%0 Journal Article
%T Association of a rare NOTCH4 coding variant with systemic sclerosis: a family-based whole exome sequencing study.
%A Cardinale CJ
%A Li D
%A Tian L
%A Connolly JJ
%A March ME
%A Hou C
%A Wang F
%A Snyder J
%A Kim CE
%A Chiavacci RM
%A Sleiman PM
%A Burnham JM
%A Hakonarson H
%J BMC Musculoskelet Disord
%V 17
%N 1
%D 11 2016 9
%M 27829420
%F 2.562
%R 10.1186/s12891-016-1320-4
%X 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.<BR>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.<BR>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.<BR>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.