Alternative titles; symbols
ORPHA: 777; DO: 0112029;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.3-p11.23 | Intellectual developmental disorder, X-linked 50 | 300115 | X-linked | 3 | SYN1 | 313440 |
A number sign (#) is used with this entry because of evidence that X-linked intellectual developmental disorder-50 (XLID50) is caused by hemizygous mutation in the SYN1 gene (313440) on chromosome Xp11.
X-linked intellectual developmental disorder-50 (XLID50) is a neurodevelopmental disorder characterized by impaired intellectual development accompanied variably by short stature, autistic features, and brain imaging anomalies. Seizures are not present. Carrier females may be affected.
Hemizygous mutation in the SYN1 gene also causes X-linked epilepsy with variable learning disabilities and behavior disorders (EPILX1; 300491), which shows overlapping features.
Claes et al. (1997) reported a family (MRX50) in which 4 males spanning 2 generations had impaired intellectual development apparent from early childhood. Additional phenotypic abnormalities were not noted, although the patients tended to have short stature and mild macrocephaly. One obligate female carrier had reduced intelligence. In a follow-up of the MRX50 family reported by Claes et al. (1997), Guarnieri et al. (2017) noted that the phenotype was nonsyndromic: none of the patients had seizures or autism spectrum disorder.
Darvish et al. (2020) reported 3 brothers, born of unrelated parents from the Middle East (family 05), with XLID50. Clinical details were limited, but they had impaired intellectual development from early childhood, mental regression, and autistic features. None had seizures. Other features included abnormal eye contact, language problems, sphincter dysfunction, and generalized frontal atrophy on brain imaging. One of the brothers had died; DNA was not available from this patient.
The transmission pattern of MRX50 in the family reported by Claes et al. (1997) was consistent with X-linked recessive inheritance, although female carriers may show mild manifestations.
Linkage analysis in the MRX50 family by Claes et al. (1997) showed location of the locus at Xp11.3-p11.21 in the pericentromeric part of the short arm of the X chromosome, overlapping with a large number of other MRX gene regions: MRX1 (309530), MRX5, MRX7, MRX8, MRX9 (309549), MRX10, MRX11, MRX12 (300957), MRX13, MRX14 (300062), MRX15, MRX18, MRX22, MRX26, MRX31, and MRX38 (see 300419). Gedeon et al. (1996) hypothesized that all of the MRX assignments clustered on the pericentromeric part of Xp could be accounted for by 2 gene locations, namely the MRX1 and the MRX10 locations. Some of these families with pericentromeric gene locations show additional characteristic abnormalities and some of them show manifestations of disease in heterozygous carriers. Claes et al. (1997) commented that whether these clinical differences reflect allelic variability or locus heterogeneity will become clear only after the cloning of the responsible genes.
In affected members of the MRX50 family (family L027) previously reported by Claes et al. (1997), Guarnieri et al. (2017) identified a hemizygous missense mutation in the SYN1 gene (S79W; 313440.0005). The mutation, which was found by direct sequencing of the SYN1 gene, segregated with the disorder in the family. It was not present in the dbSNP, 1000 Genomes Project, Exome Variant Server, or ExAC databases. In vitro functional expression studies in HeLa cells transfected with the mutation showed that the mutant protein was expressed at normal levels and formed large abnormal perinuclear aggregates that sequestered SYP (313475) and were Triton-soluble. Ultrastructural studies showed the presence of large clusters of small clear vesicles. Similar abnormal vesicle formation was observed in murine primary hippocampal cells transfected with the mutation. Although the mutation did not appear to affect early neuronal development, neurite length, or axonal branching, electrophysiologic studies showed that it was associated with increased numbers of synaptic vesicles at the presynaptic membrane and increased frequency of miniature excitatory postsynaptic currents (mESPSCs) compared to controls. Cells transfected with the mutation showed clustering of vesicles at the synaptic boutons and decreased dispersion along axons compared to wildtype SYN1. The findings suggested that the S79W mutation perturbs spontaneous vesicle exocytosis, clustering, and lateral mobility along axons, which likely disrupts the dynamics of synaptic plasticity, resulting in learning and cognitive deficits.
