduplications of chromosome segments
examples:
- DiGeorge 22q11
- WAGR syndrome 13q14.11
- PWS/Angelman syndrome
Cornelia de Lange Syndrome
incidence: 1/10,000
defect: single gene mutation in cohesion complex
- 60% gene NIPBL on chromosome 5, SMC1A, SMC3
- most sporadic
genetic testing: single gene sequencing
clinical:
- facies: short nose, long philtrum, synophrys (unibrow), arched eyebrows, long lashes, microcephaly
- physical: hirsutism, ulnar-ray defect, GORD
- IUGR, severe ID, obesity
Crouzon
assoc: advanced maternal age
clinical: tall flat forehead, proptosis, midface hypoplasis
- like Alpert’s but normal hands
DNA
4 nucleobases
purines: Adenine (A), Guanine (G)
pyrimidines: Thymine (T), Cytosine (C)
A-T: 2 hydrogen bonds
C-G: 3 hydrogen bonds
DNA>RNA>Protein
DNA to RNA (transcription) nucleus
- RNA polymerase binds promoter sequence 3’ and unwinds the helix
- DNA/RNA form H bond and DNA read 3’ to 5’
- RNA strand formed 5’ to 3’
- with bond breakage at terminator sequence
RNA to protein (translation) ER in cytoplasm
- movement 3’ to 5’ through tRNA from anti-codon side to AA binding side
Duchenne Muscular Dystrophy
incidence: 1/3500
genetics: X-linked recessive Xp21 gene, BOYS
pathophysiology:
- mutation in gene dystrophin
- excess Ca penetrates sarcolemma causing rupture, oxidative stress, cell death, necrosis
clinical:
- onset symptoms age 2-3years
- progressive proximal muscle weakness of legs/pelvis (Gower’s sugn)
- spreads to arms/neck
- early pseudohypertrophy, low endurance, difficulty standing/stairs
- LATER: cardiomyopathy, dysaarhythmias, scoliosis, respiratory disorders
prognosis:
- wheelchair dependent age 12
- life expectancy 25
diagnosis:
- CK, EMG, genetics, muscle biopsy
treatment: steroids, beta2agonists
Ehler danlos syndrome
incidence: 1/20,000
genetics: most AD type-V collagen via gene COL5A1/COL5A2/COL1A1
- also mutations in other fibrous proteins and enzymes
pathophysiology: altered structure, production, or processing of collagen/proteins
clinical:
- msk: hyperflexible joints, thoracic outlet syndrome, tearing tendons/muscle, myalgia, scoliosis
- skin: fragile, livedo reticularis
- CVS: arterial rupture, MVP, dilated aorta, Raynaud’s, cardiac conduction disorders
- hiatus hernia, GORD, anal prolapse
Epigenetics
definition: how the DNA is read and manifested
gene regulation:
- histone modification: alters DNA conformation/transcription
- DNA methylation: can silence promotors
- non coding RNA: mediate gene regulation
Fanconi anaemia
incidence: 1/130,000, Ashkenazi Jews
defect: AR mutations in both copies of DNA repair genes (17 FA genes)
pathophysiology: defect in proteins responsible for DNA repair
clinical:
- physical: congenital defects (75%), microcephaly, short, hypo/hyperpigmentation (CAL, freckles), radial ray abnormalities
- organs: renal anomalies, GI atresia, BM failure (1st decade, pancytopaenia, 90%)
- cognitive: DD
- endocrine issues 75%
Fetal alcohol syndrome
clinical:
Face: short palpebral fissues, flat philtrum, thin upper lip
Abnormal learning: jittery infants, learning disability, DD, seizures
Short: IUGR, microcephaly, short stature
criteria for diagnosis:
- all 3 facial abnormalities + growth deficit + CNS abnormality
FISH
method: fluorescent probes to bind parts of chromosome
use: specific for chromosome or region
eg. Cri Du Chat
benefits: fast
Fragile X syndrome
defect: expansion of CGG trinucleotide repeat affecting the FMR1 gene on X chromosome
genetic test: size triplet repeat (PCR/southern blot)
pathophysiology: reduced function FMR protein
premutation allele: 55-200 repeats
- late onset tremor/ataxia, learning difficulties, social anxiety
- females 21% have early menopause
full mutation: >200 repeats
- facies: long face, large ears, strabismus
- physical: high palate, hyperextensible joints, flat feet, hypotonia, macroorchidism
- cognitive: ID mild to severe, ADHD (most), >50% autism
* females with full mutation can have a full or milder phenotype
Genetic causes miscarriage
parental karyotype: inversions, translocations
coagulopathies: antiphospholipid sx/thrombophilia
endocrine issues: DM, thyroid
gynae: PCOS, uterine abnormalities
Genetic variations
point mutation: need gene sequencing
insertions/deletions: one or more nucleotides
