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Extending and Outlining the Genotypic and Phenotypic Spectrum of Novel Mutations of Nalcn Gene in Ihprf1 Syndrome: Identifying Recurrent Urinary Tract Infection Publisher Pubmed



Tehrani Fateh S1, 2 ; Bagheri S2 ; Sadeghi H3 ; Salehpour S4 ; Fazeli Bavandpour F2 ; Sadeghi B2 ; Jamshidi S2 ; Tonekaboni SH5 ; Mirfakhraie R6 ; Miryounesi M2, 6 ; Ghasemi MR2, 6
Authors
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Authors Affiliations
  1. 1. School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
  2. 2. Center for Comprehensive Genetic Services, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  3. 3. Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  4. 4. Department of Pediatrics, Clinical Research Development Unit, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  5. 5. Department of Pediatric Neurology, School of Medicine, Pediatric Neurology Research Center, Mofid Children’s Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  6. 6. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

Source: Neurological Sciences Published:2023


Abstract

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. Graphical abstract: [Figure not available: see fulltext.] © 2023, Fondazione Societa Italiana di Neurologia.
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