SLC38A3 – Developmental and Epileptic Encephalopathy

This summary evaluates the association between SLC38A3 and developmental and epileptic encephalopathy. Multiple independent studies have identified that biallelic deleterious variants in SLC38A3 are causative of a severe neurodevelopmental disorder. The evidence originates from a multi‐patient study reporting 10 individuals from 7 unrelated families, establishing a robust link between strict genotype and the consistent clinical phenotype observed (PMID:34605855).

Affected individuals present with a spectrum of clinical features including global developmental delay, seizures, visual impairment, intellectual disability, hypotonia, absent speech, and microcephaly. The uniform manifestation of these symptoms across disparate populations reinforces the clinical validity of the association. In at least one family, segregation analysis revealed that affected siblings harbored the deleterious variants, thereby further supporting the inheritance pattern (PMID:34605855).

Genetic evidence encompasses a variety of variant types, including splicing, missense, and truncating mutations. One representative variant is c.1123A>C (p.Thr375Pro), which complies with the established HGVS guidelines. The allelic heterogeneity observed across the reported families underscores the pathogenic relevance of SLC38A3 variants in this disorder (PMID:34605855).

Complementary functional assays demonstrate that the glutamine transporter SNAT3, encoded by SLC38A3, exhibits altered conductance properties when modulated by carbonic anhydrases. Experiments performed in Xenopus oocytes indicate that co-expression with various carbonic anhydrase isoforms specifically alters SNAT3 function in a substrate-dependent manner, providing a mechanistic explanation for the neurodevelopmental phenotype (PMID:21325825).

The disorder follows an autosomal recessive mode of inheritance, with two deleterious alleles required for disease manifestation. Familial segregation data, including evidence from affected siblings, consolidates the genetic framework supporting the association between SLC38A3 variants and the clinical features observed.

In conclusion, the convergence of comprehensive genetic data—comprising diverse variant types with robust segregation—and compelling functional studies affirm that the link between SLC38A3 and developmental and epileptic encephalopathy is strong. This evidence underpins diagnostic decision-making, supports commercial genetic testing initiatives, and provides a solid foundation for future therapeutic research.

References

• Brain : a journal of neurology • 2022 • Biallelic variants in SLC38A3 encoding a glutamine transporter cause epileptic encephalopathy PMID:34605855
• Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology • 2011 • Substrate-dependent interference of carbonic anhydrases with the glutamine transporter SNAT3-induced conductance PMID:21325825

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