A novel biallelic splice-site variant in the LRP4 gene causes sclerosteosis 2
- 15 May 2020
- journal article
- research article
- Published by Wiley in Birth Defects Research
- Vol. 112 (9), 652-659
- https://doi.org/10.1002/bdr2.1676
Abstract
The LRP4 gene encodes the highly conserved low-density lipoprotein receptor-related protein 4 (LRP4), which acts as a co-receptor for sclerostin. Sclerostin and LRP4 negatively regulate WNT/beta-catenin signaling pathway and lack of their inhibitory activity leads to constant osteoblastic differentiation. Consequently, increased bone formation occurs, which in the case of LRP4 mutations results in sclerosteosis type 2 (SOST2). Alterations within the LRP4 may also cause Cenani-Lenz syndactyly syndrome (CLSS), congenital myasthenia or isolated syndactyly. Here, we have reported a patient, in whom we found a novel homozygous splice-site variant c.1048+6T>C in LRP4 using whole exome sequencing. The patient was initially misdiagnosed with isolated CLSS-like or Malik-Percin-like syndactyly. However, we have finally refined the diagnosis after comprehensive radiological examination and molecularly confirmed SOST2. Additionally, we have pointed here to the splicing variants as important causative alterations that may be overlooked in the molecular analysis due to the lack of advanced, reliable algorithms, built-into the standard diagnostic pipelines. Using advanced in silico prediction tools of splice-site alterations, including Alamut Visual software, we have demonstrated that the c.1048+6T>C LRP4 variant affects the native donor site and impairs an SC35 enhancer activity. Based on our experience, we recommend comprehensive radiological imaging, including X-ray of the skull in each case of isolated syndactyly resulting from pathogenic variants of LRP4. We suggest that all previously reported patients carrying biallelic LRP4 mutations, who were diagnosed with isolated syndactyly, could actually present with SOST2 that had been unrecognized due to the incomplete clinical and radiological assessment.Funding Information
- Narodowe Centrum Badań i Rozwoju (LIDER/008/431/L‐4/12/NCBR/2013)
- Narodowe Centrum Nauki (UMO‐2016/22/E/NZ5/00270)
This publication has 28 references indexed in Scilit:
- VarSome: the human genomic variant search engineBioinformatics, 2018
- Cenani-Lenz syndactyly syndrome - a case report of a family with isolated syndactylyBMC Medical Genetics, 2018
- Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth developmentDevelopment, 2017
- Role and mechanism of action of sclerostin in boneBone, 2016
- A Novel Domain-Specific Mutation in a Sclerosteosis Patient Suggests a Role of LRP4 as an Anchor for Sclerostin in Human BoneJournal of Bone and Mineral Research, 2016
- Syndactyly/Brachyphalangy and Nail Dysplasias as Marker Lesions for SclerosteosisDermatology, 2001
- Bone Dysplasia Sclerosteosis Results from Loss of the SOST Gene Product, a Novel Cystine Knot–Containing ProteinAmerican Journal of Human Genetics, 2001
- Sclerosteosis in a Spanish male: first report in a person of Mediterranean origin.Journal of Medical Genetics, 1994
- Homozygosity Mapping: A Way to Map Human Recessive Traits with the DNA of Inbred ChildrenScience, 1987
- Totale Syndaktylie und totale radioulnare Synostose bei zwei BrüdernEuropean Journal of Pediatrics, 1967