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

Orna Staretz-Chacham, Rachel Shukrun, Ortal Barel, Ben Pode-Shakked, Oren Pleniceanu, Yair Anikster, Nechama Shalva, Carlos R. Ferreira, Admit Ben-Haim Kadosh, Justin Richardson, Shrikant M. Mane, Friedhelm Hildebrandt, Asaf Vivante

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Pages (from-to)2112-2118
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume179
Issue number10
DOIs
StatePublished - 1 Oct 2019

Keywords

  • ENPP1
  • WES
  • generalized arterial calcifications of infancy

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