TY - JOUR
T1 - FBN1 contributing to familial congenital diaphragmatic hernia
AU - Beck, Tyler F.
AU - Campeau, Philippe M.
AU - Jhangiani, Shalini N.
AU - Gambin, Tomasz
AU - Li, Alexander H.
AU - Abo-Zahrah, Reem
AU - Jordan, Valerie K.
AU - Hernandez-Garcia, Andres
AU - Wiszniewski, Wojciech K.
AU - Muzny, Donna
AU - Gibbs, Richard A.
AU - Boerwinkle, Eric
AU - Lupski, James R.
AU - Lee, Brendan
AU - Reardon, Willie
AU - Scott, Daryl A.
N1 - Publisher Copyright:
© 2015 Wiley Periodicals, Inc.
PY - 2015/4/1
Y1 - 2015/4/1
N2 - 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.
AB - 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.
KW - Congenital diaphragmatic hernia
KW - DES
KW - Exome sequencing
KW - FBN1
KW - MET
KW - Marfan syndrome
KW - Oligogenic inheritance
KW - PAX3
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U2 - 10.1002/ajmg.a.36960
DO - 10.1002/ajmg.a.36960
M3 - Article
C2 - 25736269
AN - SCOPUS:84925672333
SN - 1552-4825
VL - 167
SP - 831
EP - 836
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
IS - 4
ER -