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FMS: Genetics Week 1 > 5: Autosomal Inheritance And Disorders > Flashcards

5: Autosomal Inheritance And Disorders Flashcards

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1
Q

Dysmorphology

A

Study of birth defects

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2
Q

Autosomal Disorders (characteristics)

A

Mendelian Inheritance

Dominant

Recessive

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3
Q

Autosomal Dominant Disorder (examples)

A

Achondroplasia

Neuorfibromatosis

Marfan

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4
Q

Autosomal Recessive Disorders (examples)

A

Cystic Fibrosis

PKU

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5
Q

Mendelian Inheritance

A

Patterns of single gene inheritance
Pedigree
Autosomal (1-22) or sex-linked (X/Y)
Dominant or recessive

Problems: new mutations, adoptions, hearing loss (dominant,recessive, Y linked, mitochondrial), Germline mosaicism

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6
Q

Hearing Loss

A

Many inheritance patterns

AD, AR, XL, mitochondrial, etc…

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7
Q

Germline Mosaicism

A

Recurrence risk related

Example: unaffected parents with second child with achondroplasia

Low risk of new mutations

***Presence of more than one genetically distinct cell line

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8
Q

Autosomal Single-Gene Disorders (characteristics)

A

Enzyme defects

Receptor/transporter defects

Structural protein defects

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9
Q

Autosomes

A

Numbered chromosomes (1-22)

Genes on chromosomes (two copies or alleles)

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10
Q

Autosomal Dominant (Pedigree)

A

No skipped generations

Equal numbers of males and females

50% children of affected individual will be affected

Can see reduced penetrance

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11
Q

Reduced penetrance

A

Defined as percentage of people who carry the pathogenic variant who express the trait

Ex. Marfan syndrome (highly penetrant)

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12
Q

Variable Expressivity

A

Traits expressed vary between individuals who carry the gene, along a continuum

Intrafamily clinical variability

Ex. NF1, one has optic glioma, one has skin findings

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13
Q

Autosomal Dominant (characteristics)

A

Only need one copy

50:50 recurrence risk

New mutations common (parents unaffected), due to germ-line mutations in older fathers.
Anchondroplasia: 100% new mutations because of older fathers

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14
Q

Retinoblastoma

A

Tumor syndrome

Convenient to call it autosomal dominant
But there are obligate carriers (10% no symptoms)

Two hit hypothesis

Example of Reduced penetrance

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15
Q

Autosomal Dominant Disorders (frequency)

A

Familial hypercholesterolemia (1/500)

Neurofibromatosis Type 1 (1/3000)

Marfan syndrome (1/7-10,000)

Achondroplasia (1/25-40,000)

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16
Q

Neurofibromatosis Type 1 (symptoms)

A

Cafe-au-lait macules (spots)
Axillary/inguinal freckling, Neurofibromas
Lisch nodules (iris hamartomas- brown benign spots)
Bony lesions

17
Q

Neurofibromatosis Type 1 (characteristics)

A

Autosomal Dominant (NF1 gene disrupt protein)

100% Penetrance, (by age 6)

Variable expressivity

New Mutations account for half of cases

No needed genetic testing, clinical is enough

18
Q

Marfan Syndrome (symptoms)

A

*Dilated aortic root
*Ectopia Lentis
Long arms, long legs
Thumb and wrist sign
Skeletal changes (pecs different too)
Dural ectasia (abnormal growth)

19
Q

Marfan Syndrome (characteristics)

A

Autosomal Dominant

FBN1 gene

Fibrillin protein

25% de novo

Rare germline mosaicism

20
Q

Marfan Diagnostic Criteria

A

Without family history:

  1. Aortic dilation AND Ectopia Lentis
  2. Aortic dilation AND FBN1 pathogenic variant
  3. Aortic dilation AND systemic score>7
  4. Ectopia Lentis AND FBN1 know to cause Marfan
21
Q