DNA sequence variation: affects single base
silent mutation: change in base with no change AA
nonsense mutation: substitution that changes codon for AA to stop codon
missense mutation: substitution changes codon for one AA to another AA
splice site mutation: region between intron/exon, alters normal pre mRNA splicing (intron retention)
regulatory polymorphism: substitution alters binding affinity of transcript related proteins and protein production
Genomic imprinting
definition: differential expression of genetic information depending on maternal or paternal inheritance
examples:
- PWS/Angelman’s
Goldenhar
(oculo-auriculo-vertebral dysplasia)
defect: sporadic cause unknown
pathophysiology: 1st/2nd branchial arch maldevelopment
clinical:
- hemifacial microsomia
- confuctive deafness
- visual field defect
- vertebral defects
Homocystinuria
defect: AR single gene mutation in CBS gene
pathophysiology: cystathione beta synthase deficiency
- inability to convert homocysteine to cystathionine
- homocysteine accumulates damaging, CT/muscles/CNS
test: plasma total homocysteine
clinical: tall, stiff, ID, ectopia lentis (downwards), myopia
treatment: methionine restricted diet, folate/B12 supplementation
complications: thrombi, CVA, seizures
Hunter syndrome
genetics: XLR (only one that only affects males)
incidence: RARE, 2000 worldwide
pathophysiology: mucopolycsaccharidosis II
- lysosomal storage disease caused by deficient enzyme iduronate-2-sulfatase
- accumulation of substrated heparan sulfate and dermatan sulfate
clinical: macrocephaly, DD, short, abnormal skeletal development, hepatosplenomegally, inguinal hernia, NO CORNEAL OPACITY
Huntington’s disease
genetics: Huntingtin gene (HTT) chromosome 4
- encoding protein Huntingtin (HTT)
- gene contains trinucleotide repeat (CAG) usually <36 copies
- 36-39 reduced penetrance, 40+ full penetrance
inheritance: autosomal dominant
- new expansions as CAG repeats 28+ are unstable
- increases in repeat no. cause anticipation
clinical: onset 35 to 44 years
- personality: anxiety, depression, blunted affect, aggression
- cognition: executive function, memory
- physical: chorea
Hurler syndrome
definition: MPS-1 lysosomal storage disease (most severe)
genetics: AR
defect: genes encoding lysosomal enzymes needed to degrade glycosaminoglycans (GAG) (formerly iknown as mucopolysaccharides) causing accummulation in cells, blood, CT
clinical:severe, progressive mental/physical decline with death by 10 yrs
- onset 6-24 mths with characteristic features
- coarse facial features,large tongue, prominent forehead, short stature
- corneal clouding, hearing loss
- -* hepatosplenomegaly, cardiomyopathy
- skeletal dysplasia: dysostosis multiplex, joint stiffness
diagnosis: radiographs, urinary GAG excretion, enzyme assays
treatment: BMT, enzyme replacement.
Imprinting
definition: genetic phenomenon occurs in SOME chromosomes
method: genes marked as maternal/paternal origin
- eg. DNA methylation (turns off), histone modifications
- some genes behave differently if they’re from mother/father
imprinted chromosomes: 7, 11, 15
imprinting disorders: PWS, Angelman, BWS, RSS
methylation studies: look methylation profile maternal/paternal genes
Jervell and Lange-Nielsen syndrome
genetics: AR
- mutations in KCNE1 and KCNQ1 genes which form potassium channels
incidence: 1/1 million
clinical: bilateral SNHL, long QT
Kabuki syndrome
incidence: 1/32,000
defect: AD loss of function mutation KMT2D chromosome 12
clinical:
- facies: wide eyes, arched interrupted eyebrows, broad nose, cleft/high arched palate, large/low ears
- physical: hearing loss, short stature, short fingers, loose joints
- cognitive: ID
Kallmann syndrome
incidence: 1:10,000 M>F
gene: chromosome X KAL1 gene
clinical:
- GnRH deficiency/gonadotropin deficiency
- failure of puberty
- hypogonadism
- disorders of olfaction
- cleft palate
- skeletal defects
- renal issues
Karyotype
method: direct visualisation chromosomes
use: large changes, translocations
Key genetic terms
aneuploidy: abnormal no. of chromosomes within a cell
compound heterozygote: 2 mutations same gene leading AR phenotype
epigenetic change: alteration of phenotype w/o changing genotype
epistasis: gene/gene interaction producing different phenotype
euploidy: multiple of the monoploid no.
