The LRP4 gene is located on chromosome 11 at 11p11.2, encodes a receptor for agrin and is critical for the formation and maintenance of the neuromuscular junction. LRP4 was first reported in relation to autosomal recessive Cenani-Lenz syndactyly syndrome in 2010 (Li et al., PMID: 20381006). Cenani-Lenz syndactyly syndrome is characterized by syndactyly and/or oligodactyly and commonly presents with kidney anomalies. Some patients present with sclerosteosis. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, congenital myasthenic syndrome 17 (OMIM:616304) has been split into a separate disease entity, Cenani-Lenz syndactyly syndrome (OMIM:212780) and sclerosteosis 2 (OMIM:614305) have been lumped together. The split curation for autosomal recessive congenital myasthenic syndrome 17 has been curated separately. Sixteen variants (missense, canonical splice site, and frameshift) that have been reported in 14 probands in seven publications (PMIDs: 20381006, 21471202, 28559208, 29524275, 32286743, 33179409, 35052419) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function, causing increased WNT signaling. This gene-disease relationship is also supported by animal models, expression studies, biochemical function, and in vitro functional assays (PMIDs: 21471202, 28477420, 30327840, 34857885). The homozygous knockin mouse model displayed increased bone mass (PMID: 28477420) and the homozygous knockdown of Zebrafish lrp4 resulted in syndactyly (PMID: 30327840). Multiple variants showed impaired ability to inhibit WNT signaling (PMIDs: 30327840, 34857885). LRP4 is expressed in osteoblasts and osteocytes, is a facilitator of SOST inhibition of Wnt1/β-catenin signaling, and binds with SOST which is associated with recessive forms of sclerosteosis per ClinGen’s Dosage Sensitivity Working Group. In summary, there is definitive evidence supporting the relationship between LRP4 and autosomal recessive Cenani-Lenz syndactyly syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 04.21.2023 (SOP Version 9).
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