In SYP (also known as synaptophysin or p38) an additional nonsense variant was found in one of the 914 additional XLMR-affected subjects and an additional 4-bp deletion was identified in a second XLMR-affected subject (Fig. 1a and Table 4). The nonsense mutation showed evidence of segregation with mental retardation (lod score 1.2). Samples were not available for evaluation of the 4-bp deletion. No SYP truncating variants were found in the additional 1,129 controls. Together with the data from the primary screen, three SYP truncating variants were found in 1,122 XLMR-affected subjects examined, two of which have been examined and segregate with the disease (combined lod score 1.7), and there were no truncating variants in 1,401 controls. A missense variant found in a single subject with mental retardation at an amino acid residue that is highly conserved and which segregated with mental retardation (lod score 1.8) is also likely to be implicated in disease causation (Table 4). These data implicate SYP in XLMR. In the three families with truncating variants, mental retardation was mild to moderate and there were no consistent additional features, although epilepsy was noted in some individuals. SYP encodes an integral membrane protein of small synaptic vesicles.
