Frontiers in Genetics (Dec 2024)
Widening the infantile hypotonia with psychomotor retardation and characteristic Facies-1 Syndrome’s clinical and molecular spectrum through NALCN in-silico structural analysis
- Davide Vecchio,
- Marina Macchiaiolo,
- Michaela V. Gonfiantini,
- Filippo M. Panfili,
- Francesco Petrizzelli,
- Niccolò Liorni,
- Niccolò Liorni,
- Fabiana Cortellessa,
- Lorenzo Sinibaldi,
- Ippolita Rana,
- Emanuele Agolini,
- Dario Cocciadiferro,
- Nicole Colantoni,
- Michela Semeraro,
- Cristiano Rizzo,
- Annalisa Deodati,
- Annalisa Deodati,
- Nicola Cotugno,
- Nicola Cotugno,
- Serena Caggiano,
- Elisabetta Verrillo,
- Carlotta G. Nucci,
- Serpil Alkan,
- Jorge M. Saraiva,
- Jorge M. Saraiva,
- Jorge M. Saraiva,
- Joaquim De Sá,
- Pedro M. Almeida,
- Jayanth Krishna,
- Paola S. Buonuomo,
- Diego Martinelli,
- Carlo Dionisi Vici,
- Viviana Caputo,
- Andrea Bartuli,
- Antonio Novelli,
- Tommaso Mazza,
- Tommaso Mazza
Affiliations
- Davide Vecchio
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Marina Macchiaiolo
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Michaela V. Gonfiantini
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Filippo M. Panfili
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Francesco Petrizzelli
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
- Niccolò Liorni
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
- Niccolò Liorni
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Fabiana Cortellessa
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Lorenzo Sinibaldi
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Ippolita Rana
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Emanuele Agolini
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Dario Cocciadiferro
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Nicole Colantoni
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Michela Semeraro
- Division of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
- Cristiano Rizzo
- Division of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
- Annalisa Deodati
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Annalisa Deodati
- Diabetology and Growth Disorders Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Nicola Cotugno
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Nicola Cotugno
- Research Unit of Clinical Immunology and Vaccinology, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
- Serena Caggiano
- Pediatric Pulmonology and Cystic Fibrosis Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Elisabetta Verrillo
- Pediatric Pulmonology and Cystic Fibrosis Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Carlotta G. Nucci
- 0Neurosurgery Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Serpil Alkan
- 1Department of Pediatrics, Centre Hospitalier Universitaire, CHU, Liège, Belgium
- Jorge M. Saraiva
- 2Medical Genetics Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Jorge M. Saraiva
- 3University Clinic of Pediatrics, Faculty of Medicine, University of Coimbra, Coimbra, Portugal
- Jorge M. Saraiva
- 4Clinical Academic Center of Coimbra, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Joaquim De Sá
- 2Medical Genetics Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Pedro M. Almeida
- 2Medical Genetics Department, Hospital Pediátrico de Coimbra, Unidade Local de Saúde de Coimbra, Coimbra, Portugal
- Jayanth Krishna
- 5Krishna Institute of Medical Sciences (KIMS Hospital), Hyderabad, India
- Paola S. Buonuomo
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Diego Martinelli
- Division of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
- Carlo Dionisi Vici
- Division of Metabolic Diseases, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
- Viviana Caputo
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Andrea Bartuli
- Rare Diseases and Medical Genetics Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Antonio Novelli
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- Tommaso Mazza
- Bioinformatics Unit, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Italy
- Tommaso Mazza
- Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
- DOI
- https://doi.org/10.3389/fgene.2024.1477940
- Journal volume & issue
-
Vol. 15
Abstract
IntroductionInfantile 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.MethodsWe 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.ResultsTo 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.DiscussionBy 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