Marfan Systemic Feature Score

A 
Wrist and thumb sign
Pet us carinatum deformity, chest asymmetry
Pneumothorax
Dural ectasia 
Scoliosis 
Etc....
22
Q

Achondroplasia (symptoms)

A

Short-limbed dwarfism (Rhizomelic-shortening of arms and legs- upper)

Macrocephaly (large head),frontal bossing, depressed nasal bridge

Skeletal and CNS problems

Normal IQ

Clinically and genetically homogeneous

23
Q

Achondroplasia (characteristics)

A

Autosomal Dominant

FGFR3 variants: mostly G1138A

Mostly de novo (older fathers)

Homozygotes is lethal

24
Q

Achondroplasia (natural history)

A

Infancy: hypotonia, DD in motor
Intelligence and lifespan normal
Compression of spinal chord bad in infancy
Many die from obstructed airway

25
Q

Achondroplasia (genetics)

A

Fibroblast growth factor receptor (FGFR3 gene mutation)

FGFR3 gene is negative regulator of bone growth

Mutations cause activation of gene->more inhibition of bone growth
“Gain of function”

26
Q

Autosomal Recessive (characteristics)

A

2 variants in gene needed (based on prevalence in population)
Risk increased if related to partner
Consanguinity

Uniform expression of features
Complete penetrance
Early onset of symptoms
Heterozygotes have 50% normal function (enough)

27
Q

Consanguinity

A

In rare recessive disease

Measurement

  • Coefficient of relationship
  • First cousin marriage (1/8 DNA shared)
28
Q

Autosomal Recessive (recurrent risk)

A

For affected individual:
100% chance to child, risk to child based on partner’s risk

Unaffected couple:
25% chance each child after one affected child produced will be affected
50% chance each child will be carrier
(1/2 carriers and 2/3 unaffected carriers because one person obviously affected and don’t include them)

29
Q

Autosomal Recessive (Pedigree)

A

Affected individuals born to unaffected parents

Skipped generations

Males and females equal

Possible consanguinity

30
Q

Autosomal Recessive Disorders (examples)

A

Sickle Cell Anemia

Cystic Fibrosis

Metabolism errors:
PKU
+
Galactosemia, Homocystinuria, Lysosomal storage disorders

31
Q

Sickle Cell Disease

A

Autosomal Recessive

Point mutation producing HbS (protects against malaria)

Cells sickle under low pH or deoxygenation

Heterozygotes (40% HbS)
Homozygotes (100% HbS)

32
Q

Cystic Fibrosis (genetics)

A

Autosomal Recessive

CFTR mutations, chloride channel
Multiple tissues affected

In caucasian

Sweat chloride test

33
Q

Cystic Fibrosis (symptoms)

A

Neonatal: meconium ileus, abdominal calcifications
Infancy: failure to thrive, chronic diarrhea, pneumonia
Childhood: nasal polyposis, intussusception (guts coiling into other parts of gut, obstruction)
Adolescence/adulthood: nasal polyposis, bronchiectasis, delayed puberty, azoospermia

34
Q

Cystic Fibrosis (mutation variants)

A

Channel:

No synthesis, block in processing, block in regulation, altered conductance, reduced synthesis.

35
Q

CF Lung Pathogenesis

A

Defective chloride secretion and sodium hyperabsorption leads to depletion of layer of airway surface fluid.

Airway surface fluid layer GONE
Leads to sticky gummy stuff leading to infections and so on

36
Q

Phenylketonuria (PKU)

A

Autosomal Recessive

Can’t process phenylalanine (hydroxylase deficiency)
Brain damage, macrocephaly, severe MR, epilepsy
Musty odor, eczema, hypopigmentation
Variable expression
Better with good diet (low protein)

37
Q

Maternal PKU

A

PHE crosses placenta readily

Fetus is sensitive to increased levels of PHE and may suffer malformations if maternal level not controlled.

FMS: Genetics Week 1 (10 decks)

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