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ABPN 2022 > Genetics > Flashcards

Genetics Flashcards

1
Q

Penetrance

A

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

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2
Q

Variable Expressivity

A

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

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3
Q

Pleiotropy

A

Same gene/mutation can cause multiple different phenotypes

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4
Q

Locus heterogeneity

A

Many different genes can cause the same disease
Related term is allelic heterogeneity, referring to different mutations in same gene causing same disease

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5
Q

Imprinting

A

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)

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6
Q

Polygenic

A

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

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7
Q

De novo

A

New mutations that arise in an individual•No family history

Severe, autosomal dominant disorders that are highly penetrant generally are de novo

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8
Q

Mitochondrial inheritance

A

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

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9
Q

Testing for structural variants

A

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

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10
Q

Testing for SNPs

A

Whole genome sequencing

Whole exome sequencing

Gene panels

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11
Q

Genetic testing for repeat expansions

A

MC via Southern blot

Usually need to order a specialized test for a given repeat expansion

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12
Q

Genetic testing for mitochondrial DNA

A
  • 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
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13
Q

Fragile X syndrome

A

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.

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14
Q

Fragile X-associated tremor/ataxia syndrome (FXTAS)

A

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

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15
Q

FXTAS imaging findings

A
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16
Q

Smith-Lemli-Opitz syndrome

A

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

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17
Q

Rett Syndrome

A

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

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18
Q

Prader-Willi syndrome

A

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

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19
Q

Angelman syndrome

A

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

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20
Q

Familial hemiplegic migraines

A

Channelopathy

Genetics: Can be familial or sporadic. Most often mutations in ATP1A2 or CACNA1A, less commonly SCN1A (also implicated in Dravet)

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21
Q

Episodic Ataxia Type 1

A

Channelopathy

Due to mutations in KCNA1 (AD)

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22
Q

Episodic Ataxia Type 2

A

Channelopathy

Due to mutations in CACNA1A (AD)

50% of patients with EA2 have hemiplegic migraine

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23
Q

Hyperkalemic periodic paralysis

A

Channelopathy

SCN4A (AD) mutations are most common

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24
Q

Hypokalemic periodic paralysis

A

Channelopathy

CACNA1S or SCN4A mutations, typically AD

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25
Q

Myotonia congenita

A

Mutations in CLCN1 (AD)

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26
Q

Paramyotonia congenita

A

Mutations in SCN4A (AD)

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27
Q

Huntington’s disease

A

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

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28
Q

Spinobulbar muscular atrophy (Kennedy’s disease)

A

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.

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29
Q

Spinocerebellar ataxias

A

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

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30
Q

Spinocerebellar ataxia type 3 (Machado-Joseph disease)

A

Trinucleotide repeat

CAG repeat in ATXN3 (AD)

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31
Q

Friedreich ataxia

A

Trinucleotide repeat

Autosomal recessive GAA repeat in FXN (sometimes referred to as FRDA gene)

Involved in regulating mitochondrial iron content

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32
Q

Spinal muscular atrophy

A

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

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33
Q

CMT1

A

Majority are due to duplication of PMP22 - AD

Other genes: MPZ, LITAF, ERG2, NEFL

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34
Q

Hereditary neuropathy with pressure palsies (HNPP)

A

Due to PMP22 deletions and point mutations - AD

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35
Q

CMT2

A

Most commonly due to MFN2 mutations (AD or AR)

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36
Q

Hereditary spastic paraplegia

A

Due to length-dependent degeneration of corticospinal tract axons

Can be AD, AR, or XLR

Multiple genes implicated

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37
Q

Parkinson’s disease

A

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
38
Q

Early onset generalized dystonia (DYT1)

A

AD mutations in TOR1A

39
Q

Adolescent-onset mixed dystonia (DYT6)

A

AD mutations in THAP1

40
Q

Myoclonus-dystonia

A

Mutations in SGCE (maternally imprinted)

41
Q

Paroxysmal kinesigenic dyskinesia (PKD)

A

Episodic choreoathetosis and dystonia brought on by voluntary movement.

Lasts less than one minute

Due to PRRT2 mutations (AD)

42
Q

Paroxysmal nonkinesigenic dyskinesia (PNKD)

A

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)

43
Q

Paroxysmal exertion-induced dyskinesia

A

Dyskinesia and dystonia induced by prolonged exertion, fasting and stress.

