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).
- spondylometaphyseal dysplasia with corneal dystrophy (smdcd)
- hypomorphic variant
- pip2 accumulation
- disorganization of actin cytoskeletal network
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ASHG 2016 by SMR as poster presentation: PgmNr 2339, Oct 18-22, Vancouver, CANADA.
*SBS and SMR contributed equally to this work, with standard working and abbreviations.
Contributors All authors made a significant contribution to data collection, data interpretation and critical assessment of this study. Specifically, SBS, SMR, NLMS, DV, BRA and AL contributed to study design and concept. LA initiated the study, recruited the family, and performed clinical evaluations of the patients. AMA helped in patients assessment and clinical tests. SBS and NLMS analyzed WES data and Sanger sequencing. SBS and SMR performed functional studies. AL and BKI have done the molecular modeling. NAA and AJ helped in Sanger sequencing. SAH helped in blood sample collection. PT isolated the genomic DNA from blood samples. LA, DV and BRA coordinated the study. All authors read and approved the final manuscript.
Funding The laboratories of LA and BRA are funded by the United Arab Emirates University (grant #31M241). This work was also supported by NHGRI grants 2T32GM07814 to the Baylor-Hopkins Center for Mendelain Genomics and UM1HG006542.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Al-Ain District Human Research Ethics Committees (protocol number ERH-2015â€“324115â€“115).
Provenance and peer review Not commissioned; externally peer reviewed.
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