FBN1 contributing to familial congenital diaphragmatic hernia.

TitleFBN1 contributing to familial congenital diaphragmatic hernia.
Publication TypeJournal Article
Year of Publication2015
AuthorsBeck, TF, Campeau, PM, Jhangiani, SN, Gambin, T, Li, AH, Abo-Zahrah, R, Jordan, VK, Hernandez-Garcia, A, Wiszniewski, WK, Muzny, DM, Gibbs, RA, Boerwinkle, E, Lupski, JR, Lee, B, Reardon, W, Scott, DA
JournalAm J Med Genet A
Date Published2015 Apr
KeywordsAdult, Child, Preschool, DNA Mutational Analysis, Exome, Female, Fibrillin-1, Fibrillins, Frameshift Mutation, Genetic Association Studies, Hernias, Diaphragmatic, Congenital, Humans, Male, Marfan Syndrome, Microfilament Proteins, Pedigree

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.

Alternate JournalAm J Med Genet A
PubMed ID25736269
PubMed Central IDPMC4522925
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
U54HG006542 / HG / NHGRI NIH HHS / United States
R01 HD064667 / HD / NICHD NIH HHS / United States
R25 GM056929-16 / GM / NIGMS NIH HHS / United States
R25 GM056929 / GM / NIGMS NIH HHS / United States
P30 DK056338 / DK / NIDDK NIH HHS / United States

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