SLC12A6 – Agenesis of Corpus Callosum with Peripheral Neuropathy

Andermann syndrome (agenesis of the corpus callosum with peripheral neuropathy; MONDO:0000902) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic variants in SLC12A6 (HGNC:10914), encoding the neuronal K⁺–Cl⁻ cotransporter KCC3. Clinically, affected individuals present with complete or partial agenesis of the corpus callosum, progressive motor and sensory demyelinating neuropathy, global developmental delay, hypotonia, seizures, scoliosis and variable facial diplegia (HP:0001274) ([PMID:20020398]). Disease onset is typically in infancy or early childhood, with survival often limited to the second or third decade.

Genetic evidence for SLC12A6 involvement in Andermann syndrome is robust. Biallelic SLC12A6 variants have been described in ≥8 unrelated probands from consanguineous and non-consanguineous families, including compound heterozygous missense and splice-site mutations (e.g., c.1616G>A (p.Gly539Asp)) and homozygous truncating alleles ([PMID:20020398], [PMID:22462673], [PMID:24341143], [PMID:30868738], [PMID:32765936], [PMID:39988558]). Segregation analysis in discordant sibships and multiple families confirms full concordance of biallelic SLC12A6 genotypes with the ACCPN phenotype.

The variant spectrum is heterogeneous, encompassing missense (e.g., c.1616G>A (p.Gly539Asp)), frameshift (c.571_572dup (p.Tyr192fs)), nonsense (c.3031C>T (p.Arg1011Ter)) and splice-site changes (c.1943+1G>T). Many alleles are private, although c.3031C>T recurs in non-French Canadian populations ([PMID:17893295]). No deep-intronic or structural variants have been reported to date. Carrier frequency is highest in founder populations but rare worldwide.

Functional studies demonstrate that truncating and missense mutations abrogate KCC3-mediated K⁺–Cl⁻ cotransport. Heterologous expression of frameshift and nonsense alleles in Xenopus laevis oocytes shows absent transport activity despite proper membrane glycosylation ([PMID:12368912]). A Slc12a6 knockout mouse recapitulates human locomotor deficits, peripheral neuropathy and sensorimotor gating defects. More recent work shows that the p.His371Arg missense protein is mislocalized to the cytoplasm, disrupting ion homeostasis and inducing cellular senescence ([PMID:39988558]).

Mechanistically, Andermann syndrome arises from loss-of-function of KCC3 leading to impaired neuronal volume regulation and abnormal axonal excitability. Protein interaction studies reveal that truncations disrupt binding to brain-type creatine kinase, further compromising transporter activation and membrane trafficking ([PMID:18566107]). Rescue of transporter localization by curcumin highlights potential therapeutic avenues ([PMID:21628467]).

In summary, the SLC12A6–ACCPN association meets ClinGen definitive criteria: multiple unrelated probands (≥8), consistent autosomal recessive segregation and extensive functional concordance. Molecular testing for SLC12A6 should be prioritized in patients with early-onset demyelinating neuropathy and callosal dysgenesis. Identification of pathogenic KCC3 variants directly informs diagnosis, prognosis and genetic counseling.

References

• Nature genetics • 2002 • The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. PMID:12368912
• Neuropediatrics • 2009 • Andermann syndrome can be a phenocopy of hereditary motor and sensory neuropathy--report of a discordant sibship with a compound heterozygous mutation of the KCC3 gene. PMID:20020398
• Journal of the peripheral nervous system : JPNS • 2012 • Expanding the differential diagnosis of inherited neuropathies with non-uniform conduction: Andermann syndrome. PMID:22462673
• Genetic counseling (Geneva, Switzerland) • 2013 • A new patient with Andermann syndrome: an underdiagnosed clinical genetics entity? PMID:24341143
• American journal of medical genetics. Part A • 2019 • First case of Roma ethnic origin with Andermann syndrome: A novel frameshift mutation in exon 20 of SLC12A6 gene. PMID:30868738
• Journal of pediatric genetics • 2020 • A Novel Splice-Site Variant in SLC12A6 Causes Andermann Syndrome without Agenesis of the Corpus Callosum. PMID:32765936
• Clinical genetics • 2025 • A Novel Missense Mutation in SLC12A6 Impairs Ion Transport Function of the Protein to Cause Agenesis of the Corpus Callosum With Peripheral Neuropathy. PMID:39988558

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