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Genetics > Atypical Inheritance > Flashcards

Atypical Inheritance Flashcards

1
Q

Patterns of Pseudoautosomal inheritance

A

Inheritance pattern for genes located in the pseudoautosomal region of the X and Y chromosomes that can undergo homologous recomb.
DYSCHONDROSTEOSIS-skeletal dysplasia with disproportionate short stature and deformity of the forearm. Gene codes for a transcription factor and escapes X-inactivation. (pattern looks x-linked, but we don’t know for sure)

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2
Q

Mosaicism

A

Presence of at least 2 cell lines in an individual the differ genetically but originate from a single zygote. Can be somatic, germ line or both.
Ex: X chrome inactivation

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3
Q

Somatic mosaicism

A

Mutation occurs during embryogenesis and affects morphogenesis, may manifest in patchy abnormality. NF-1 sometimes SEGMENTAL->only certain body part affected
Urea cycle enzyme OTC,Hemophilia A, DMD

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4
Q

Germline mosaicism

A

parent phenotypically normal and can have affected children as a result of a NEW mutation. 30 mitotic divisions prior to meiosis in females and hundreds in males->opportunities for mutation.
Ex: 6% of osteogenesis imperfecta, hemophilia A and B, DMD.
*Mutation will be missed b/c we analyze somatic cells(i.e. lymphs)-often see the condition in offspring which is how we find out.

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5
Q

What are diseases due to unstable repeat expansions?

A

CHARACTERISED BY AN EXPANSION OF REPEATING UNITS OF 3 OR MORE NUCLEOTIDES IN TANDEM W/IN THE AFFECTED GENE. Often 3 nucleotide repeat, but 4/5 also seen.
WILD TYPE ALLELES THAT ARE POLYMORPHIC.
DYNAMIC MUTATIONS of micro satellite repeats usually seen in vicinity of genes.

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6
Q

What are the general features of diseases with unstable repeat expansions?

A

ANTICIPATION-all gene expansion cases show anticipation. Appearance of the disease at an earlier age as it is transmitted through a family-Increase in severity as the disease is passed on.
PARENTAL TRANSMISSION BIAS: Friedrich’s ataxia, myotonic dystrophy, fragile X syndrome are unstable when maternally transmitted.
Huntington’s disease repeats expand when paternally transmitted.
PRIMARILY NEUROLOGICAL:ataxia, cognitive defects, dementia, nystagmus, parkinsonism, spasticity.

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7
Q

What is the likely mechanism to which unstable repeat expansions occur?

A

Slipped mispairing: Replication is started->replicating strand detaches inappropriately from template strand->replicating stand slips from proper alignment by 1 repeat (R) length->mismatched 2 repeat lengths (2R) out. Newly synthesised strand contains an extra repeat.
Expanded region continues in DNA

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8
Q

What is an example of a disease due to tetra nucleotide repeat expansion?

A

Myotonic dystrophy 2(close genocopy of myotonic dystrophy). Repeat of “CCTG”

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9
Q

What is an example of a disease due to a pentanucleotide repeat expansion?

A

Spinocerebellar atrophy 10-> repeat of “A T T C T”

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10
Q

Unstable repeat expansions: Huntington disease

A

AD, CAG, HD gene, coding region. >40 repeats are affected

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11
Q

Unstable repeat expansions: Fragile X

A

X-linked Dom. CGG. FMR1 gene, 5’ untranslated region. >200 affected

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12
Q

Unstable repeat expansions: Myotonic Dystrophy

A

AD, CTG, DMPK gene. 3’ untranslated region. 80-2000 affected.

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13
Q

Unstable repeat expansions: Friedreich ataxia

A

AR, AAG repeat. FRDA gene, Intron regions. >100 affected

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14
Q

Fragile X Syndrome

A

XD.Expansion of triplet CGG, 5’ UT region of the 1st exon of FMR1 gene.
2nd most common cause of moderate retardation.
Xq27.3 is fragile site

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15
Q

What is the mechanism of inactivation of FMR1 gene?

