Genetics Flashcards
Penetrance
Proportion of individuals with mutation who develop disease
Most diseases have incomplete penetrance
Incomplete penetrance may be due to genetic modifiers
Penetrance can be age-dependent
Variable Expressivity
Same gene associated with range of phenotypic severity
Expressivity may be age-dependent
Variable expressivity may be due to genetic modifiers
Example: Neurofibromatosis type 1 can be associated with range of disease severity from very mild to severe
Pleiotropy
Same gene/mutation can cause multiple different phenotypes
Locus heterogeneity
Many different genes can cause the same disease
Related term is allelic heterogeneity, referring to different mutations in same gene causing same disease
Imprinting
Mutation causes disease dependent on parent-of-origin
Sometimes will skip generations
Paternal imprinting: Paternal copy of gene is normally imprinted or silenced. Mutation must be inherited from mother to cause disease. Example: Angelman syndrome (can be 2/2 maternal uniparental disomy)
Maternal imprinting Maternal copy of gene is normally imprinted or silenced. Mutation must be inherited from father to cause disease. Example: Prader Willi syndrome (can be 2/2 paternal uniparental disomy)
Polygenic
1000s of genetic variants in the genome each contribute a small amount to disease risk
Often have strong environmental component
Typically won’t show classic Mendelian inheritance patterns
Example: Late onset Alzheimer’s disease
De novo
New mutations that arise in an individual•No family history
Severe, autosomal dominant disorders that are highly penetrant generally are de novo
Mitochondrial inheritance
Mutations in the mitochondrial genome
Are transmitted from mother to child
Demonstrate heteroplasmy: variable proportions of mitochondria carry mutation among cells
There are also mitochondrial genes encoded in the nuclear genome which don’t follow this pattern
Example: MT-TL1 mutations causing MELAS
Testing for structural variants
Karotype: Aneuplodies, major chsmal rearrangements
FISH: Tests for specific submicroscopic chsmal rearrangements, dels, and dups
Comparative genomic hybridization (CGH): Test for copy number variants via flurophobes
Chromosal microarray: Test for copy number variants by looking for regions with more or less DNA content than expected
Testing for SNPs
Whole genome sequencing
Whole exome sequencing
Gene panels
Genetic testing for repeat expansions
MC via Southern blot
Usually need to order a specialized test for a given repeat expansion
Genetic testing for mitochondrial DNA
- Specialized next generation sequencing methods to identify mtDNA
- Often done from biopsied tissues (e.g., muscle)
- Note that nuclear-encoded mitochondrial genes are detected by other methods
Fragile X syndrome
ID
XLR
Due to CGG repeat in FMR1
Normal: 6-55 repeats
Premutation and FXAS: 55-200
Fragile X when repeat length>200
MOA: Repeat expansion leads to epigenetic changes locally and altered FMR1expression.
Fragile X-associated tremor/ataxia syndrome (FXTAS)
ID
Presents in males (and sometimes females) in late-life (after age 50)
Tremor resembling essential tremor
Cerebellar Ataxia +/- cognitive and parkinsonian features
About ¼ of female carriers have premature ovarian failure.
Due to CGG repeat in FMR1 in the “premutation” range of 55-200
FXTAS imaging findings
Smith-Lemli-Opitz syndrome
ID
DHCR7 mutations (AR)->Deficiency of the enzyme 7-dehydroxycholesterol reductase -> altered cholesterol synthesis
ID, behavioral issues (self-injurious behavior), autism
Microcephaly, facial dysmorphism: ptosis, micrognathia, temporal narrowing, cleft palate, epicanthal folds
Growth retardation
Rett Syndrome
ID
XLD, MECP2 gene
Normal development from 0-6 months -> head growth deceleration at 3 mo-4yo ->Developmental regression ~1-4 yo: loss of purposeful hand movements and speech, social withdrawal, stereotypic hand movements (“washing” or “wringing”), gait dyspraxia, epilepsy
Prader-Willi syndrome
ID
Occurs in the setting of maternal imprinting where maternal copy of gene/chsm 15 is silenced
Can be 2/2 deletion of paternal arm of chsm 15, maternal isodisomy, imprinting defect. All can be detected via genetic methylation studies.
