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

BMC Musculoskeletal Disorders

Research Article

Lifeng Tian¹  Rosetta M. Chiavacci¹  Michael E. March¹  Dong Li¹  Christopher J. Cardinale¹  John J. Connolly¹  Cuiping Hou¹  Fengxiang Wang¹  Cecilia E. Kim¹  James Snyder¹  Hakon Hakonarson²  Patrick M. Sleiman²  Jon M. Burnham³ 

[1] Center for Applied Genomics, Abramson Pediatric Research Center, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, 19104, Philadelphia, PA, USA;Center for Applied Genomics, Abramson Pediatric Research Center, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, 19104, Philadelphia, PA, USA;Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 19104, Philadelphia, PA, USA;Division of Rheumatology, Department of Pediatrics, The Children’s Hospital of Philadelphia, 19104, Philadelphia, PA, USA;

关键词: Whole exome sequencing;    Systemic sclerosis;    Scleroderma;    NOTCH4;    Mendelian genetics;   

DOI  :  10.1186/s12891-016-1320-4

 received in 2016-07-30, accepted in 2016-11-01,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundSystemic 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.MethodsWe 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.ResultsBioinformatic 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.ConclusionThis 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.

【 授权许可】

CC BY   
© The Author(s). 2016