Defect in phosphoinositide signalling through a homozygous variant in PLCB3 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 similar to 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 PLCB4 and PCYT1A, are known to cause bone dysplasia with or without eye anomalies, which led us to select PLCB3 as a strong candidate. This gene encodes phospholipase C beta 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP 2) to inositol 1,4,5 triphosphate (IP3) and diacylglycerol. Results The identified variant (c.2632G>T) substitutes a serine for a highly conserved alanine within the Ha' element of the proximal C-terminal domain. This disrupts binding of the Ha' element to the catalytic core and destabilises PLCB3. Here we show that this hypomorphic variant leads to elevated levels of PIP 2 in patient fibroblasts, causing disorganisation of the F-actin cytoskeleton. Conclusions Our results connect a homozygous loss of function variant in PLCB3 with a new SMD associated with corneal dystrophy and developmental delay (SMDCD).