Biallelic variants in SLC4A10 encoding a sodium-dependent bicarbonate transporter lead to a neurodevelopmental disorder
Year: 2023
Type: article
Abstract: PURPOSE: 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.
Source: Genetics in Medicine
Authors: Reza Maroofian, Mina Zamani, Rauan Kaiyrzhanov, Lutz Liebmann, Ehsan Ghayoor Karimiani, Barbara Vona, Antje K. Huebner, Daniel G. Calame, Vinod K. Misra, Saeid Sadeghian, Reza Azizimalamiri, Mohammad Hasan Mohammadi, Jawaher Zeighami, Sogand Heydaran, Mehran Beiraghi Toosi, Javad Akhondian, Meisam Babaei, Narges Hashemi, Rhonda E. Schnur, Mohnish Suri, Jonas Setzke, Matias Wagner, Theresa Brunet, Christopher M. Grochowski, Lisa Emrick, Wendy K. Chung, Ute A. Hellmich, Miriam Schmidts, James R. Lupski, Hamid Galehdari, Mariasavina Severino, Henry Houlden, Christian A. Hübner
Institutions: UCL Queen Square Institute of Neurology, University College London, Shahid Chamran University of Ahvaz, Jena University Hospital, Friedrich Schiller University Jena, St George's, University of London, Universitätsmedizin Göttingen, Baylor College of Medicine, Texas Children's Hospital, Central Michigan University, Ahvaz Jundishapur University of Medical Sciences, Zabol University of Medical Sciences, Mashhad University of Medical Sciences, Ghaem Hospital, North Khorasan University of Medical Sciences, Nottingham University Hospitals NHS Trust, TUM Klinikum, Helmholtz Munich, Institut für Humangenetik, Technical University of Munich, Boston Children's Hospital, Harvard University, Goethe University Frankfurt, Radboud University Nijmegen, University of Freiburg, Radboud University Medical Center, Istituto Giannina Gaslini
Language: English
Topic: Genomics and Rare Diseases
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,200
Funders: Michael J. Fox Foundation for Parkinson's Research, Wellcome Trust, Brain Research UK, National Institute for Health and Care Research, Ataxia UK, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, Deutsche Forschungsgemeinschaft, National Institutes of Health, Medical Research Council, Biotechnology and Biological Sciences Research Council, National Human Genome Research Institute, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Medical Research Foundation
Awards: G1062904336, G1093531541, G119964413, G1247727865, G1267371503, G1828158801, G1910334207, G193949873, G1940454515, G2191741699, G2291118540, G2473961061, G259924242, G281949974, Synaptopathies: genetics, biophysics and circuit mechanisms of paroxysmal neurological disorders., G2973790809, G3230453412, G3344748572, G3357879741, G3728362326, SFB 1453: Nephrogenetik (NephGen), G411559429, G4205326115, G436110613, G4517872433, G4639588712, G4651133406, G4711116409, G4760961572, G4814911389, EXC 2189: CIBSS Centre for Integrative Biological Signalling Studies, G5079592282, G561423854, Development of an Institute of Neurology Next Generation Sequencing Facility Equipment Grant., G5842430364, G605089744, EXC 2051: Balance of the Microverse, G668785241, Hereditäre Schwerhörigkeit: von Gen zum Mechanismus, G8072094966, G8129640651, G8192143363, G85824679, G8798930353, STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE, Boston Children's Hospital/HMS Intellectual and Developmental Disabilities Research Center, Baylor College of Medicine - Mendelian Genomics Research Center (BCM-MGRC)
OpenAlex ID: W4389280359