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Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease

Journal of Human Genetics volume 66, pages 689–695 (2021)Cite this article

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Abstract

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

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The data that support the findings of this study are available from the corresponding author upon request.

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Acknowledgements

We thank the study families for their participation. The authors extend their appreciation to the Deputyship for Research & Innovation, Ministry of Education in Saudi Arabia for funding this research work through project number 821.

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Authors and Affiliations

  1. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Monis Bilal Shamsi, Essa Alharby & Naif A. M. Almontashiri

  2. Section of Medical Genetics, Children’s Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia

    Mohamed Saleh, Ali Alasmari & Eissa A. Faqeih

  3. Department of Medical Imaging, King Abdulaziz Medical City, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, Riyadh, Saudi Arabia

    Makki Almuntashri

  4. Molecular Pathology, Pathology and Clinical Laboratory Medicine Administration, King Fahad Medical City, Riyadh, Saudi Arabia

    Manar Samman

  5. Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA, USA

    Roy W. A. Peake

  6. Unit of Genetic Diseases, Department of Pediatrics, Maternity and Children’s Hospital, Almadinah Almunwarah, Saudi Arabia

    Fatima M. Al-Fadhli

  7. Faculty of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia

    Naif A. M. Almontashiri

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  1. Monis Bilal Shamsi
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Correspondence to Naif A. M. Almontashiri.

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Bilal Shamsi, M., Saleh, M., Almuntashri, M. et al. Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease. J Hum Genet 66, 689–695 (2021). https://doi.org/10.1038/s10038-021-00904-2

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