SLC7A3 – Autism Spectrum Disorder

The SLC7A3 gene encodes the CAT-3 cationic amino acid transporter, mediating neuronal uptake of arginine, ornithine, and lysine. It is located on the X chromosome and exhibits selective expression in brain tissue. SLC7A3 is highly intolerant to variation, with low deleterious allele frequency in control populations (PMID:26215737). Prior to 2015, human phenotypes had not been definitively linked to CAT-3 dysfunction. A seminal study then implicated rare hypomorphic SLC7A3 variants in male subjects with autism spectrum disorder. These findings have since provided a new avenue for understanding ASD pathogenesis.

In a discovery cohort of two brothers with ASD, exome sequencing identified a hemizygous missense variant in SLC7A3. This initial observation prompted targeted sequencing of the coding region in 148 unrelated male ASD patients, yielding three additional rare missense alleles in independent cases (PMID:26215737). All carriers were hemizygous males, consistent with an X-linked recessive inheritance mode. One proband presented with high-functioning autism and epilepsy and also harbored a de novo 16p11.2 duplication potentially modifying his phenotype. No healthy male carriers were reported in cohort or public databases. These genetic data suggest that SLC7A3 variation may contribute to ASD risk in males.

Overall, five hemizygous male probands across four unrelated families were identified with SLC7A3 variants (PMID:26215737). A segregation analysis in the sib-pair confirmed maternal transmission in one family (affected_relatives = 1). Clinical information from extended pedigrees is limited, but co-segregation in the two brothers supports a pathogenic role. No female carriers exhibited ASD, suggesting sex-specific penetrance. Carrier frequency in control males is negligible, consistent with rarity of these alleles. These genetic observations support a Moderate level of clinical validity.

All four reported variants were missense changes leading to single amino acid substitutions. Although specific HGVS strings were not provided in the publication, functional assays defined two alleles with severe loss of CAT-3 activity and two with moderate impairment (PMID:26215737). The hypomorphic nature of these variants suggests a partial loss-of-function mechanism. No truncating, splice, or deep-intronic variants were described in the ASD cohort. Recurrent or founder alleles have not been observed. Population allele frequencies in ExAC and gnomAD are exceptionally low.

In vitro functional studies in heterologous cells demonstrated that two variants cause altered protein stability, reducing total CAT-3 levels at the plasma membrane. The other two variants exhibited abnormal intracellular trafficking, leading to retention away from the cell surface (PMID:26215737). Transport assays measuring uptake of radiolabeled arginine confirmed severe or moderate loss of cationic amino acid flux for these alleles. These concordant results establish a hypomorphic mechanism that plausibly disrupts neuronal amino acid homeostasis. No rescue experiments were reported. The functional concordance across independent assays strengthens the gene–disease association.

While these findings implicate SLC7A3 hypomorphic variants in male ASD, additional genetic factors may be required for full phenotypic expression, as illustrated by the co-occurrence of a 16p11.2 duplication in the most severely affected proband. The X-linked recessive inheritance pattern predicts risk predominantly in males, with heterozygous females likely asymptomatic carriers. There is no reported evidence for de novo SLC7A3 variants or autosomal cases. Penetrance estimates remain undefined given the small sample size. Segregation data beyond the initial sib-pair are lacking. Larger cohorts and population studies are needed to clarify penetrance and expressivity.

In summary, SLC7A3 demonstrates a Moderate level of clinical validity for contribution to ASD in male subjects based on five hemizygous cases, segregation in one sib-pair, and concordant functional evidence of hypomorphic transporter activity. This association is categorized as Moderate within ClinGen frameworks. Genetic testing for SLC7A3 variants should be considered in male ASD patients, particularly those with comorbid epilepsy. Functional assessment can aid interpretation of missense alleles. Further studies should expand case series, explore female carriers, and assess genotype–phenotype correlations. Key take-home: Hypomorphic SLC7A3 variants lead to partial CAT-3 loss-of-function and represent a clinically actionable genetic contributor to autism spectrum disorder in males.

References

• Amino acids • 2015 • Hypomorphic variants of cationic amino acid transporter 3 in males with autism spectrum disorders. PMID:26215737

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