Introduction: 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, and his associated genetic findings.
Methods: DNA samples were isolated from the patient and both biological parents. Genomic DNA was extracted from buccal swabs. Targeted exome capture followed by 74 base paired-end sequencing on the Illumina HiSeq 2000 platform. Bioinformatic analysis called de novo and transmitted single nucleotide variants and insertions/deletions. Candidate mutations were confirmed by Sanger sequencing.
PCR-based screens of known Dent-causing genes (CLCN5, OCRL1) were performed.
Results: 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 deleterious. No mutations were detected on the coding regions of CLCN5.
Conclusions: 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 PIP3 metabolism in this mechanism.
Patient Care: A better understanding of the molecular mechanisms underlying the development of frequently encountered pediatric neurosurgical conditions such as Chiari malformations and syringohydromyelia may open doors for improved early genetic diagnosis, prognosis and treatment strategies.
Learning Objectives: The role of PIP3 metabolism in neurosurgically-relevant brain structural malformations; The use of whole-exome sequencing as a means of identifying variants in rare cases that present with neurosurgical diseases.