expressivity: variable phenotype individuals same genotype
linkage: tendency of genes close to be inherited together
polymorphism: genetic region more than one allele present >1% (mutation is
47XXY
Klinefelter syndrome
incidence: 1:1,000
genetics: non dysjunction sex chromosomes in meiosis (47 XXY), 20% mosaicism
genetic test: karyotype, microarray
clinical:
- physical: weak, tall, poor coordination, less hair, small genitals, breast growth
- cognitive: low IQ, impulsive, poor attention/judgement/insight
- fertility: primary gonadal failure (normal age onset of puberty but no secondary sexual changes), less interest in sex
investigations: high FSH/LH, low testosterone (testosterone may be normal to mid-puberty)
comorbidities: breast cancer
treatment: androgen treatment age 11-12, aromatase inhibitors for gynaecomastia
LEOPARD syndrome
genetics: 2 genes PTPN11 and RAF1
clinical: Noonan syndrome with multiple lentigines
Lentigines: reddish/brown macules to skin (80%)
ECG abnormalities ie axis devations, hypertrophy, conduction defects, BBB
Ocular hypertelorism
Pulmonary stenosis
Abnormal genitals
Retarded growth
Deafness (SNHL)
Lesch-Nyhan Disease
deficiency hypoxanthine-guanine phosphoribosyltransferase (enzyme brain)
HPRT gene
increased purine synthesis
X-linked
1:200,000
normal at birth but hypotonia, vomiting
hyperuricaemia, ID, dystonic movements, choreoathetosis, dysarthric speech, self-biting
MRI: reduced size basal ganglia
treat allopurinol, dental extraction
Marfans syndrome
incidence: 1/5,000
genetics: AD single gene mutation of FBN1 on chromosome 15q21.1 encoding fibrillin-1 (glycoprotein in ECM)
- 25% sporadic
clinical:
- cardiac: aortic root disease (dilation, aortic regurg, dissection), MVP
- eyes: ectopic lens (up and outwards) 80%, myopia
- msk: tall/thin, hypermobile joints (Steinberg thumb sign/Walker-Murdoch wrist sign), decreased elbow extension, arachnodactyly, pectus deformity, scoliosis, decreased upper/lower ratio, ductal ectasia, hindfoot valgus
- skin: striae
NORMAL IQ
ghent criteria positive if:
- ARD + ectopia lentis
- ARD + FBN1
- ARD + systemic score >7
(in absence of FHx)
treatment: beta blockers/ARBs (slow aortic dilatation)
McCune Albright Syndrome
genetics: somatic mutation ch 20
- G protein mutation stimulated cAMP forming oncoprotein causing gland hyperfunction
DIAGNOSIS (2 of 3):
- Cafe au lait spots (Coast of Maine)
- rarely cross midline - Peripheral precocious puberty
- Polyostotic fibrous dysplasia
also: hypophosphatemic rickets, GH excess, Cushing’s thyrotoxicosis, arrhythmias, cholestasis
McKusick-Kaufman syndrome
genetics: autosomal recessive, MKKS gene mutation
population: Amish
clinical: polydactyly, cardiac abnormalities, GU issues
- similiar to Bardet-Biedel but no visual loss of MR
Menke kinky hair disease
inheritance: X-linked recessive
gene: chromosome Xp13 ATP7A gene
defect: error copper transporting ATPase protein
clinical:
- progressive neurodegeneration/severe MR
- seizures, hypotonia, feeding difficulties, optic atrophy
- colourless hair, kinky, fragile
- chubby red cheeks
- death <3yrs
investigations:
- hair shaft: trichorrhexis nodosa, pili torti, monilethrix
- serum: copper/caerulosplasmin low
management:
- copper-histidine subcutaneously
Microarray
method: molecular karyotype
- patients blood and control blood is labelled and mixed together
- spread across bored and discolouration if unbalanced expression of DNA region
use: 1st line investigation, detects deletion/duplications
negatives: will detect variance of unknown significant, will NOT detect balanced translocations/point mutations
Microsatellite instability
definition: short segments of repetitive DNA bases scattered throughout genome in non-coding DNA
pathophysiology: propenisity to develop changes in no. of repeats due to DNA repair errors during replication
examples: colorectal, endometrial, ovarian and gastric cancers
Mitochondrial inheritance
Mitochondria=Mother
- sperm bring very little mitochondria to embryo
- mito genome= mtDNA
- mitochondrial DNA replicates autonomously with high mutation rate
- ALL offspring mother affected
