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



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.



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 × 10-5by the data of the Exome Aggregation Consortium.



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.
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Christopher J
CJ
Cardinale
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Dong
D
Li
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Lifeng
L
Tian
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
John J
JJ
Connolly
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Michael E
ME
March
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Cuiping
C
Hou
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Fengxiang
F
Wang
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
James
J
Snyder
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Cecilia E
CE
Kim
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.
Rosetta M
RM
Chiavacci
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Patrick M
PM
Sleiman
Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.|Division of Rheumatology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
Jon M
JM
Burnham
Center for Applied Genomics, Abramson Pediatric Research Center, The Children's Hospital of Philadelphia, 3615 Civic Center Blvd Ste 1216, Philadelphia, PA, 19104, USA. hakonarson@chop.edu.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. hakonarson@chop.edu.
Hakon
H
Hakonarson
D000483:Alleles; D002648:Child; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D019295:Computational Biology; D059472:Exome / Q000235:genetics*; D005260:Female; D005799:Genes, Dominant / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D000066502:Grandparents; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D019683:Penetrance; D000072417:Protein Domains / Q000235:genetics; D000074562:Receptor, Notch4 / Q000235:genetics*; D012595:Scleroderma, Systemic / Q000235:genetics*; D017422:Sequence Analysis, DNA
C106075:NOTCH4 protein, human; D000074562:Receptor, Notch4
Mendelian genetics; NOTCH4; Scleroderma; Systemic sclerosis; Whole exome sequencing