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FBN1 contributing to familial congenital diaphragmatic hernia
Author(s) -
Beck Tyler F.,
Campeau Philippe M.,
Jhangiani Shalini N.,
Gambin Tomasz,
Li Alexander H.,
AboZahrah Reem,
Jordan Valerie K.,
HernandezGarcia Andres,
Wiszniewski Wojciech K.,
Muzny Donna,
Gibbs Richard A.,
Boerwinkle Eric,
Lupski James R.,
Lee Brendan,
Reardon Willie,
Scott Daryl A.
Publication year - 2015
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.36960
Subject(s) - congenital diaphragmatic hernia , diaphragmatic hernia , medicine , diaphragmatic breathing , hernia , anatomy , surgery , genetics , biology , pathology , pregnancy , fetus , alternative medicine
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. © 2015 Wiley Periodicals, Inc.