- all eggs have different degrees of mutation
Mitochondrial myopathy
genetics: maternal inheritance
pathophysiology:
- ragged red changes to muscle
clinical: muscle weakness, neurological issues, hearing loss
Mitosis
Mitosis: somatic cells
- results in 2 diploid cells
Meiosis: germline cells
- results in 4 sister gametes (haploid cells)
Moebius syndrome
incidence: 2:1,000,000
pathogenesis: underdevelopment CN VI/VII caused by distruption of blood flow in prenatal development
characteristics:
- facial paralysis
- inability to move eyes vertically or close eyes
- upper lip retraction
- limb/chest wall anomalies
Morquio syndrome
(MPS IV)
incidence: 1/200,000 most common MPS (type IV)
defect:
- type I: deficient galactosamine-6-sulfatase
- type II: deficient beta-galactosidase
pathophysiology: excess GAGs cause organ damage
clinical:
- macrocephaly
- hypermobile joints
- short stature
- abnormal development bones: scoliosis, bell-shaped chest
- coarse facies, wide spaced teeth
Mosaicism
definition: occurence of cells that differ in their genetic component from other cells in the body
germline: affecting ova/sperm
somatic: affecting cells other than germline
mixed: germline/somatic
Myotonia congenita
definition: neuromuscular channelopathy
genetics: CLCN1 gene
pathogenesis: CIC forms Cl- channel causing delayed relaxation of skeletal muscle fibers
clinical: prolonged muscle contractions mainly LL
- worse with inactivity
types: Becker (later/more severe), Thomson
Myotonic dystrophy
genetics: trinucleotide repeat disorder
DM1: DMPK gene chromosome 19 CTG repeat
DM2: ZNF9 gene on chromosome 3 CCTG repeat
inheritance: autosomal dominant
clinical:
DM1: severe congenital + milder childhood forms
- facial muscles, distal muscles forearm, respiratory failure and death
DM2: severe congenital + adult
- rarer, proximal myotonic myopathy
Neurofibromatosis 2
incidence: 1/25,000
defect: NF2 gene on Ch22q1.11
diagnosis with 1 of 4:
- Bilateral vestibular schwannomas
- 1st degree relative NF2 + uni vestibular schwannoma
OR any 2 other tumours (meningioma, schwannoma, glioma, neurofibroma, posterior subscapular lenticular opacities)
- Uni vestibular schwannomas + 2 other tumours
- Multiple meningiomas and uni vestibular schwannoma OR 2 other tumours
diagnosis: clinical
prognosis: 40% medical problem, 50% learning problem, 6% ID, 5% morbidity
Neurofibromatosis type 1
definition: tumour disorder
incidence: 1/100,000, no assoc sex/race
defect: AD mutation NF1 gene on chomosome 17 encoding neurofibromin
- 1/3 are new mutations
- 100% penetrance by 5 years
diagnosis (at least 2 of the following):
1. >5 CAL macules
- >5 mm in diameter prepubertal/>15 mm postpubertal
- 100% NF1 have CAL
2. >1 neurofibroma or 1 plexiform neurofibroma
3. freckling axillary/inguinal regions
- 80% by 6 yrs
4. >1 Lisch nodule
- 40% by 4 years, 100% adults
5. optic glioma (low grade astrocytoma)
6. distinctive bony lesion
- sphenoid dysplasia, thickening of long bone cortex, pseudoarthrosis
7. 1st degree relative with NF1
associations: macrocephaly, learning difficulties 30%, seizures 8%, scoliosis 10%, HTN, malignant malformations 3%, aqueductal stenosis, precocious puberty
investigations:
MRI: unidentified bright objects (disappear by 30 yrs)
Noonans syndrome
incidence: 1/1000, both sexes
defect: AD, 60% mutation PTPN1 chromosome 12q24.1 encoding tyrosine phosphatase SHP-2
gene testing: single gene sequencing, of PTPN11 and 11 other Noonan genes
clinical:
- cardiac: PS, LVH, HOCM 20%
- neuro: ID, DD
- haem: bleeding disorders, small risk leukaemia
- physical: downslanting palpebral fissures, hypertelorism, low set ears, webbed neck, chest wall deformity
- gonads: delayed puberty, cryptorchidism
diagnosis:
- ECG: LAD and dominant S wave over precordial leads
Northern blotting (RNA)
method: Southern blot but RNA instead of DNA
use: to determine size of mRNA/total RNA fragment produced by specific gene
Osteogenesis imperfecta
(brittle bone disease)
incidence: 1/20,000
defect: mutations COL1A1 (most) and COL1A2 encoding type 1 collagen
- most AD
genetic testing: OI gene panel or sequencing
pathophysiology:
- type I: insufficient quantity collagen, mild disease
- type II: insuffiency quality/quantity, severe/lethal perinatal period
- type III: collagen defective, progressive deformity
- type IV: decrease quality/quantity, deformed mesh like bones
clinical:
- physical: short, blue sclerae, hearing loss, fractures
- neuro: communication hydrocephalus, basilar invagination, seizures
treatment: bisphosphonate
PCR
mechanism: amplify DNA fragment between two primers
method: select DNA, increase temp to separate strands, add primer, add polymerase
use:
- selective DNA isolation eg. ecoli, paternity
- amplification/quantification DNA to analyse small amounts DNA eg. ancient DNA
- disease diagnosis eg. infections, cancer
Pendred syndrome
genetics: AR, SLC26A4 gene encoding pendrin protein chromosome 7
pathophysiology: SLC26A4 in the cochlea, thyroid, kidney and participate in the excretion of bicarbonate
clinical: congenital SNHL, goitre 75% (euthyroid/hypothyroid)
Peutz-Jegher syndrome
incidence: 1/25,000
genetics: AD STK11 gene
clinical:
- hyperpigmented macules to lips/oral mucosa (melanosis)
- GI hamartomatous polyps
- bowel obstruction due to intussusception age 6-18yrs
- 70% cancer: colorectal, stomach, small bowel, pancreas
management:
- bowel radiography every 2 yrs
- colonoscopy every 2 years
- CT/MRI pancreas yearly
Pfeiffer syndrome
clinical: midface hypoplasia, broad thumbs, variable syndactyly, proptosis
types:
- type 1: mildest, normal IQ
- type 2: clover leaf skull, severe proptosis
- type 3: as for 2 without clover head
Pierre Robin Sequence
NOT A SYNDROME
pathogenesis: underdevelopmet of jaw causes abnormal placement of tongue causing cleft palate and resp obstruction
clinical: micrognathia, airway obstruction, CP
association: Stickler syndrome is the commonest associated syndrome
- cleft palate, bifid uvula, ocular defects, HF hearing loss, muskuloskeletal issues (scoliosis, femoral head failure, OA)
Pleiotropy
definition: multiple phenotypes caused by single mutation
Polygenic inheritence
definition: disease results from combination of multiple genes
examples: most non pathological eg. eye colour, height
different sex threshold: risk of disease different between sex
eg. if mother CAD higher risk in children than father, if mother pyloric stenosis then lower risk
Prader Willi Syndrome
incidence: 1:10,000
defect: 15q11-q13 encoding SNRPN/necdin genes
- deletion paternal sequence (20% uniparental) (maternal copy imprinted)
- 99% sporadic
genetic test: methylation testing 15q
clinical:
- triad H2O: hypotonia, hyperphagia, obesity
- facies: almond eyes, strabismus, thin upper lip
- physical acromicria (small hands/feet), obesity, insatiable appetite (high ghrelin), hypogonadism, undescended testes, hypopigmentation
- cognitive: developmental delay, mild ID, psych issues
treatment: GH injections
Prenatal diagnosis
CVS: from 11 weeks, placenta sampling, MS 1/100
Amnio: from 15 wks, amniotic fluid, MC 1/200
PGD: DNA extraction embryo and mutation detection testing
Non-invasive prenatal testing: FISH for common variations
Proteus syndrome
genetic: very rare, unknown mutation
clinical: overgrowth skin, bones, muscle, fatty tissues, blood, lymphatics
- tumours of skin, bone, ovaries, testical, meningioma, parotid glands as they age
Refsum disease
genetics: AR
pathophysiology: peroxisomal disorder with impaired alpha oxidation of branched chain FAs resulting in buildup of phytanic acid in tissues
- caused by PHYH mutations
clinical: onset in childhood/adolescence
- neurological damage: cerebellar dysfunction, PN
Repeat disorders
big repeats: worse from mother (eg. MD)
small repeats: worse from father (HD)
characteristics: unstable between generations, assoc anticipation, repeat size doesn’t accurately predict phenotype
triplet repeat disorders: Frederich ataxia, MD, Fragile X, HD
Retinitis Pigmentosa
etiology: syndromic or non-syndromic (1/4000)
genetics: most inheretic forms of retinal degeneration
- multiple genes and inheritance
syndromes: Usher (deafness), Kearns-Sayre (opthalmoplegia, dysphagia, ataxia), abetalipoproteinaemia (retardation, PN, ataxia, stearorrhoea), Bardet Biedel (DD, hypogonadism)
