5: Autosomal Inheritance And Disorders

Question 1

Dysmorphology

Answer 1

Study of birth defects

Question 2

Autosomal Disorders (characteristics)

Answer 2

Mendelian Inheritance

Dominant

Recessive

Question 3

Autosomal Dominant Disorder (examples)

Answer 3

Achondroplasia

Neuorfibromatosis

Marfan

Question 4

Autosomal Recessive Disorders (examples)

Answer 4

Cystic Fibrosis

PKU

Question 5

Mendelian Inheritance

Answer 5

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

Question 6

Hearing Loss

Answer 6

Many inheritance patterns

AD, AR, XL, mitochondrial, etc…

Question 7

Germline Mosaicism

Answer 7

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

Question 8

Autosomal Single-Gene Disorders (characteristics)

Answer 8

Enzyme defects

Receptor/transporter defects

Structural protein defects

Question 9

Autosomes

Answer 9

Numbered chromosomes (1-22)

Genes on chromosomes (two copies or alleles)

Question 10

Autosomal Dominant (Pedigree)

Answer 10

No skipped generations

Equal numbers of males and females

50% children of affected individual will be affected

Can see reduced penetrance

Question 11

Reduced penetrance

Answer 11

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

Ex. Marfan syndrome (highly penetrant)

Question 12

Variable Expressivity

Answer 12

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

Question 13

Autosomal Dominant (characteristics)

Answer 13

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

Question 14

Retinoblastoma

Answer 14

Tumor syndrome

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

Two hit hypothesis

Example of Reduced penetrance

Question 15

Autosomal Dominant Disorders (frequency)

Answer 15

Familial hypercholesterolemia (1/500)

Neurofibromatosis Type 1 (1/3000)

Marfan syndrome (1/7-10,000)

Achondroplasia (1/25-40,000)

Question 16

Neurofibromatosis Type 1 (symptoms)

Answer 16

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

Question 17

Neurofibromatosis Type 1 (characteristics)

Answer 17

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

Question 18

Marfan Syndrome (symptoms)

Answer 18

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

Question 19

Marfan Syndrome (characteristics)

Answer 19

Autosomal Dominant

FBN1 gene

Fibrillin protein

25% de novo

Rare germline mosaicism

Question 20

Marfan Diagnostic Criteria

Answer 20

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

Question 21

Marfan Systemic Feature Score

Answer 21

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

Question 22

Achondroplasia (symptoms)

Answer 22

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

Question 23

Achondroplasia (characteristics)

Answer 23

Autosomal Dominant

FGFR3 variants: mostly G1138A

Mostly de novo (older fathers)

Homozygotes is lethal

Question 24

Achondroplasia (natural history)

Answer 24

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

Question 25

Achondroplasia (genetics)

Answer 25

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"

Question 26

Autosomal Recessive (characteristics)

Answer 26

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)

Question 27

Consanguinity

Answer 27

In rare recessive disease Measurement - Coefficient of relationship - First cousin marriage (1/8 DNA shared)

Question 28

Autosomal Recessive (recurrent risk)

Answer 28

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)

Question 29

Autosomal Recessive (Pedigree)

Answer 29

Affected individuals born to unaffected parents Skipped generations Males and females equal Possible consanguinity

Question 30

Autosomal Recessive Disorders (examples)

Answer 30

Sickle Cell Anemia Cystic Fibrosis Metabolism errors: PKU + Galactosemia, Homocystinuria, Lysosomal storage disorders

Question 31

Sickle Cell Disease

Answer 31

Autosomal Recessive Point mutation producing HbS (protects against malaria) Cells sickle under low pH or deoxygenation Heterozygotes (40% HbS) Homozygotes (100% HbS)

Question 32

Cystic Fibrosis (genetics)

Answer 32

Autosomal Recessive CFTR mutations, chloride channel Multiple tissues affected In caucasian Sweat chloride test

Question 33

Cystic Fibrosis (symptoms)

Answer 33

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

Question 34

Cystic Fibrosis (mutation variants)

Answer 34

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

Question 35

CF Lung Pathogenesis

Answer 35

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

Question 36

Phenylketonuria (PKU)

Answer 36

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)

Question 37

Maternal PKU

Answer 37

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