SLC12A2 – SLC12A2-related Syndromic Intellectual Disability

SLC12A2 encodes the Na^+-K^+-2Cl^- cotransporter NKCC1, which maintains intracellular Cl^- homeostasis critical for neuronal development and function. Pathogenic variants in SLC12A2 are known in autosomal dominant hearing loss and de novo neurodevelopmental disorders, but autosomal recessive presentations have only recently been characterized.

Using whole-exome sequencing, four affected individuals from two unrelated families were found to harbor a homozygous splice-site variant in SLC12A2, presenting with severe global developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with variable congenital hearing loss (4 probands, 2 families) (PMID:33500540). The variant segregated with disease in both families, supporting autosomal recessive inheritance.

All reported recessive variants cluster in the highly conserved C-terminal domain, underscoring its essential role in NKCC1 function. A representative truncating variant, c.3076_3086del (p.Val1026PhefsTer2), was identified in an unrelated patient with multisystem dysfunction including intellectual disability, confirming loss-of-function via nonfunctional transporter expression and misfolding in patient fibroblasts (PMID:27900370).

Functional studies in NKCC1-deficient mouse models demonstrate disrupted ion transport and developmental defects in neural tissues, and patient fibroblast assays reveal absent NKCC1-mediated K^+ influx, consistent with a loss-of-function mechanism. Moreover, de novo SLC12A2 variants reduce transporter activity in Xenopus oocytes and impair corticogenesis in human radial glial cells (PMID:32658972).

Collectively, these data establish autosomal recessive SLC12A2-related syndromic intellectual disability underpinned by homozygous loss-of-function mutations in the C-terminal domain. While additional cases will strengthen the evidence, current findings support diagnostic testing for SLC12A2 in patients with early onset global developmental delay, microcephaly, and respiratory involvement.

Key Take-home: Biallelic loss-of-function SLC12A2 variants cause a consistent syndromic intellectual disability phenotype, justifying inclusion in diagnostic gene panels.

References

• Journal of human genetics • 2021 • Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease. PMID:33500540
• Cold Spring Harbor molecular case studies • 2016 • A patient with multisystem dysfunction carries a truncation mutation in human SLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1. PMID:27900370
• Brain : a journal of neurology • 2020 • SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect. PMID:32658972

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