pathophysiology: progressive degeneration of the rod photoreceptor in the retina
clinical: onset infancy to adulthood
- tunnel vision eventually extending into central field, night blindness (nyctalopia), and accumulation of bone spicules in the fundus
mRNA Structure
5’ upstream, 3’ downstream
Exons: sense portion (Essential)
Introns: non-sense portions that need to be removed pre-translation by slicing (Idiots)
Codons: 3 units in mRNA encode specific AAs
- 3 stop/start codons, 61 AA codons (only 20 AAs)
RNA- 3 types
mRNA (messenger): mirror image of DNA with uracil instead of thiamine
tRNA (transfer): brings AA back to ribosomes
rRNA (ribosomal): make up the ribosome with enzymes
Rubenstein-Taybi syndrome
genetics: microdeletion syndrome in 16p13.3 encoding the CREBBP gene
clinical:
- short, ID, short/broad thumbs, hairy, cryptoorchodism
- facies: beaked nose, high palate, downward palpebral fissues, broad nasal bridge
*risk with anaesthesia
Russel Silver syndrome
incidence: 1/50,000
defect: 11p methylation defect resulting in decrease IGF-2 production
genetic test: methylation testing 11p
clinical:
- neonatal: SGA, feeding issues, hypoglycaemia, wide/late closing fontanelle, GORD
- physical: macrocephaly, triangle face, cafe au laie spots, blue sclerae, clinodactyly, body asymmetry, precocious puberty, low subcutaneous fat
- NORMAL IQ
treatment: growth hormone
Sex expression
(non-mendelian inheritance)
- some genes expressed only in 1 sex
eg. male pattern baldness
Sialidosis
genetic: AR, mutation in gene chromosome 10 encoding neuroaminidase
pathogenesis: deficiency of neuraminidase causing accumulation of oligosaccharides; storage in liver, BM, brain
clinical:
type I: presents 2nd decade with myoclonus and cherry red spots
type II: congenital/ infantile/ juvenile
- congenital: hydrops, ascites, HSM, stippling epiphyses, periosteal cloaking, stillbirth
- infantile: dysostosi multiplex, moderate MR, visceromegaly, corneal clouding, cherry red spot, seizures
- juvenille: edema, ascites, skeletal dysplasia, cherry red spot, dysostosis multiplex, visceromegaly, MR, dysmorphism, corneal clouding, neurological impairment, cherry red spots
Smith Lemli Optiz
defect: AR mutation in DHCR7 causing inborn error of cholesterol synthesis
clinical:
- facies: low/rotated ears, cleft lip/palate
- physical: cerebellar hypoplasia, agenesis CC, polydactyly hands/feet, short thumb, syndactyly 1/2 toes, ambiguous genitals
- CHD, renal/pulmonary/eye abnormalities
Sotos syndrome
aka cerebral giantism
defect: NSD1 gene mutation (95% sporadic)
clinical:
- facies: high hairline, high bossed forehead, long face, pointed chin
- physical: overgrowth prenatal/postnatal, advanced bone age, hypotonia, premature tooth eruption
- cardiac: PDA, ASD
- cognitive: mild-severe ID
investigations:
- MRI: dilated ventricles, cortical atrophy, abnormal corpus callosum
Southern blotting DNA
method: transfer of electrophoresis separated DNA fragments to a filter membrane and subsequent fragment detection by probe hybridization
use: linkage to a DNA polymorphism
Old method uncommon now
Spinal Muscular Atrophy
genetics: AR, gene SMN1
clinical: wasting or proximal muscles and lung
- progressive muscular wasting and mobility issues
Stickler syndrome
genetics: AD, COL2A1 gene
pathophysiology: subtype of collagenopathy affecting type II and XI
clinical:
- flattened facial appearance
- ocular: high myopia, retinal detachment, glaucoma
- hearing loss
- joint problems: hypermobile, arthritis
Tay-Sachs
definition: lysosomal enzyme disorder
incidence: AR, 1:25 carrier in Ashkenazi jews
pathophysiology: mutation in HEXA gene Ch15 encodes hexoaminidase A a lysosomal enzyme
clinical:
- initially normal development
- hypotonia by 4-6 months
- rapid regression by age 1 with spasticity/paralysis/MR/seizures
- progressive blindness/deafness
- macrocephaly
- death by 5 yrs
diagnosis: decreased B-hexosaminidase A activity
Translocations
unbalanced: a trisomy with the extra chromosome attached to a difference chromosone
balanced: disomy but 1 of the chromosomes stuck to another chromosome (normal phenotype)
