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Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome
Author(s) -
StaretzChacham Orna,
Shukrun Rachel,
Barel Ortal,
PodeShakked Ben,
Pleniceanu Oren,
Anikster Yair,
Shalva Nechama,
Ferreira Carlos R.,
BenHaim Kadosh Admit,
Richardson Justin,
Mane Shrikant M.,
Hildebrandt Friedhelm,
Vivante Asaf
Publication year - 2019
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61334
Subject(s) - mutation , phenotype , genetic heterogeneity , medicine , etiology , exome sequencing , pseudoxanthoma elasticum , genetics , pathology , biology , gene
Generalized arterial calcifications of infancy (GACI) is caused by mutations in ENPP1 . Other ENPP1 ‐related phenotypes include pseudoxanthoma elasticum, hypophosphatemic rickets, and Cole disease. We studied four children from two Bedouin consanguineous families who presented with severe clinical phenotype including thrombocytopenia, hypoglycemia, hepatic, and neurologic manifestations. Initial working diagnosis included congenital infection; however, patients remained without a definitive diagnosis despite extensive workup. Consequently, we investigated a potential genetic etiology. Whole exome sequencing (WES) was performed for affected children and their parents. Following the identification of a novel mutation in the ENPP1 gene, we characterized this novel multisystemic presentation and revised relevant imaging studies. Using WES, we identified a novel homozygous mutation (c.556G > C; p.Gly186Arg) in ENPP1 which affects a highly conserved protein domain (somatomedin B2). ENPP1 ‐associated genetic diseases exhibit phenotypic heterogeneity depending on mutation type and location. Follow‐up clinical characterization of these families allowed us to revise and detect new features of systemic calcifications, which established the diagnosis of GACI, expanding the phenotypic spectrum associated with ENPP1 mutations. Our findings demonstrate that this novel ENPP1 founder mutation can cause a fatal multisystemic phenotype, mimicking severe congenital infection. This also represents the first reported mutation affecting the SMB2 domain, associated with GACI.