Submission Details

Variants in SYP were first reported in relation to non-syndromic X-linked intellectual disability in 2009 (Tarpey et al., PMID: 19377476). Four variants were identified in families with two or more males with intellectual disability, including 2 frameshift, 1 nonsense, and 1 missense variants. Two of these variants segregated with the phenotype in males from large multigenerational pedigrees. The phenotype description was limited; in the three families with truncating variants, intellectual disability was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. Subsequent functional studies showed that the 4 variants failed to rescue the synaptic vesicle transport deficits in cultured neurons derived from Syp KO mice (PMID: 23966691). Two other missense variants have been reported in humans since then (Philips et al., PMID: 24721225 and Harper et al., PMID: 28887151), but both were later found to have high population frequencies in gnomAD. According to gnomAD (v.2.1.1), SYP is constrained for loss of function variants (pLI = 0.92) but not missense variants (Z score = 1.33). The mechanism for disease is loss of function. This gene-disease association is further supported by gene expression studies and functional studies in hippocampal cultures of Syp knockout mice (1.5 points). In summary, there is moderate evidence to support the association between SYP and non-syndromic X-linked intellectual disability. Given that no other families with pathogenic SYP variants have been identified since the original report by Tarpey et al. in 2009, additional genetic evidence is necessary to strengthen this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/16/2020 (SOP Version 8).

Variants in SYP were first reported in relation to non-syndromic X-linked intellectual disability in 2009 (Tarpey et al., PMID: 19377476). Four variants were identified in families with two or more males with intellectual disability, including 2 frameshift, 1 nonsense, and 1 missense variants. Two of these variants segregated with the phenotype in males from large multigenerational pedigrees. The phenotype description was limited; in the three families with truncating variants, intellectual disability was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. Subsequent functional studies showed that the 4 variants failed to rescue the synaptic vesicle transport deficits in cultured neurons derived from Syp knockout mice (PMID: 23966691). Two other missense variants have been reported in humans since then (Philips et al., PMID: 24721225 and Harper et al., PMID: 28887151), but both were later found to have high population frequencies in gnomAD. According to gnomAD (v.2.1.1), SYP is constrained for loss of function variants (pLI = 0.92) but not missense variants (Z score = 1.33). The mechanism for disease is loss of function. This gene-disease relationship is also supported by functional studies in hippocampal cultures of Syp knockout mice.

In summary, there is moderate evidence to support the relationship between SYP and non-syndromic X-linked intellectual disability. Given that no other families with pathogenic SYP variants have been identified since the original report by Tarpey et al. in 2009, additional genetic evidence is necessary to strengthen this gene-disease relationship. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 16, 2020 (SOP Version 8).