In 2 brothers, born of unrelated parents from the Middle East (family 05), with XLID50, Darvish et al. (2020) identified a hemizygous missense mutation in the SYN1 gene (R420Q; 313440.0006). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The mutation was not present in public databases, including gnomAD. Primary hippocampal neurons transfected with the mutation in vitro showed decreased expression of the mutant protein compared to controls, and also demonstrated significantly decreased neurite outgrowth compared to controls.
In a 21-year-old man (family 1402) who presented at age 5 years with mild intellectual disability and autistic features, Ibarluzea et al. (2020) identified a heterozygous missense (V266M) variant in the SYN1 gene. The variant was inherited from the unaffected mother and was present in a maternal uncle who had low-normal intellect and schizophrenia. Functional studies of the variant were not performed, and the authors classified it as a variant of unknown significance (VUS).
Reclassified Variants
The T567A variant (313440.0004) reported by Fassio et al. (2011) has been reclassified as a variant of unknown significance. In 2 unrelated males from a cohort segregating autism spectrum disorder, Fassio et al. (2011) identified a hemizygous missense mutation (T567A; 313440.0004) in the SYN1 gene. The mutation was not found in 709 control chromosomes. In vitro functional expression assays showed that the mutation impaired normal synaptic vesicle trafficking in mouse hippocampal cells lacking the Syn1 gene. There was impaired release of vesicles from the reserve and readily releasable pools, consistent with a loss of function. The mutant T567A protein did not properly localize to the presynapse. One of the patients also carried an ala51-to-glu (A51G) substitution in the SYN1 gene on the same allele, which may have caused an effect on protein function, but functional studies were not performed on the A51G variant. The T567A mutation did not affect phosphorylation of the SYN1 protein or binding to SH3 domains of other proteins.
Claes, S., Vogels, A., Holvoet, M., Devriendt, K., Raeymaekers, P., Cassiman, J. J., Fryns, J. P. Regional localization of two genes for nonspecific X-linked mental retardation to Xp22.3-p22.2 (MRX49) and Xp11.3-p11.21 (MRX50). Am. J. Med. Genet. 73: 474-479, 1997. [PubMed: 9415477]
Darvish, H., Azcona, L. J., Tafakhori, A., Mesias, R., Ahmadifard, A., Sanchez, E., Habibi, A., Alehabib, E., Johari, A. H., Emamalizadeh, B., Jamali, F., Chapi, M., Jamshidi, J., Kajiwara, Y., Paisan-Ruiz, C. Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes. Sci. Rep. 10: 968, 2020. [PubMed: 31969655] [Full Text: https://doi.org/10.1038/s41598-020-57929-4]
Fassio, A., Patry, L., Congia, S., Onofri, F., Piton, A., Gauthier, J., Pozzi, D., Messa, M., Defranchi, E., Fadda, M., Corradi, A., Baldelli, P., and 9 others. SYN1 loss-of-function mutations in autism and partial epilepsy cause impaired synaptic function. Hum. Molec. Genet. 20: 2297-2307, 2011. [PubMed: 21441247] [Full Text: https://doi.org/10.1093/hmg/ddr122]
Gedeon, A. K., Donnelly, A. J., Mulley, J. C., Kerr, B., Turner, G. How many X-linked genes for non-specific mental retardation (MRX) are there? Am. J. Med. Genet. 64: 158-162, 1996. [PubMed: 8826466] [Full Text: https://doi.org/10.1002/(SICI)1096-8628(19960712)64:1<158::AID-AJMG26>3.0.CO;2-L]
Guarnieri, F. C., Pozzi, D., Raimondi, A., Fesce, R., Valente, M. M., Delvecchio, V. S., Van Esch, H., Matteoli, M., Benfenati, F., D'Adamo, P., Valtorta, F. A novel SYN1 missense mutation in non-syndromic X-linked intellectual disability affects synaptic vesicle life cycle, clustering and mobility. Hum. Molec. Genet. 26: 4699-4714, 2017. [PubMed: 28973667] [Full Text: https://doi.org/10.1093/hmg/ddx352]
Ibarluzea, N., de la Hoz, A. B., Villate, O., Llano, I., Ocio, I., Marti, I., Guitart, M., Gabau, E., Andrade, F., Gener, B., Tejada, M. I. Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes (Basel) 11: 51, 2020. [PubMed: 31906484] [Full Text: https://doi.org/10.3390/genes11010051]