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 congenital myasthenic syndrome 17 in 2014 (Ohkawara et al., PMID: 24234652). 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 Cenani-Lenz syndactyly syndrome has been curated separately. Two variants (c.3697G>A (p.Glu1233Lys) and c.3830G>A (p.Arg1277His)) which have been reported in one proband in one publication (PMID: 24234652) are included in this curation. The mechanism of pathogenicity is reported to be biallelic loss of function, inhibiting LRP4’s affinity for MuSK and agrin. This gene-disease relationship is also supported by an animal model, expression studies, in vitro functional assays, and biochemical function (PMIDs: 18957220, 24234652, 25319686). Conditional knockdown of Lrp4 in mice displayed progressive loss of muscle mass and strength, scoliosis, and ultimately death, consistent with a myasthenic phenotype (PMID: 25319686). Artificially engineered variants at the same functional domain as those observed in the proband (3rd β-propeller domain) compromised agrin-mediated upregulation of MuSK signaling (PMID: 24234652). The expression of LRP4 in myotubes and concentration at the neuromuscular junction as well as its role in attenuating neuronal agrin binding, MuSK activation, and induction of AChR clustering in muscle cells support this gene-disease relationship (PMID: 18957220). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 04.21.2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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