Clinical features: Neonatal hypotonia, hyperphagia, rapid eight gain, hypogonadism, developmental delay
Angelman syndrome
Occurs in the setting of paternal imprinting, where paternal copy of gene is slence
Can be 2/2 deletion of maternal arm of chr15, paternal isodisomy, mutation is UBE3A, impriting defect
Clinical features: Developmental delay, movement disorder (gait ataxia, tremor), behavioral abnormalities: frequent laughing, smiling, hand flapping, little or no spoken language, seizures
Familial hemiplegic migraines
Channelopathy
Genetics: Can be familial or sporadic. Most often mutations in ATP1A2 or CACNA1A, less commonly SCN1A (also implicated in Dravet)
Episodic Ataxia Type 1
Channelopathy
Due to mutations in KCNA1 (AD)
Episodic Ataxia Type 2
Channelopathy
Due to mutations in CACNA1A (AD)
50% of patients with EA2 have hemiplegic migraine
Hyperkalemic periodic paralysis
Channelopathy
SCN4A (AD) mutations are most common
Hypokalemic periodic paralysis
Channelopathy
CACNA1S or SCN4A mutations, typically AD
Myotonia congenita
Mutations in CLCN1 (AD)
Paramyotonia congenita
Mutations in SCN4A (AD)
Huntington’s disease
Trinucleotide repeat
AD with variable penetrance
Due to CAG repeat expansion in HTT: < 28 repeats is normal, 28-35: no symptoms but the next generation is at small risk to develop expansion into disease-causing range, 36-39 are incompletely penetrant with later age of onset, >40 is fully penetrant
Age of onset ranges from childhood to the eighth decade, but most common in mid-life.
Presymptomatic testing only after extensive counseling of an at-risk patient (i.e., positive family history)
Westphal variant - occurs in adolescence, usually inherited from father
Spinobulbar muscular atrophy (Kennedy’s disease)
Trinucleotide repeat
CAG repeat in androgen receptor; X-linked recessive
X-linked motor neuron disease with slower progression than ALS -> weakness and atrophy affecting facial, bulbar, and limb muscles.Often mild signs of feminization (gynecomastia, reduced fertility, testicular atrophy)
Usual onset of symptoms 20-30 Important to consider in younger males with signs of motor neuron disease.
Spinocerebellar ataxias
Trinucleotide repeaet
AD inheritance
1,2,3,6, and 7 are CAG expansions
1,2,3,6 are MC
6 due to CAG expansion in CACNA1A
Spinocerebellar ataxia type 3 (Machado-Joseph disease)
Trinucleotide repeat
CAG repeat in ATXN3 (AD)
Friedreich ataxia
Trinucleotide repeat
Autosomal recessive GAA repeat in FXN (sometimes referred to as FRDA gene)
Involved in regulating mitochondrial iron content
Spinal muscular atrophy
Biallelic deletions or mutations in SMN1 (AR)
Mutation in SMN2 can lead to variable production of functional SMN2 protein that can compensate for SMN1 loss
CMT1
Majority are due to duplication of PMP22 - AD
Other genes: MPZ, LITAF, ERG2, NEFL
Hereditary neuropathy with pressure palsies (HNPP)
Due to PMP22 deletions and point mutations - AD
CMT2
Most commonly due to MFN2 mutations (AD or AR)
Hereditary spastic paraplegia
Due to length-dependent degeneration of corticospinal tract axons
Can be AD, AR, or XLR
Multiple genes implicated
Parkinson’s disease
Sporadic Parkinson’s disease is polygenic; lots of genes each with small effect size
Several familial forms of PD:
- PARK1: SNCA mutations (AD), relatively early onset with rapid progression
- PARK2: PRKN mutations (AR), early onset with slow progression
- PARK8: LRRK2 mutations (AD): middle to late typical PD
- PARK14: PLA2G6 mutations (AR); early onset with rapid progression and cerebral atrophy
Early onset generalized dystonia (DYT1)
AD mutations in TOR1A
Adolescent-onset mixed dystonia (DYT6)
AD mutations in THAP1
Myoclonus-dystonia
Mutations in SGCE (maternally imprinted)
Paroxysmal kinesigenic dyskinesia (PKD)
Episodic choreoathetosis and dystonia brought on by voluntary movement.
