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OCRL1  and its paralog  INPP5B  encode phosphatidylinositol 5-phosphatases that localize to the primary cilium and have roles in ciliogenesis. Mutations in  OCRL1  cause the X-linked Dent disease type 2 (DD2; OMIM# 300555), characterized by low-molecular weight proteinuria, hypercalciuria, and the variable presence of cataracts, glaucoma and intellectual disability without structural brain anomalies. Disease-causing mutations in  INPP5B  have not been described in humans. Here, we report the case of an 11-year-old boy with short stature and an above-average IQ; severe proteinuria, hypercalciuria and osteopenia resulting in a vertebral compression fracture; and Chiari I malformation with cervico-thoracic syringohydromyelia requiring suboccipital decompression. Sequencing revealed a novel,  de novo  DD2-causing 462 bp deletion disrupting exon 3 of  OCRL1  and a maternally inherited, extremely rare (ExAC allele frequency 8.4×10 −6 ) damaging missense mutation in  INPP5B  (p.A51V). This mutation substitutes an evolutionarily conserved amino acid in the protein’s critical PH domain.  In silico  analyses of mutation impact predicted by SIFT, PolyPhen2, MetaSVM and CADD algorithms were all highly deleterious. Together, our findings report a novel association of DD2 with Chiari I malformation and syringohydromyelia, and document the effects of digenic mutation of human  OCRL  paralogs. These findings lend genetic support to the hypothesis that impaired ciliogenesis may contribute to the development of Chiari I malformation, and implicates OCRL-dependent PIP 3  metabolism in this mechanism.

Digenic mutations of human OCRL paralogs in Dent’s disease type 2 associated with Chiari I malformation