A

CGG repeats in 5’ UT UP TO 60->NORMAL
60-200 REPEATS->PREMUTATION
>200 FULL MUTATION->HYPERMETHYLATION OF 5’ UTR AND PROMOTER->SHUTS DOWN TRANSCRIPTION.

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16
Q

What are the clinical features of males with Fragile X?

A

delayed dev milestones, retardation, abn temprament:tantrums, autism. Abnormal craniofacies: long face, coarse facial features.
Macro-orchidism, Strabismus, joint hyperextensibility, mitral valve prolapse, pesplanus

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17
Q

Fragile X syndrome premutation is unstable and expands when?

What can carriers of permutation develop?

A

When transmitted by mother!
Carriers can develop ADULT-ONSET DISORDER FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME.
2-5x increase in FMR1 mRNA->gain of function->formation of intranuclear neuronal inclusions.
1/4 of female carriers will have ovarian failure by 40 yrs.

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18
Q

Huntington Disease?

A

CAG repeat in coding region/exon->codes for glu->poly-glutamination of protein. AD neurodegen disorder.
Shows PATERNAL TRANSMISSION BIAS. almost always inherited from affected father.

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19
Q

What is the mutation for Huntingtons disease?

A

Abn INCREASE IN # OF CAG REPEATS IN THE CODING REGIONS.
Normal:9-35 repeatss
Premutation: 29-35 repeats
Borderline repeats: 36-39-> assoc. w/ HD at advanced age.
Full mutation:≥ 40 repeats
70-121 repeats: severe juvenile onset HD.

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20
Q

What are the clinical features of Huntingtons disease?

A

AGE DEPENDENT CORRELATION-age of onset correlated to number of repeats. Mean age is 40. Early on, minor motor abns: clumsiness, hyperreflexia, eye movement->evolve to involuntary movements (CHOREA), progressive dementia and psychological disturbances.

21
Q

What is Friedreich Ataxia?

A

AR, Expansion of GAA repeats in 1st intron of FRDA gene.Normal=5-34, Path >100-200.
LOF from both alleles is required to produce the disease

22
Q

What are some clinical features of Friedreich Ataxia?

A

Diagnostic triad: Progressive ataxia, Cardiomyopathy, Absent/diminshed tendon reflexes. . . Spino-cerebellar ataxia, difficulty w/speech, scoliosis, foot deformities, type 2 diabetes.
Clinical onset before adolescence.

23
Q

What is Myotonic Dystrophy?

A

AD,CTG repeat, Progressive muscle weakness/wasting, with myotonia.
Myotonia=delayed relaxation and muscle stiffness.

24
Q

What is the mutated gene in Myotonic Dystrophy?

A

DMPK gene, (Myotonic Dystrophy Protein Kinase)/Myotonin. chrome 19

25
Q

What mutation causes the pathology for myotonic dystrophy?

A

Expansion of CTG at 3’ UT region->impairs mRNA stability.
Normal: 5-30 repeats
Premutations: 38-54
Pathologic > 50 . . . Severity and age of onset correlated with # of repeats.

26
Q

What are the clinical features of Myotonic Dystrophy?

A

Progressive Neuromuscular weakness, Myotonia(prolonged relaxtion time), cardiac conduction defect-A-V block, cardiomyopathy,disturbed GI peristalsis, lack of facial expression, frontal balding, testicular atrophy. Lack of penetrance and variable expressivity common.

27
Q

What is the Congenital form of Myotonic Dystrophy?

A

Infants w/hypotonia, resp distress-life threatening. Myotonic facies: lack of facial expression, tented up lip with fish mouth appearance, mild retardation.

28
Q

How is Myotonic Dystrophy inherited and what is it associated with?

A

Associated with ANTICIPATION->enlargement of molecular defects.
Parental bias-ALMOST ALL CONGENITAL CASES ARE MATERNALLY INHERITED.

29
Q

Imprinting in Pedigrees: What is Albright Hereditary Osteodystrophy (AHO)

A

AD,Fully penetrant, Defect in GNAS gene which transmits PTH signal inside cell. . . . Pedigree shows 2 types of disorders.

