Whole-genome analysis reveals that mutations in inositol polyphosphate phosphatase-like 1 cause opsismodysplasia

Abstract

Opsismodysplasia is a rare, autosomal-recessive skeletal dysplasia characterized by short stature, characteristic facial features, and in some cases severe renal phosphate wasting. We used linkage analysis and whole-genome sequencing of a consanguineous trio to discover that mutations in inositol polyphosphate phosphatase-like 1 (INPPL1) cause opsismodysplasia with or without renal phosphate wasting. Evaluation of 12 families with opsismodysplasia revealed that INPPL1 mutations explain ~60% of cases overall, including both of the families in our cohort with more than one affected child and 50% of the simplex cases.

Figure 1

Characteristic Physical Findings in Children and Adults with Opsismodysplasia (A–D) Typical features of the face include relative macrocephaly, a prominent forehead, and a short nose with a depressed nasal bridge. (E and F) Acquired abnormalities resulting from undermineralization of the long bones include bowing of the upper limb (E) and/or lower limb (F). Case identifiers: AII-1 (A, E, F), AII-2 (B), FII-1 (C), and FII-2 (D), corresponding to those in Table 1, where a detailed description of each individual is provided.

Figure 2

Radiographs of Individual AII-1 at 2 Years and 11 Months of Age (A) Lateral image of skull showing midface hypoplasia and underdevelopment of the maxilla. (B) Anterior-posterior (AP) image of the pelvis showing decreased mineralization, dislocated hips, poorly formed acetabula, and loss of normal architecture of the proximal femurs. (C and E) AP image of the chest notable for under mineralization of the vertebrae and platyspondyly. (D) The metacarus, metatarsus, and all of the phalanges are short and irregular with flared metaphyses. (F and G) Delayed mineralization and absence of growth centers in the upper (F) and lower (G) limbs.

Figure 3

Genomic Structure and Allelic Spectrum of INPPL1 Mutations that Cause Opsismodysplasia INPPL1 is composed of 28 exons that encode untranslated regions (orange) and protein coding sequence (blue) domains including SH2 (red), catalytic (yellow), a proline-rich region (orange), ubiquitin-interacting region (light blue), and SAM (green). Arrows indicate the locations of nine different mutations found in seven families with opsismodysplasia. Inverted hatch mark indicates recurrent mutation.