robertsonian translocation: balanced translocation between short arms (p)
- chromosomes 13, 14, 15, 21, 22 have very short p arms that only code ribosomal RNA
- short arms break away and attach another chromosome and long arms fuse
- results in 45 instead of 46 chromosomes
- risk of unbalanced translocation in an offspring
insertional translocation: integration of donor segment into another chromosome
reciprocal translocations: non-homologous chromosomes swap parts
inversions: 2 breaks with segment flipped
- normal phenotype but can mave miscarriages
Treacher-Collins
incidence: 1/50,000
defect: AD single gene disorder in TCOF1
clinical:
- facies: mandibulofacial dysostosis, sloping eyes, lower eyelid coloboma, malar hypoplasia, microtia
- conductive hearing loss
Triplet repeat sequences
definition: repeated sequence expands in successive generations leadomg tp abnormal phenotypes
examples: myotonic dystrophy, huntington’s disease
Trisomy 13
Patau syndrome
defect: 3 copies of chromosome 13
- usually nondysjunction and rarely translocation
genetic test: karyotype, microarray, FISH
clinical: holoprosencephaly, cleft lip/palate, heart abnormalities, scalp defect, ID
prognosis: mean survival 10 days
- 80% die by 3 months and 92% by 1 yr
NOT LETHAL BUT HIGH MORBIDITY/MORTALITY
Trisomy 18
Edward’s syndrome
defect: 3 copies chromosome 18 mostly nondysjunction
genetic test: karyotype, microarray, FISH
clinical: IUGR, wizened appearance, prominent occiput, overlapping fingers, rockerbottom feet, multiple malformations
prognosis: FDIU, death in first year most common
- mean survival 14 days
- 80% die by 3 months, 92% by 1 year
Trisomy 21
Down syndrome
defect: 3 copies chromosome 21
- dysjunction (95%), translocation (4%), mosaic (1%)
genetic test: karyotype, microarray, FISH
clinical:
- facies: upslanting palpebral fissures, epicanthal folds, flat nasal bridge, brachycephalic head, small mouth, large tongue
- CHD (50%): TOF, AVSD, PDA
- GI: duodenal atresia (12%), hirschsprungs (<1%)
- hypothyroid: congenital (1%), lifetime (15%)
- deafness (75%), visual problems (60%)
- OSA (50-75%)
other: low IQ, AML, atlanto-axial instability, dementia, sandle gap
Tuberous sclerosis
“Zits, Fits + Deficits”
incidence: 1/6,000
genetics: AD mutation TSC1/TSC2 encoding hamartin/tuberin that form tumour suppressor complex
- 2/3 sporadic
clinical: CNS involvement is the hallmark
diagnosis: 2 major or 1 major and 2 minor criteria
(see table)
others: seizures (20% of infantile spasms), autism, behavioural issues, low IQ, increased malginancy (RCC, giant cell astrocytoma), lymphangiomyomatosis
45XO
Turners Syndrome
incidence: 1:5,000 (only 8% live births)
genetics: 45, X (50% mosaic)
- maternal X retained in 66% SHOX
clinical:
- physical: short stature, shield chest, wide spaced nipples, wide carrying angle, high arched palate, hearing problems
- eyes: amblyopia/strabismus/ptosis/hypertelorism
- CHD (30%): bicuspid aortic valve 15%, coarctation of the aorta 10%, aortic dissection, HTN
- renal anomalies (50%): kidney dysplasia (horseshoe, abnormal vasc supply, uteropelvic obstruction)
- fertility: amenorrhoea (30% enter puberty spontaneously), gonadal failure (infertile), gonadoblastoma, osteoporosis
- AI: hypothyroidism (30%), ceoliac (10%), IBD), insulin resistance
treatment: GH injections, hormone replacements age 12
prognosis: mortality x3 normal pop
VACTERL
incidence: 1/40,000
- associated maternal DM but usually sporadic
cause: unknown, not syndrome but association
clinical:
Vertebral defects: small hypoplastic vertebrae/hemivertebrae
Anal atresia 55%: atresia or imperforate anus
Cardiac defects 75%: VSD/ASD/TOF
Tracheooesophageal fistula 70%
Esophageal atresia
Renal 50%/Radial abnormalities
Limb defects 70%: hypoplastic thumb, polydactyly, syndactyly, radial aplasia
22q11 deletions
incidence: 1/4000
gene: AD 22q11.2 deletion (most common microdeletion syndrome involving 3 megabases of DNA with 30 genes)
AKA: DiGeorge syndrome, velocardiofacial syndrome
genetic test: FISH, microarray
pathophysiology: abnormal development 3rd and 4th branchial arches
clinical:‘CATCH’
