Abstract
Infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) is caused by biallelic mutations in the NALCN gene, the major ion channel responsible for the background Na + conduction in neurons. Through whole-exome sequencing (WES), we report three novel homozygous variants in three families, including c.1434 + 1G > A, c.3269G > A, and c.2648G > T, which are confirmed and segregated by Sanger sequencing. Consequently, intron 12’s highly conserved splice donor location is disrupted by the pathogenic c.1434 + 1G > A variation, most likely causing the protein to degrade through nonsense-mediated decay (NMD). Subsequently, a premature stop codon is thus generated at amino acid 1090 of the protein as a result of the pathogenic c.3269G > A; p.W1090* variation, resulting in NMD or truncated protein production. Lastly, the missense mutation c.2648G > T; p.G883V can play a critical role in the interplay of functional domains. This study introduces recurrent urinary tract infections for the first time, broadening the phenotypic range of IHPRF1 syndrome in addition to the genotypic spectrum. This trait may result from insufficient bladder emptying, which may be related to the NALCN channelosome’s function in background Na + conduction. This work advances knowledge about the molecular genetic underpinnings of IHPRF1 and introduces a novel phenotype through the widespread use of whole exome sequencing.
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The data that support the findings of this study are available from the corresponding authors, upon request.
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Sincere gratitude to the families for their participation in this study.
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STF: conceptualization; data curation; investigation; visualization; formal analysis; methodology; software; validation; writing — review and editing; SB: conceptualization; data curation; investigation; visualization; roles/writing — original draft; HS: conceptualization; investigation; visualization; software; validation; writing — review and editing; SS: methodology; investigation; validation, writing—review and editing; FFB: validation; writing — review and editing. BS: investigation; validation; writing — review and editing. SJ: investigation; methodology; writing — review and editing. SHT: methodology; investigation; validation, writing — review and editing; RM: conceptualization; investigation; methodology; supervision; validation; writing — review and editing; MM: conceptualization; data curation; formal analysis; funding acquisition; investigation; methodology; project administration; resources; supervision; validation; writing — review and editing. MRG: conceptualization; data curation; formal analysis; investigation; project administration; resources; supervision; validation; writing — review and editing.
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This study was approved by the Research Ethics Committee of the Faculty of Medicine, Shahid Beheshti University of Medical Sciences, and was conducted in accordance with the tenets of the Declaration of Helsinki. Informed consent was obtained from parents.
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Tehrani Fateh, S., Bagheri, S., Sadeghi, H. et al. Extending and outlining the genotypic and phenotypic spectrum of novel mutations of NALCN gene in IHPRF1 syndrome: identifying recurrent urinary tract infection. Neurol Sci 44, 4491–4498 (2023). https://doi.org/10.1007/s10072-023-06960-0
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DOI: https://doi.org/10.1007/s10072-023-06960-0