Defect in phosphoinositide signalling through a homozygous variant in causes a new form of spondylometaphyseal dysplasia with corneal dystrophy.

BACKGROUND

Bone dysplasias are a large group of disorders affecting the growth and structure of the skeletal system.

METHODS

In the present study, we report the clinical and molecular delineation of a new form of syndromic autosomal recessive spondylometaphyseal dysplasia (SMD) in two Emirati first cousins. They displayed postnatal growth deficiency causing profound limb shortening with proximal and distal segments involvement, narrow chest, radiological abnormalities involving the spine, pelvis and metaphyses, corneal clouding and intellectual disability. Whole genome homozygosity mapping localised the genetic cause to 11q12.1-q13.1, a region spanning 19.32 Mb with ~490 genes. Using whole exome sequencing, we identified four novel homozygous variants within the shared block of homozygosity. Pathogenic variants in genes involved in phospholipid metabolism, such as and are known to cause bone dysplasia with or without eye anomalies, which led us to select as a strong candidate. This gene encodes phospholipase C β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP) to inositol 1,4,5 triphosphate (IP) and diacylglycerol.

RESULTS

The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha2' element of the proximal C-terminal domain. This disrupts binding of the Ha2' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton.

CONCLUSIONS

Our results connect a homozygous loss of function variant in with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).