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Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study.

Abstract：

BACKGROUND:Systemic sclerosis (SSc) is a rheumatologic disease with a multifactorial etiology. Genome-wide association studies imply a polygenic, complex mode of inheritance with contributions from variation at the human leukocyte antigen locus and non-coding variation at a locus on chromosome 6p21, among other modestly impactful loci. Here we describe an 8-year-old female proband presenting with diffuse cutaneous SSc/scleroderma and a family history of SSc in a grandfather and maternal aunt. METHODS:We employed whole exome sequencing (WES) of three members of this family. We examined rare missense, nonsense, splice-altering, and coding indels matching an autosomal dominant inheritance model. We selected one missense variant for Sanger sequencing confirmation based on its predicted impact on gene function and location in a known SSc genetic locus. RESULTS:Bioinformatic analysis found eight candidate variants meeting our criteria. We identified a very rare missense variant in the regulatory NODP domain of NOTCH4 located at the 6p21 locus, c.4245G > A:p.Met1415Ile, segregating with the phenotype. This allele has a frequency of 1.83 × 10-5 by the data of the Exome Aggregation Consortium. CONCLUSION:This family suggests a novel mechanism of SSc pathogenesis in which a rare and penetrant coding variation can substantially elevate disease risk in contrast to the more modest non-coding variation typically found at this locus. These results suggest that modulation of the NOTCH4 gene might be responsible for the association signal at chromosome 6p21 in SSc.

journal_name

BMC Musculoskelet Disord

journal_title

BMC musculoskeletal disorders

authors

Cardinale CJ,Li D,Tian L,Connolly JJ,March ME,Hou C,Wang F,Snyder J,Kim CE,Chiavacci RM,Sleiman PM,Burnham JM,Hakonarson H

doi

10.1186/s12891-016-1320-4

subject

Has Abstract

pub_date

2016-11-09 00:00:00

pages

462

issue

1

issn

1471-2474

pii

10.1186/s12891-016-1320-4

journal_volume

17

pub_type

杂志文章

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