Family-based whole-exome sequencing identifies novel loss-of-function mutations of FBN1 for Marfan syndrome.

Zhening Pu,Keshuai He,Yongfeng Shao,Weidong Gu,Junjie Du,Yue Cheng,Buqing Ni,Haoliang Sun,Juncheng Dai

doi:10.7717/peerj.5927

Abstract

BackgroundMarfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. Our purpose was to investigate the role of novel genetic variants in determining MFS clinical phenotypes.MethodsWe sequenced the whole exome of 19 individuals derived from three Han Chinese families. The sequencing data were analyzed by a standard pipeline. Variants were further filtered against the public database and an in-house database. Then, we performed pedigree analysis under different inheritance patterns according to American College of Medical Genetics guidelines. Results were confirmed by Sanger sequencing.ResultsTwo novel loss-of-function indels (c.5027_5028insTGTCCTCC, p.D1677Vfs*8; c.5856delG, p.S1953Lfs*27) and one nonsense variant (c.8034C>A, p.Y2678*) of FBN1 were identified in Family 1, Family 2 and Family 3, respectively. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously.ConclusionsOur study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS.

Highlights

Marfan syndrome (MFS) is an inherited connective tissue disorder with autosomal dominant transmission
We identified three novel loss of function (LOF) mutations in FBN1 likely to cause MFS in these patients
MFS was diagnosed through a medical record review, physical examination and family history based on Ghent nosology: (i) Ectopia lentis; (ii) Systemic score ! 7; (iii) Aortic root Z-score ! 2, when there is history of MFS in a primary relative (Loeys et al, 2010)

Summary

Introduction

Marfan syndrome (MFS) is an inherited connective tissue disorder with autosomal dominant transmission. Marfan syndrome (MFS) is an inherited connective tissue disorder affecting the ocular, skeletal and cardiovascular systems. Previous studies of MFS have demonstrated the association between genetic defects and clinical manifestations. All affected members carried pathogenic mutations, whereas other unaffected family members or control individuals did not. These different kinds of loss of function (LOF) variants of FBN1 were located in the cbEGF region and a conserved domain across species and were not reported previously. Conclusions: Our study extended and strengthened the vital role of FBN1 LOF mutations in the pathogenesis of MFS with an autosomal dominant inheritance pattern. We confirm that genetic testing by next-generation sequencing of blood DNA can be fundamental in helping clinicians conduct mutation-based pre- and postnatal screening, genetic diagnosis and clinical management for MFS

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Discussion

Conclusion