Lecture 20

Question 1

Christopher’s case led to what

Answer 1

discovery of FoxF1 as a major causative gene for ACD

Question 2

Alveolar Capillary Disease

Answer 2

• A lethal developmental anomaly of the pulmonary vasculature
o Failure of formation of the normal air-blood diffusion barrier in the newborn lung; associated w/ misalignment of the pulmonary veins

Question 3

ACD Clinical Presentation

Answer 3

o Infants become ill in the 1st few days of life w/ severe hypoxia and pulmonary hypertension
o Average life expectancy 24 days
o Majority of patients will also have cardiovascular, gastrointestinal, urogenital, or musculoskeletal anomalies
o Diagnosis is typically confirmed by lung biopsy or autopsy; genetic testing is now available
o Autopsy: paucity of alveolar capillaries, widened alveolar septae, and increased muscularization of pulmonary arterioles
o ACD diagnoses are probably higher due to misdiagnoses as other sudden infant deaths

Question 4

ACD Inheritance

Answer 4

o >200 cases reported
o No sex preference
o 30-40% of cases due to FoxF1 gene, remaining cases unknown cause
o ~10% of cases have a familial association (siblings) – indicating that in some cases this may be an autosomal recessive inheritance
• Majority of the rest of the cases seem to be de novo w/ a likely low recurrence risk
• Some cases appear to have autosomal recessive inheritance; parents counseled that they have 25% chance
• One father’s germline was mutated that his 3 children had it (2 full sib, 1 half sib)

Question 5

Positional Cloning

Answer 5

identifies a gene when only its approximate chromosomal location is known. Linkage analysis is usually used first to identify this region and then positional cloning is used to narrow the candidate region until the gene is identified.
o To search for ACD gene, positional cloning and eventual mapping of ACD gene implemented
 Families of genes that are important in the normal development of the pulmonary, GI, renal, and CV systems are investigated as possible candidates

Question 6

ACD Genetics

Answer 6

a microdeletion on chr 16
o 16q24.1 – 2 Mb
o OMIM genes in region (2) – FOXC2, FOXL1
o Other genes in region (2) – MTHFSD, FLJ30679

• 30-40% of cases have foxf1 gene mutation or deletion encompassing the foxf1 and foxc2 genes
o Pts w/ deletions of both genes have CHD, GI atresias, urinary tract malformations
o All cases of foxf1 identified so far have been de novo w/ a likely low recurrence risk (one twin w/ acd and one w/o)
o 2 pts identified w/ deletions upstream of the fox gene cluster on chr 16