Novel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.

TitleNovel homozygous ENPP1 mutation causes generalized arterial calcifications of infancy, thrombocytopenia, and cardiovascular and central nervous system syndrome.
Publication TypeJournal Article
Year of Publication2019
AuthorsStaretz-Chacham, O, Shukrun, R, Barel, O, Pode-Shakked, B, Pleniceanu, O, Anikster, Y, Shalva, N, Ferreira, CR, Kadosh, ABen-Haim, Richardson, J, Mane, SM, Hildebrandt, F, Vivante, A
JournalAm J Med Genet A
Volume179
Issue10
Pagination2112-2118
Date Published2019 Oct
ISSN1552-4833
Abstract

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.

DOI10.1002/ajmg.a.61334
Alternate JournalAm. J. Med. Genet. A
PubMed ID31444901
Grant List / / Fulbright Post-doctoral Scholar Award /
/ / Mallinckrodt Research Fellowship Award /
/ / Manton Center Fellowship /
U54 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01-DK076683 / NH / NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States
R01-DK076683 / NH / NIH HHS / United States