30
Q

Imprinting in Pedigrees: AHO: Pseudopseudohypoparathyroidism (pseudoPHP) or

A

AHO only! Obesity, short stature, subcutaneous calcifications, and brachydactyly

31
Q

Imprinting in Pedigrees: AHO: Pseudohypoparathyroidism with . . .

A

AHO (PHP1a). Calcium abnormality due to deficient action of PTH, elevated levels of PTH and renal tubular resistance to action of PTH in addition to features of PseudoPHP ( obesity, short stature, subcutaneous calcifications, brachydactyly.

32
Q

Imprinting in Pedigrees: Can a family have both PPHP and PHP1a?

A

Yes, but within a sibship either all have PPHP or PHP1a since GNAS is imprinted only in certain tissues including renal tubular cells. Only copy from mother is expressed.
PHP1a occurs when one inherits defective copy from mother.
In tissues without imprinting, features of AHO develop.

33
Q

What is the Mitochondrial DNA genome?

A

Double stranded circular DNA molecule. Encodes 13 subunits of Oxidative phosphorylation proteins, 2 rRNA, and 22 tRNA. 1000 mtDNA distributed among hundreds of mitochondria in a cell, except oocytes which mtDNA accounts for 1/3 of total DNA.

34
Q

What about mtDNA and nuclear DNA?

A

Mutation in nuclear genes also can show phenotype of mitochondrial diseases, but patterns are mendelian.
Other 74 peptides of OX Phos are coded by nuclear DNA. Nuclear genome also expresses proteins required for maintenance and expression of mtDNA or assembly of oxidative phosphorylation complexes.

35
Q

What are the patterns of mtDNA diseases?

A

Maternal inheritance ONLY! Males do not transmit mitochondrial disorder. If males have it, it will end with them.
Replicative segregation, homoplasmy, heteroplasmy.

36
Q

What is heteroplasmy responsible for?

A

Pleiotropy
Reduced penetrance
Variable expression

37
Q

Elaborate on mtDNA disorders and pedigrees . . .

A

All mitochondria in the offspring originate from the mother. The father does not contribute any mtDNA! All children of an affected female will inherit the mutated mtDNA.

38
Q

Patterns of mtDNA diseases: what is Replicative segregation?

A

No tightly controlled segregation of mitochondrial genome.

39
Q

Patterns of mtDNA diseases: What is Homoplasmy?

A

Daughter cells receive a pure population of mtDNA - May be normal or mutant

40
Q

Patterns of mtDNA diseases:What is heteroplasmy?

A

Daughter cells receive a mixture of mutant and normal mtDNA. . . .the more mutant mitochondria, increased severity of disease.

41
Q

Patterns of mtDNA diseases: What is mitochondrial genetic bottleneck?

A

Variability arises from only a subset of mtDNA during oogenesis. Mother has higher proportion of mutant DNA->clinically affected offspring are more likely->Exception: deleted mtDNA are not generally transmitted to offspring. (i.e. if mother has heteroplasmy for deletion mutation)

42
Q

Leber’s Hereditary Optic Neuropathy.

A

rapid optic nerve death, leading to blindness in young adult life. Commonly, males affected assoc with smoking.

43
Q

NARP, Leigh disease

A

Neuropathy, Ataxia, Retinitis Pigmentosa, developmental delay, mental retardation, lactic acidemia

44
Q

MELAS

A

Mitochondrial Encephalomyopathy Lactic Acidosis and Strokelike episodes; may manifest only as diabetes mellitus

45
Q

MERRF

A

Myoclonic Epilepsy Ragged Red Fibers in muscle, ataxia, sensorineural deafness

46
Q

Deafness

A

Progressive sensorineural deafness, often induced by amino glycoside antibiotics

47
Q

Chronic Progressive External Opthalmoplegia CPEO

A

Nonsyndromic sensorineural deafness, progressive weakness of extra ocular muscles

48
Q

Pearson Syndrome

A

Pancreatic insufficiency, pancytopenia, lactic acidosis

49
Q

Kearns-Sayre Syndrome (KSS)

A

PEO of early onset with heart-block, retinal pigmentation

Genetics (12 decks)

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