Lasts less than one minute
Due to PRRT2 mutations (AD)
Paroxysmal nonkinesigenic dyskinesia (PNKD)
Spontaneous episodes of dystonia and/or choreoathetosis not triggered by exercise or activity.
May be precipitated by alcohol, coffee, tea, fatigue, stress, or excitement
Episodes last minutes to hours
Due to PNKD mutations (AD)
Paroxysmal exertion-induced dyskinesia
Dyskinesia and dystonia induced by prolonged exertion, fasting and stress.
GLUT1 mutations; very rare - genetically heterogeneous but seen to be AD in familial cases
Dopa-responsive dystonia (Segawa)
Due to mutations in GCH1 (AR)
Ataxia telangiectasia
Due to mutations in ATM tumor suppressor gene (AD)
Ataxia with oculomotor apraxia (AOA)
Autosomal recessive ataxias that generally present early
Cerebellar ataxia with oculomotor apraxia, chorea, facial/limb dystonia, sensorimotor polyneuropathy, and cognitive impairment
AOA1 is due to APTX mutations - AR
AOA2 is due to SETX mutations - AR
Autosomal recessive cerebellar ataxia
Type 1:Due to SCAR8 or SYNE1 mutations - AR
Type 2: Due to ANO10 mutations - AR
CANVAS
Cerebellar ataxia, neuropathy, and vestibulopathy
Due to RFC1 mutations (AR)
Hereditary vitamin E deficiency
Due to one of a few entities: 1) Ataxia with isolated vitamin E deficiency (AVED) from alpha tocopheral mutations 2) Abetalipoproteinemia (Bassen-Kornzweigdisease)
Autosomal recessive disorders with slowly progressive gait-predominant ataxia
Also can have neuropathy and cognitive dysfunction
Improved with Vitamin E supplementation
Cerebrotendinous xanthomatosis
Due to CYP27A1 mutations (AR)
Dentatorubral-pallidoluysianatrophy (DRPLA)
Due to CAG repeats in atrophin-1 (ATN1) - AD
Fabry’s disease
X-linked mutations in alpha galactosidase A - XLR (?) [Although Fabry disease was previously considered to be an X-linked recessive disorder, Wang et al. (2007) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients.]
CADASIL
NOTCH3 mutations (AD)
CARASIL
Overall similar to CADASIL, but earlier and no migraines
AR mutations in HTRA1
Retinal vasculopathy with cerebral leukodystrophy
Due to mutations in TREX1 (AD)
COL4A1- related disease
Due to mutations in COL4A1 (AD)
Early-onset cerebral small vessel disease
Presents around age 40
Diffuse leukoariosis, microbleeds, lacunar strokes
Can also get migraine with aura
ACTA2- related disease
Multisystem smooth muscle dysfunction, which can result in cerebral arteriopathy
Can present as pediatric stroke
Also thoracic aortic aneurysms, early CAD, dissections
Angiography: Arteries appear very straight
Due to mutations in ACTA2 (AD)
Von Hippel Lindau syndrome
Clinical features: Angiomatosis retinae (retinal hemangioblastoma), Hemangioblastomas of brain (cerebellar/ infratentorial) and spinal cord 20%, Endolymphatic sac tumors (causes hearing loss), Renal cell cancer (leading cause of mortality)
Mean age of onset ~25. Nearly all patients affected by age 65
AD mutations in VHL (tumor suppressor gene mediating cellular response to hypoxia)
Hereditary hemorrhagic telangiectasias (Osler Weber Rendu syndrome)
Key clinical features: Telangiectasias of the skin, mucous membranes, and internal organs, AVMs in brain/spine/meninges; ICH or SAH, Paradoxical emboli through pulmonary AVMs resulting in cerebral infarction or abscesses, Epistaxis, Visceral lesions, Headache and dizziness, Seizures
Genetics, HHT1: ENG, HHT2: ACVRL1 - Both AD and often de novo - Both involved in a TGF-β binding protein receptors important for vessel development
Alzheimer’s disease
Sporadic AD has a polygenic basis: lots of variants each with small effect
APOE is a large effect size common genetic variant: APOE4: 15x baseline risk, APOE3: baseline risk, APOE2: 40% of baseline risk