Cardiac 40%: conotruncal/aortic arch defects
- interrupted AA, truncus arteriosus (34%), TOF, VSD
Abnormal facies: low set/rotated ears, hypertelorism, high nasal bridge, micrognathia, short upward palpebral fissues
Thymic aplasia: variable level of T cell dysfunction, only 1% SCID
Cleft palate 50%: full or submucosal cleft, NO LIP
Hypocalcaemia/hypoparathyroidism: abnormal PT gland formation
ALSO: seizures, psychosis (60%), autism (20%), renal anomalies, ID (30%), learning difficulties (70%), hearing loss, facies (tubulara nose, large ears, small mouth)
Waardenburg Syndrome
incidence: 1/50,000
genetics: AD, sporadic, mutations in variable genes
variance: types I-V
characteristics:
- deafness
- pigmentation anomalies: heterchromia, poliosis, patches hypopigmenation
- defects of structures from neural crest: telecanthus, cleft lip/palate, spinal defects, hirschsprung’s
WAGR Syndrome
Wilm’s tumour
Aniridia
Genitourinary abnormalities
Retardation
Western blot (protein)
method: protein from cell extract separated by gel electrophoresis, placed on membrane, washed with Ab to protein, then washed 2nd Ab with dye
use: obtain information about size/amount of mutant protein of particular disorders
Williams syndrome
incidence: 1/20,000
defect: heterozygous microdeletion on 7 due to misalignment in meiosis
genetic test: microarray, FISH
clinical:
facial features: widely spaced teeth, long philtrum, flattened nasal bridge, stellate eyes, puffy eyes
physical: short stature, developmental delay
cardiac: supravalvular aortic stenosis
endocrine: hypercalcaemia, hypothyroidism
gastic: colic, diverticulitis
neuro: low IQ, very talkative, social disinhibition, attention problems
behavioural: noctural enuresis
Wiskott-Aldrich Syndrome
incidence: rare X-linked WASp gene, 1:25000
clinical: eczema, thrombocytopaenia, immune deficiency, blood diarrhoea,
investigations: low IgM, normal IgE/IgA, high IgG
treatment: avoid NSAIDs, BMT
X chromosome disorders
Rett syndrome
- deletion methyl-CpG-binding protein 2 (MeCP2)
- lethal to males inutero
- female: normal development/HC then regression
Fragile X
- CGG repeat in FMR-1 gene
- males more severe
- clinical: autism, MR, long face, protruding jaw, big ears
Menke Kinky Hair disease
- copper transporting ATPase gene
- defective copper absorption
- clinical: neurodegeneration 1st months, seizures, rosy cheeks, kinky hair
Adrenoleucodystrophy
- ABCD-1 gene: prevents transport VLCFA into peroxisomes
- clinical: 4-8 yrs, learning difficulties, behaviour issues, neurological degeneration
Duchenne muscular dystrophy
- Xp21 deletion: dystrophin gene (1% X chromosome)
- 1/3 sporadic
- clinical: boys, onset 18m, weakness, cardiomyopathy, resp muscle weakness, contractures, scoliosis, MR
X-linked
Recessive
- Fragile X
- Haemophilia
- DMD/BMD
Dominant
- Incontinentia Pigmenti
XYY syndrome
genetics: aneuploidy of sex chromosomes due to error in separation during anaphase II meiosis ie nondysjunction
clinical: increase growth velocity, increase height, normal sex development/fertility, 50% learning disability/speech + language delay
investigations: normal testosterone
Zellweger syndrome
defect: AR defect in protein require for assembly of peroxisomes (PEX genes)
pathophysiology: reduced function peroxisomes and accumulation of VLCFAs normally degrades in peroxisomes
clinical: hypotonia, tall forehead, midface hypoplasia, hepatomegally, eye abnormalities, renal cysts
investigations: abnormal MRI, elevated VLCFAs
prognosis: fatal by 12 months
Associations Retinitis Pigmentosa
- Usher syndrome: hearing then RP
- Bardet Biedel: polydactyly, obesity, renal, MR
- Nephronopthisis
Leri-Weill dyschondrosteosis
clinical:
- mesomelic shortening
- curved radius/ulna (Madelung deformity)
- short 4th MC
- muscular hypertrophy
genetic: AD SHOX gene mutation
Rett syndrome
genetics: 1:20,000, X linked dominant gene MeCP2
- fatal in males
clinical: onset 5-48 months
- decreased head growth
- loss of purposeful hand skills and social interests
- stereotyped hand movements
- gait disorder
- seizures
Usher syndrome
incidence: 1/100,000
genetics: AR 11 genes
clinical: retinitis pigmentosa, SNHL
