SYP

Inheritance Pattern: XL

Disease ID:MONDO:0010429

Submitter: G2P

Inheritance Pattern: XL

Disease ID:MONDO:0010429

Submitter: PanelApp Australia

Inheritance Pattern: XL

Disease ID:MONDO:0010429

Submitter: Ambry Genetics

Inheritance Pattern: XL

Disease ID:MONDO:0010429

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

*SYP* is located on chromosome Xp11.23 and encodes synaptophysin, a synaptic vesicle membrane protein that regulates synaptic vesicle endocytosis. *SYP* was 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 two frameshift variants (one predicted to result in premature truncation and one leading to protein elongation), one nonsense variant, and one missense variant. The missense variant segregated with the phenotype in males from a multigenerational pedigree. The phenotype description was limited; in the three families with frameshift or nonsense 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 none of the four variants could fully rescue the synaptic vesicle transport deficits in cultured neurons derived from *Syp* knockout mice (PMID: 23966691). The two variants resulting in premature truncation showed mislocalization and impaired synaptobrevin II retrieval from the plasma membrane after exocytosis, whereas the frameshift variant leading to elongation and the missense variant were correctly localized but showed impaired synaptobrevin II retrieval (PMID: 23966691). Three other missense variants have been reported since then (PMIDs: 24721225, 28887151, 32193494), but two were later found to have high population frequencies in gnomAD. Of note, one of the missense variants, present in 40 hemizygotes in gnomAD v4, exhibited impaired activity-dependent synaptobrevin II retrieval when expressed in neurons, similar to what is observed in *Syp* knockout neurons (PMID: 28887151), calling into question the relevance of this alteration for the interpretation of variant pathogenicity. According to gnomAD (v4.1.1), *SYP* is constrained for loss-of-function variants (pLI = 1, LOEUF = 0.26) but not missense variants (Z score = 1.32). The mechanism of pathogenicity appears to be complete or partial loss of function (PMID: 23966691). This gene-disease relationship is also supported by a *Syp* knockout mouse model (PMID: 19393300) with impaired learning and memory, and functional studies in hippocampal cultures of *Syp* knockout mice (PMID: 21658579). 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 gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel in 2018 and reevaluated on December 16, 2020. It was reevaluated again on September 2, 2026 (SOP Version 12). As a result of this reevaluation, no additional patients were identified. Although a mouse model was added, the classification did not change.

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

Inheritance Pattern: XL

Disease ID:MONDO:0010429

Submitter: Illumina

The SYP gene is located on chromosome X at Xp11.23 and encodes the synaptophysin protein, which is associated with regulation of synaptic vesicle endocytosis and is the most abundant synaptic vesicle protein by mass, accounting for about 10% of total vesicle protein. Variants in the SYP gene were first reported in relation to X-linked intellectual disability in 2007 (19377476: Tarpey et al. 2009). This study reported two frameshift variants predicted to result in premature truncation and one each of a frameshift variant leading to elongation and a missense variant. The two frameshift variants resulting in premature truncation, showed mislocalization and impaired synaptobrevin II retreival in syp-/- cultured neurons (23966691: Gordon and Cousin, 2013). The missense variant and the frameshift variant leading to elongation only showed impaired synaptobrevin II retreival. 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 thatcontradicts the gene-disease relationship.