Autosomal Inheritance and Disorders Flashcards
examples of autosomal dominant (AD) disorders
- achondroplasia
- neurofibromatosis (NF-1)
- Marfan syndrome
examples of autosomal recessive (AR) disorders
- cystic fibrosis
- sickle cell anemia
- PKU (and most metabolic diseases: galactosemia, homocytinuria, lysosomal storage disorders)
confounders of inheritance of autosomal disorders
- variable expressivity
- reduced penetrance
- consanguinity
- de novo mutations
- germline mosaicism
pedigree analysis useful for
- single gene disorders (mendelian inheritance)
* autosomal (1-22) or sex-linked (X or Y)
examples of autosomal single gene disorders
- enzyme defects
- receptor/transport defects (ie cystic fibrosis)
- structural protein defects (ie marfan syndrome)
pedigree features (ideal) for autosomal dominant inheritance
- no skipped generations
- male and female affected equally
- ~50% of children to an affected individual will be affected
- (reduced penetrance would affect the ideal pedigree)
neurofibromatosis type 1 (NF-1) clinical features
- cafe-au-lait spots
- axillary/inguinal freckling
- neurofibromas
- lisch nodules (iris hamartomas)
- bony lesions: tibial bowing
NF-1 inheritance
- virtually 100% inheritance, dx usually clear by age 6
- expressivity highly variable
- de novo mutations account for 50% of all cases
- **genetic testing usually not done -> clinical criteria sufficiently sensitive
Marfan syndrome clinical features
•FBN1 gene -> fibrillin protein •DILATED AORTIC ROOT •ECTOPIA LENTIS (dislocated lens) •skeletal changes •dural ectasia (widening of dural sac) 25% de novo
marfan diagnostic criteria
•in absence of family history:
1) aortic dilation AND ectopia lentis
2) aortic dilation AND FBN1 mutation
3) aortic dilation AND systemic score > 7
4) ectopia lentis AND FBN1 mutation
issues affecting “real life” pedigrees
- reduced penetrance
* variable expressivity
achondroplasia
- most common form of short-limbed dwarfism
- ~1/30,000 births
- AD inheritance
- complete penetrance
FGFR3 gene
fibroblast growth factor receptor
•mutation causes achondroplasia
•it’s a negative regulator of bone growth
∴mutations cause activation of the gene -> inhibition of bone growth (gain of function mutation)
clinical features of achondroplasia
- short-limbed dwarfism (rhizomelic, rhizo=root)
- macrocephaly
- skeletal and CNS complications
- normal IQ
important statistics in achondroplasia
- 98% of pathogenic variants are G1138A
- 80% are de novo
- homozygotes generally die
Lifespan of patients with acondroplasia
- IQ and life span usually normal
* compression of spinal cord and/or upper airway obstructions increases risk of death in infancy (7-8%)
consanguinity
- increases risk of autosomal recessive disorders
* first cousin marriage = 1/8 of DNA shared
autosomal recessive pedigree features
- affected individuals born to unaffected parents
- skipped generations
- males and females affected equally
sickle cell disease
- autosomal recessive
- point mutation producing HbS
- defective protein -> cells sickle under stress
- heterozygotes seem protected against malaria
cystic fibrosis
- autosomal recessive (most common AR disorder in caucasians)
- mutations in CFTR=chloride channel
- best way to test for it: sweat chloride test
clinical symptoms of CF - neonatal
- meconium ileus
* abdominal calcifications
clinical symptoms of CF - infancy
- failure to thrive
- chronic diarrhea
- pneumonia
clinical symptoms of CF - childhood
- nasal polyposis
* intussusception
clinical symptoms of CF - adolescence and adulthood
- nasal polyposis
- bronchiectasis
- delayed puberty
- azoospermia secondary to congenital bilateral absence of vas deferens
CF lung pathogenesis
- defective chloride secretion
- sodium hyperabsorption
- ^^lead to depletion of layer of airway surface fluid -> breakdown of mucociliary transport
Phenylketonuria (PKU)
- autosomal recessive
* phenylalanine (PHE) accumulations -> brain damage: microcephaly, severe DD, and epilepsy
variable expression of the gene for PKU
- PKU: PHE>600 micromol/L
* hyperphenylalinemia: PHE=200-600 micromol/L
maternal PKU
- PHE readily crosses placenta
* If mom’s PHE levels are not controlled, developing fetus may suffer malformations