GLUT1 mutations; very rare - genetically heterogeneous but seen to be AD in familial cases

44
Q

Dopa-responsive dystonia (Segawa)

A

Due to mutations in GCH1 (AR)

45
Q

Ataxia telangiectasia

A

Due to mutations in ATM tumor suppressor gene (AD)

46
Q

Ataxia with oculomotor apraxia (AOA)

A

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

47
Q

Autosomal recessive cerebellar ataxia

A

Type 1:Due to SCAR8 or SYNE1 mutations - AR

Type 2: Due to ANO10 mutations - AR

48
Q

CANVAS

A

Cerebellar ataxia, neuropathy, and vestibulopathy

Due to RFC1 mutations (AR)

49
Q

Hereditary vitamin E deficiency

A

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

50
Q

Cerebrotendinous xanthomatosis

A

Due to CYP27A1 mutations (AR)

51
Q

Dentatorubral-pallidoluysianatrophy (DRPLA)

A

Due to CAG repeats in atrophin-1 (ATN1) - AD

52
Q

Fabry’s disease

A

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.]

53
Q

CADASIL

A

NOTCH3 mutations (AD)

54
Q

CARASIL

A

Overall similar to CADASIL, but earlier and no migraines

AR mutations in HTRA1

55
Q

Retinal vasculopathy with cerebral leukodystrophy

A

Due to mutations in TREX1 (AD)

56
Q

COL4A1- related disease

A

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

57
Q

ACTA2- related disease

A

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)

58
Q

Von Hippel Lindau syndrome

A

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)

59
Q

Hereditary hemorrhagic telangiectasias (Osler Weber Rendu syndrome)

A

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

60
Q

Alzheimer’s disease

A

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)

61
Q

Frontotemporal dementia

A

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

62
Q

Pantothenate-kinase associated neurodegeneration

A

Due to PANK2 mutations (AR)

63
Q

Benign familial neonatal convulsions

A

Due to AD mutations in KCNQ2 or KCNQ3 (voltage-gated potassium channel)

KCNQ2 can also cause a severe infantile epileptic encephalopathy syndrome

64
Q

Autosomal Dominant Nocturnal Frontal Lobe Epilepsy

A

Often due to nicotinic ACh receptor mutations (CHRNA2/4, CHRNB2) - AD

65
Q

Autosomal Dominant Partial/Focal Epilepsy With Auditory Features

A

Due to LGI1 mutations (AD)

66
Q

Canavan’s disease

A

Leukodystrophy

Due to aspartoacylase deficiency (ASPA)

AR inheritance

Aspartoacylase breaks down N-acetyl aspartate (NAA) into aspartic and acetic acid

67
Q

Pelizaeus-Merzbacher disease

A

Leukodystrophy

Dysmyelinating disorder: X-linked recessive with alterations in proteolipid protein (PLP1)

68
Q

Alexander disease

A

Leukodystrophy

AD mutations in glial fibrillary acidic protein (GFAP); astrocyte gene

69
Q

Metachromatic leukodystrophy

A

Leukodystrophy

AR mutations in arylsulfatase (ARSA)

70
Q

X-linked adrenoleukodystrophy

A

Leukodystrophy

X-linked recessive ABCD1 mutations in peroxisomal membrane protein

71
Q

Krabbe globoid cell leukodystrophy

A

Leukodystrophy

AR mutations in GALC (galactosylceramidase, which degrades lipids during myelin turnover)

72
Q

LIS1

A

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)

73
Q

Aicardi syndrome

A

XLD but unknown gene

74
Q

Phenocopy

A

Mutations in the different genes may produce the same effect

75
Q

Western blot

A

Protein detection using antibody for specificity

76
Q

Southern blot

A

DNA detection using sequence for specificity

77
Q

cDNA microarrays

A

Expression profiling on mRNA for a particular cell type/disease, used in Oncology

78
Q

Type I and II repeat expansion diseases

A

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.

79
Q

Parent of origin effect and exception

A

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

80
Q

Polyglutamine disease

A
81
Q

Lissencephaly genetics

A
82
Q

Holoprosencephaly genetics

A
83
Q

Agenesis of corpus collosum

A

Aicardi, FG, Mowat Wilson

84
Q

Polymicrogyria

A

Bifrontal - GPR65, AR

85
Q

Schizencephaly

A

Bilateral or unilateral

Some familial cases, EMX2

86
Q

NF type I

A

AD, NF1 gene on 17q11

87
Q

NF type 2

A

AD NF2 gene on 22q12

88
Q

Tuberous sclerosis

A

AD TSC1; 9q (hemartin)

AD, TSC2; 16p (tubarin)

89
Q

VHL

A

AD, VHL 3p25-26

90
Q

Li-Fraumeni syndrome

A

AD, TP53 in 17p13

91
Q

Basal cell nevus

A

AD, PTCH in 9q22.3

ABPN 2022 (26 decks)

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