5: Autosomal Inheritance And Disorders Flashcards
Dysmorphology
Study of birth defects
Autosomal Disorders (characteristics)
Mendelian Inheritance
Dominant
Recessive
Autosomal Dominant Disorder (examples)
Achondroplasia
Neuorfibromatosis
Marfan
Autosomal Recessive Disorders (examples)
Cystic Fibrosis
PKU
Mendelian Inheritance
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
Hearing Loss
Many inheritance patterns
AD, AR, XL, mitochondrial, etc…
Germline Mosaicism
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
Autosomal Single-Gene Disorders (characteristics)
Enzyme defects
Receptor/transporter defects
Structural protein defects
Autosomes
Numbered chromosomes (1-22)
Genes on chromosomes (two copies or alleles)
Autosomal Dominant (Pedigree)
No skipped generations
Equal numbers of males and females
50% children of affected individual will be affected
Can see reduced penetrance
Reduced penetrance
Defined as percentage of people who carry the pathogenic variant who express the trait
Ex. Marfan syndrome (highly penetrant)
Variable Expressivity
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
Autosomal Dominant (characteristics)
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
Retinoblastoma
Tumor syndrome
Convenient to call it autosomal dominant
But there are obligate carriers (10% no symptoms)
Two hit hypothesis
Example of Reduced penetrance
Autosomal Dominant Disorders (frequency)
Familial hypercholesterolemia (1/500)
Neurofibromatosis Type 1 (1/3000)
Marfan syndrome (1/7-10,000)
Achondroplasia (1/25-40,000)
Neurofibromatosis Type 1 (symptoms)
Cafe-au-lait macules (spots)
Axillary/inguinal freckling, Neurofibromas
Lisch nodules (iris hamartomas- brown benign spots)
Bony lesions
Neurofibromatosis Type 1 (characteristics)
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
Marfan Syndrome (symptoms)
*Dilated aortic root
*Ectopia Lentis
Long arms, long legs
Thumb and wrist sign
Skeletal changes (pecs different too)
Dural ectasia (abnormal growth)
Marfan Syndrome (characteristics)
Autosomal Dominant
FBN1 gene
Fibrillin protein
25% de novo
Rare germline mosaicism
Marfan Diagnostic Criteria
Without family history:
- Aortic dilation AND Ectopia Lentis
- Aortic dilation AND FBN1 pathogenic variant
- Aortic dilation AND systemic score>7
- Ectopia Lentis AND FBN1 know to cause Marfan
Marfan Systemic Feature Score
Wrist and thumb sign Pet us carinatum deformity, chest asymmetry Pneumothorax Dural ectasia Scoliosis Etc....
Achondroplasia (symptoms)
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
Achondroplasia (characteristics)
Autosomal Dominant
FGFR3 variants: mostly G1138A
Mostly de novo (older fathers)
Homozygotes is lethal
Achondroplasia (natural history)
Infancy: hypotonia, DD in motor
Intelligence and lifespan normal
Compression of spinal chord bad in infancy
Many die from obstructed airway
Achondroplasia (genetics)
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”
Autosomal Recessive (characteristics)
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)
Consanguinity
In rare recessive disease
Measurement
- Coefficient of relationship
- First cousin marriage (1/8 DNA shared)
Autosomal Recessive (recurrent risk)
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)
Autosomal Recessive (Pedigree)
Affected individuals born to unaffected parents
Skipped generations
Males and females equal
Possible consanguinity
Autosomal Recessive Disorders (examples)
Sickle Cell Anemia
Cystic Fibrosis
Metabolism errors:
PKU
+
Galactosemia, Homocystinuria, Lysosomal storage disorders
Sickle Cell Disease
Autosomal Recessive
Point mutation producing HbS (protects against malaria)
Cells sickle under low pH or deoxygenation
Heterozygotes (40% HbS)
Homozygotes (100% HbS)
Cystic Fibrosis (genetics)
Autosomal Recessive
CFTR mutations, chloride channel
Multiple tissues affected
In caucasian
Sweat chloride test
Cystic Fibrosis (symptoms)
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
Cystic Fibrosis (mutation variants)
Channel:
No synthesis, block in processing, block in regulation, altered conductance, reduced synthesis.
CF Lung Pathogenesis
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
Phenylketonuria (PKU)
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)
Maternal PKU
PHE crosses placenta readily
Fetus is sensitive to increased levels of PHE and may suffer malformations if maternal level not controlled.
