Delineation of a Novel Mirror Syndrome: <i>NFIC</i> Variants Cause Syndromic Intellectual Disability With Macrocephaly

Nuclear factor I (NFI) transcription factors regulate neural stem and progenitor differentiation during brain development. While NFIA, NFIB, and NFIX are linked to neurodevelopmental disorders, the role of NFIC (MIM: 600729) in human disease remains unclear. This study aimed to determine whether NFIC contributes to a neurodevelopmental syndrome, define its phenotype, and assess dosage-dependent effects. We established the first cohort of 11 individuals, including NFIC deletions and single nucleotide variants. Genotype-phenotype correlations, including critical region mapping, were performed. Murine data and bioinformatics were integrated to explore underlying pathomechanisms. We report 11 individuals with NFIC variants, including four with de novo SNVs and seven with deletions encompassing the gene, of whom nine have not been previously reported. A core phenotype of syndromic intellectual disability and macrocephaly was delineated. Opposing cranial phenotypes relative to proximal 19p13.3 duplication cases support a dosage-sensitive effect and a mirror-syndrome model. NFIC-related disorder represents a novel neurodevelopmental syndrome characterized by intellectual disability and macrocephaly, highlighting the importance of NFIC dosage supporting a mirror-syndrome model.

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Publication Details

Journal
Clinical Genetics
Published
2026-07-24
DOI
https://doi.org/10.1111/cge.70215
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
0.00

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article

Delineation of a Novel Mirror Syndrome: NFIC Variants Cause Syndromic Intellectual Disability With Macrocephaly

Lucas Hérissant, Aurélie Gouronc, Trine Bjørg Hammer, Fabienne Giuliano et al.
Clinical Genetics
Genomic variations and chromosomal abnormalities
article

Delineation of a Novel Mirror Syndrome: NFIC Variants Cause Syndromic Intellectual Disability With Macrocephaly

Lucas Hérissant, Aurélie Gouronc, Trine Bjørg Hammer, Fabienne Giuliano, Céline Poirsier, Jonathan Lévy, Chloé Angelini, Claire Bénéteau, Perrine Pennamen, Christina Fenger, Martin Zenker, Matthieu Egloff, Paul Kuentz, Slavica Trajkova, Sophie Scheidecker, Véronique Satre, Mathilde Nizon, Charles Coutton, Marlène Rio, Anne‐Claude Tabet, Guillaume Jouret, Valentine Marquet, Houda Karmous‐Benailly, Emilie Landais, Ina Schanze, Nathalie Vanden Eynde, Stephen R. Braddock, Lingying Liu, Biljana Gagachovska, Gaëlle Vieville, François Cartault, Geneviève Baujat, Éric Bieth, Audrey Schalk, Martine Doco‐Fenzy, Patrick Callier, Caroline Rooryck, Brynn Shrom‐Model, Bertrand Isidor, Paul Hillman
article en

Abstract

Nuclear factor I (NFI) transcription factors regulate neural stem and progenitor differentiation during brain development. While NFIA, NFIB, and NFIX are linked to neurodevelopmental disorders, the role of NFIC (MIM: 600729) in human disease remains unclear. This study aimed to determine whether NFIC contributes to a neurodevelopmental syndrome, define its phenotype, and assess dosage-dependent effects. We established the first cohort of 11 individuals, including NFIC deletions and single nucleotide variants. Genotype-phenotype correlations, including critical region mapping, were performed. Murine data and bioinformatics were integrated to explore underlying pathomechanisms. We report 11 individuals with NFIC variants, including four with de novo SNVs and seven with deletions encompassing the gene, of whom nine have not been previously reported. A core phenotype of syndromic intellectual disability and macrocephaly was delineated. Opposing cranial phenotypes relative to proximal 19p13.3 duplication cases support a dosage-sensitive effect and a mirror-syndrome model. NFIC-related disorder represents a novel neurodevelopmental syndrome characterized by intellectual disability and macrocephaly, highlighting the importance of NFIC dosage supporting a mirror-syndrome model.

Clinical Genetics
Université Fédérale de Toulouse Midi-Pyrénées (FR), Centre Hospitalier Universitaire de Grenoble (FR), Hotel Dieu Hospital (CA), Rigshospitalet (DK), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Nice (FR), Institut Necker Enfants Malades (FR), Centre Hospitalier Universitaire de La Réunion (RE), Hôpital Couple Enfant (FR), Cardinal Glennon Children’s Medical Center (US), Centre Hospitalier Universitaire de Reims (FR), Klinikum Magdeburg (DE), Centre Hospitalier Universitaire de Poitiers (FR), Centre Hospitalier Universitaire de Limoges (FR), Hôpital Robert-Debré (FR), University Hospital Magdeburg (DE), Maison des Sciences sociales et des Humanités de Dijon (FR), Laboratoire National de Santé (LU), The University of Texas Health Science Center (US), Biologie de la Reproduction, Environnement, Epigénétique et Développement (FR), University of Turin (IT), Université de Strasbourg (FR), Ss. Cyril and Methodius University in Skopje (MK), Université Grenoble Alpes (FR), Université de Franche-Comté (FR), Université de Reims Champagne-Ardenne (FR), Nantes Université (FR)
European Commission
Openalex Percentile: Top 9%
Genomic variations and chromosomal abnormalities
DOISourceOpenAlex
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