FBN1 contributing to familial congenital diaphragmatic hernia.
Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central--for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that causes Marfan syndrome. A diagnosis of Marfan syndrome had not been considered previously in this family. However, a review of the literature demonstrated that FBN1 mutations have an unusual pattern of CDH in which paraesophageal hernias are particularly common. Subsequent clinical evaluations revealed evidence for ectopia lentis in affected family members supporting a clinical diagnosis of Marfan syndrome. Since only two other cases of familial CDH have been described in association with FBN1 mutations, we investigated an oligogenic hypothesis by examining ES data for deleterious sequence changes in other CDH-related genes. This search revealed putatively deleterious sequence changes in four other genes that have been shown to cause diaphragm defects in humans and/or mice--FREM1, DES, PAX3 and MET. It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. However, their individual contribution is likely to be small compared to that of the frameshift mutation in FBN1. We conclude that ES can be used to identify both major and minor genetic factors that may contribute to CDH. These results also suggest that ES should be considered in the diagnostic evaluation of individuals and families with CDH, particularly when other diagnostic modalities have failed to reveal a molecular etiology.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.
Tyler F
TF
Beck
Philippe M
PM
Campeau
Shalini N
SN
Jhangiani
Tomasz
T
Gambin
Alexander H
AH
Li
Reem
R
Abo-Zahrah
Valerie K
VK
Jordan
Andres
A
Hernandez-Garcia
Wojciech K
WK
Wiszniewski
Donna
D
Muzny
Richard A
RA
Gibbs
Eric
E
Boerwinkle
James R
JR
Lupski
Brendan
B
Lee
Willie
W
Reardon
Daryl A
DA
Scott
D000328:Adult; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D016368:Frameshift Mutation; D056726:Genetic Association Studies; D065630:Hernias, Diaphragmatic, Congenital / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics; D008840:Microfilament Proteins / Q000235:genetics*; D010375:Pedigree; D054392:Adipokines
D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse
DES; FBN1; MET; Marfan syndrome; PAX3; congenital diaphragmatic hernia; exome sequencing; oligogenic inheritance