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ORIGINAL RESEARCH article

Front. Genet.
Sec. Human and Medical Genomics
Volume 15 - 2024 | doi: 10.3389/fgene.2024.1477940
This article is part of the Research Topic Application of Next-Generation Sequencing in Clinical Settings View all 5 articles

Widening the Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies-1 Syndrome’s Clinical and Molecular Spectrum through NALCN in-silico Structural Analysis

Provisionally accepted
Davide Vecchio Davide Vecchio 1*Marina Macchiaiolo Marina Macchiaiolo 1Michaela V Gonfiantini Michaela V Gonfiantini 1Filippo Maria Panfili Filippo Maria Panfili 1Francesco Petrizzelli Francesco Petrizzelli 2Niccolò Liorni Niccolò Liorni 2,3Fabiana Cortellessa Fabiana Cortellessa 1Lorenzo Sinibaldi Lorenzo Sinibaldi 1Ippolita Rana Ippolita Rana 1Emanuele Agolini Emanuele Agolini 4Dario Cocciadiferro Dario Cocciadiferro 4Nicole Colantoni Nicole Colantoni 5Michela Semeraro Michela Semeraro 6Cristiano Rizzo Cristiano Rizzo 6Annalisa Deodati Annalisa Deodati 5,7Nicola Cotugno Nicola Cotugno 5,8Serena Caggiano Serena Caggiano 9Elisabetta Verrillo Elisabetta Verrillo 9Carlotta Ginevra Nucci Carlotta Ginevra Nucci 10Serpil Alkan Serpil Alkan 11Jorge M Saraiva Jorge M Saraiva 12,13,14Joaquim de Sá Joaquim de Sá 12Pedro M Almeida Pedro M Almeida 12Jayanth Krishna Jayanth Krishna 15Paola Sabrina Buonuomo Paola Sabrina Buonuomo 1Diego Martinelli Diego Martinelli 6Carlo Dionisi Vici Carlo Dionisi Vici 6Viviana Caputo Viviana Caputo 3Andrea Bartuli Andrea Bartuli 1Antonio Novelli Antonio Novelli 4Tommaso Mazza Tommaso Mazza 2
  • 1 Rare Diseases and Medical Genetics Unit, University Hospital Pediatric Department, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy
  • 2 Bioinformatics unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
  • 3 Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
  • 4 Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 5 Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
  • 6 Division of Metabolic Diseases, Bambino Gesù Children's Hospital IRCCS, Rome, Italy
  • 7 Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 8 Research Unit of Clinical Immunology and Vaccinology, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 9 Pediatric Pulmonology and Cystic Fibrosis Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 10 Neurosurgery Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 11 Department of Pediatrics, Centre Hospitalier Universitaire, CHU, Liège, Belgium
  • 12 Medical Genetics Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
  • 13 University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
  • 14 Clinical Academic Center of Coimbra, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
  • 15 Krishna Institute of Medical Sciences (KIMS hospital), Hyderabad, India

The final, formatted version of the article will be published soon.

    Introduction: Infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1, MIM#615419) is a rare, birth onset, autosomal recessive disorder caused by homozygous or compound heterozygous truncating variants in NALCN gene (MIM#611549) resulting in a loss-of-function effect. Methods: We enrolled a new IHPRF1 patients' cohort in the framework of an international multicentric collaboration study. Using specialized in-silico pathogenicity predictors and ad hoc structural analyses, we assessed the mechanistic consequences of the deleterious variants retrieved on NALCN structure and function. Results: To date 38 different NALCN variants have been retrieved from 33 different families, 26 from unrelated and 22 from related patients. We report on five new IHPRF1 patients from four different families, harboring four newly identified and one previously retrieved variant that exhibited a markedly significant functional impact, thereby compromising the functionality of the protein complex. Discussion: By widening the functional spectrum of biallelic variants affecting the NALCN gene, this article broadens the IHPRF1 syndrome's genotype-phenotype correlation and gives new insight into its pathogenic mechanism, diagnosis, and clinical management.

    Keywords: NALCN, IHPRF1, CLIFAHDD, channelosome complex, genotype-phenotype correlation, Rhythmic behaviors, Structural Biology

    Received: 08 Aug 2024; Accepted: 27 Nov 2024.

    Copyright: © 2024 Vecchio, Macchiaiolo, Gonfiantini, Panfili, Petrizzelli, Liorni, Cortellessa, Sinibaldi, Rana, Agolini, Cocciadiferro, Colantoni, Semeraro, Rizzo, Deodati, Cotugno, Caggiano, Verrillo, Nucci, Alkan, Saraiva, de Sá, Almeida, Krishna, Buonuomo, Martinelli, Dionisi Vici, Caputo, Bartuli, Novelli and Mazza. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Davide Vecchio, Rare Diseases and Medical Genetics Unit, University Hospital Pediatric Department, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.