RT Journal Article SR Electronic T1 Defect in phosphoinositide signalling through a homozygous variant in PLCB3 causes a new form of spondylometaphyseal dysplasia with corneal dystrophy JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP jmedgenet-2017-104827 DO 10.1136/jmedgenet-2017-104827 A1 Salma Ben-Salem A1 Sarah M Robbins A1 Nara LM Sobreira A1 Angeline Lyon A1 Aisha M Al-Shamsi A1 Barira K Islam A1 Nadia A Akawi A1 Anne John A1 Pramathan Thachillath A1 Sania Al Hamed A1 David Valle A1 Bassam R Ali A1 Lihadh Al-Gazali YR 2017 UL http://jmg.bmj.com/content/early/2017/11/09/jmedgenet-2017-104827.abstract AB 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 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 β 3, an enzyme that converts phosphatidylinositol 4,5 bisphosphate (PIP2) 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 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 PIP2 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).