Publication Date
3-1-2024
Journal
Genetics in Medicine
DOI
10.1016/j.gim.2023.101034
PMID
38054405
PMCID
PMC11157690
PubMedCentral® Posted Date
3-1-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Humans, Mice, Bicarbonates, Chloride-Bicarbonate Antiporters, Intellectual Disability, Membrane Transport Proteins, Mice, Knockout, Neurodevelopmental Disorders, Sodium, Sodium Bicarbonate, Sodium-Bicarbonate Symporters, Bicarbonate transporters, Intracellular pH dynamics, Neurodevelopmental disorders, SLC4A10, Slit ventricles
Abstract
PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness.
METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modeling were performed to study the possible functional consequences of the variant alleles.
RESULTS: The families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In silico analyses showed 6 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants.
CONCLUSION: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice.
Graphical Abstract
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