There are several forms of familial AD: Develop AD age 30-60, Account for small proportion of AD, Mutations in APP (amyloid precursor protein), Mutations in PSEN1 and PSEN2 (both involved in processing amyloid)
Frontotemporal dementia
Approximately 2/3 of cases are sporadic. No clear family history. Likely polygenic basis for these cases
Some FTD cases are more “Mendelian” - these show AD inheritance, though highly variable penetrance - C9ORF72: hexanucleotide repeat, MAPT: encodes for tau, GRN: encodes progranulin
Pantothenate-kinase associated neurodegeneration
Due to PANK2 mutations (AR)
Benign familial neonatal convulsions
Due to AD mutations in KCNQ2 or KCNQ3 (voltage-gated potassium channel)
KCNQ2 can also cause a severe infantile epileptic encephalopathy syndrome
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
Often due to nicotinic ACh receptor mutations (CHRNA2/4, CHRNB2) - AD
Autosomal Dominant Partial/Focal Epilepsy With Auditory Features
Due to LGI1 mutations (AD)
Canavan’s disease
Leukodystrophy
Due to aspartoacylase deficiency (ASPA)
AR inheritance
Aspartoacylase breaks down N-acetyl aspartate (NAA) into aspartic and acetic acid
Pelizaeus-Merzbacher disease
Leukodystrophy
Dysmyelinating disorder: X-linked recessive with alterations in proteolipid protein (PLP1)
Alexander disease
Leukodystrophy
AD mutations in glial fibrillary acidic protein (GFAP); astrocyte gene
Metachromatic leukodystrophy
Leukodystrophy
AR mutations in arylsulfatase (ARSA)
X-linked adrenoleukodystrophy
Leukodystrophy
X-linked recessive ABCD1 mutations in peroxisomal membrane protein
Krabbe globoid cell leukodystrophy
Leukodystrophy
AR mutations in GALC (galactosylceramidase, which degrades lipids during myelin turnover)
LIS1
PAFAH1B1 mutations (LIS1) (most common) - AD
DCX (most common in female SBH)
Microdeletions of 17p13.3 that include PAFAH1B1(typically causing MDS)
And many others (TUBA1A, ARX, etc)
Aicardi syndrome
XLD but unknown gene
Phenocopy
Mutations in the different genes may produce the same effect
Western blot
Protein detection using antibody for specificity
Southern blot
DNA detection using sequence for specificity
cDNA microarrays
Expression profiling on mRNA for a particular cell type/disease, used in Oncology
Type I and II repeat expansion diseases
Type I - exonic: Huntington’s disease, Kennedy’s disease, spinocerebellar ataxia (1, 2, 3, 6, 7, and 17), dentatorubro-pallidolusyian atrophy, oculopharyngeal muscular dystrophy. Mechanism of pathology: bold = polyglutamine disease, here expansion leads to sticky glutamine aggregates that disrupt cell f(x), polyalanine disease like oculopharyngeal muscular dystrophy less well-understood.
Type II - non-coding: SCA (8, 10, 12), progressive myoclonic epilepsy type I, Fragile X. Mechanism of pathology is mRNA mediated toxicity: mRNA with expanded repeat region binds to and sequesters critical nuclear proteins: splicing factors, RNA binding proteins, absence/reduction of these proteins lead to errors in processing of other mRNAs.
Parent of origin effect and exception
TNT repeat instability during meiosis, for most repeat expansion diseases, paternal transmission is more often associated with expansion. The exception is myotonic dystrophy, where massive expansions may occur with maternal transmission->congenital myoclonic dystrophy
Polyglutamine disease
Lissencephaly genetics
Holoprosencephaly genetics
Agenesis of corpus collosum
Aicardi, FG, Mowat Wilson
Polymicrogyria
Bifrontal - GPR65, AR
Schizencephaly
Bilateral or unilateral
Some familial cases, EMX2
NF type I
AD, NF1 gene on 17q11
NF type 2
AD NF2 gene on 22q12
Tuberous sclerosis
AD TSC1; 9q (hemartin)
AD, TSC2; 16p (tubarin)
VHL
AD, VHL 3p25-26
Li-Fraumeni syndrome
AD, TP53 in 17p13
Basal cell nevus
AD, PTCH in 9q22.3
