FBN1 contributing to familial congenital diaphragmatic hernia

Tyler F. Beck, Philippe M. Campeau, Shalini N. Jhangiani, Tomasz Gambin, Alexander H. Li, Reem Abo-Zahrah, Valerie K. Jordan, Andres Hernandez-Garcia, Wojciech Wiszniewski, Donna Muzny, Richard A. Gibbs, Eric Boerwinkle, James R. Lupski, Brendan Lee, Willie Reardon, Daryl A. Scott

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)831-836
Number of pages6
JournalAmerican Journal of Medical Genetics, Part A
Volume167
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

Fingerprint

Exome
Marfan Syndrome
Genes
Frameshift Mutation
Ectopia Lentis
Mutation
Hiatal Hernia
Fibrillin-1
Congenital Diaphragmatic Hernias
Diaphragm

Keywords

  • DES
  • FBN1
  • MET
  • PAX3
  • Congenital diaphragmatic hernia
  • Exome sequencing
  • Marfan syndrome
  • Oligogenic inheritance

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics
  • Medicine(all)

Cite this

Beck, T. F., Campeau, P. M., Jhangiani, S. N., Gambin, T., Li, A. H., Abo-Zahrah, R., ... Scott, D. A. (2015). FBN1 contributing to familial congenital diaphragmatic hernia. American Journal of Medical Genetics, Part A, 167(4), 831-836. https://doi.org/10.1002/ajmg.a.36960

FBN1 contributing to familial congenital diaphragmatic hernia. / Beck, Tyler F.; Campeau, Philippe M.; Jhangiani, Shalini N.; Gambin, Tomasz; Li, Alexander H.; Abo-Zahrah, Reem; Jordan, Valerie K.; Hernandez-Garcia, Andres; Wiszniewski, Wojciech; Muzny, Donna; Gibbs, Richard A.; Boerwinkle, Eric; Lupski, James R.; Lee, Brendan; Reardon, Willie; Scott, Daryl A.

In: American Journal of Medical Genetics, Part A, Vol. 167, No. 4, 01.04.2015, p. 831-836.

Research output: Contribution to journalArticle

Beck, TF, Campeau, PM, Jhangiani, SN, Gambin, T, Li, AH, Abo-Zahrah, R, Jordan, VK, Hernandez-Garcia, A, Wiszniewski, W, Muzny, D, Gibbs, RA, Boerwinkle, E, Lupski, JR, Lee, B, Reardon, W & Scott, DA 2015, 'FBN1 contributing to familial congenital diaphragmatic hernia', American Journal of Medical Genetics, Part A, vol. 167, no. 4, pp. 831-836. https://doi.org/10.1002/ajmg.a.36960
Beck TF, Campeau PM, Jhangiani SN, Gambin T, Li AH, Abo-Zahrah R et al. FBN1 contributing to familial congenital diaphragmatic hernia. American Journal of Medical Genetics, Part A. 2015 Apr 1;167(4):831-836. https://doi.org/10.1002/ajmg.a.36960
Beck, Tyler F. ; Campeau, Philippe M. ; Jhangiani, Shalini N. ; Gambin, Tomasz ; Li, Alexander H. ; Abo-Zahrah, Reem ; Jordan, Valerie K. ; Hernandez-Garcia, Andres ; Wiszniewski, Wojciech ; Muzny, Donna ; Gibbs, Richard A. ; Boerwinkle, Eric ; Lupski, James R. ; Lee, Brendan ; Reardon, Willie ; Scott, Daryl A. / FBN1 contributing to familial congenital diaphragmatic hernia. In: American Journal of Medical Genetics, Part A. 2015 ; Vol. 167, No. 4. pp. 831-836.
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AU - Li, Alexander H.

AU - Abo-Zahrah, Reem

AU - Jordan, Valerie K.

AU - Hernandez-Garcia, Andres

AU - Wiszniewski, Wojciech

AU - Muzny, Donna

AU - Gibbs, Richard A.

AU - Boerwinkle, Eric

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AU - Reardon, Willie

AU - Scott, Daryl A.

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