HSPG2 was first reported in relation to autosomal recessive Schwartz-Jampel Syndrome, type 1 in 2000 (Nicole et al., PMID: 11101850) and autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type in 2001 (Arikawa-Hirasawa et al., PMID: 11279527). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism AND phenotypic variability. Therefore, the following disease entities have been split into two disease entities, Schwartz-Jampel Syndrome, type 1 (OMIM:255800), and Dyssegmental dysplasia, Silverman-Handmaker type (OMIM:224410). The split curation for autosomal recessive Dyssegmental dysplasia, Silverman-Handmaker type has been curated separately. 21 variants (including missense, nonsense, frameshift, deletions, and splice variants) have been reported in 14 probands in 6 publications (PMID: 11101850; Arikawa-Hirasawa et al., 2002, PMID: 11941538; Stum et al., 2006, PMID: 16927315; Lin et al., 2021, PMID: 33767660; Iwata et al., 2015, PMID: 26031903; Das Bhowmik et al., 2016, PMID: 27521129) and are included in this curation. The mechanism of pathogenicity is known to be loss of function hypomorphic variants. This gene-disease association is also supported by expression studies (Bauché et al., 2013, PMID: 24011702), functional alteration (Xu et al., 2016, PMID: 27578148) and animal models (Rodgers et al., 2007, PMID: 17213231; Stum et al., 2008, PMID: 18647752). In summary, HSPG2 is definitively associated with autosomal recessive Schwartz-Jampel Syndrome, type 1. 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 Gene Curation Expert Panel on the meeting date 04.26.2022 (SOP Version 8).
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