Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodel
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ORIGINAL INVESTIGATION
Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin‑remodeling genes Aldesia Provenzano1 · Andrea La Barbera1 · Mirko Scagnet2 · Angelica Pagliazzi1 · Giovanna Traficante3 · Marilena Pantaleo3 · Lucia Tiberi1 · Debora Vergani3 · Nehir Edibe Kurtas3 · Silvia Guarducci3 · Sara Bargiacchi3 · Giulia Forzano1 · Rosangela Artuso3 · Viviana Palazzo3 · Ada Kura4 · Flavio Giordano2 · Daniele di Feo5 · Marzia Mortilla5 · Claudio De Filippi5 · Gianluca Mattei6 · Livia Garavelli7 · Betti Giusti4 · Lorenzo Genitori2 · Orsetta Zuffardi8 · Sabrina Giglio1,3 Received: 4 August 2020 / Accepted: 20 October 2020 © The Author(s) 2020
Abstract Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.
Claudio De Filippi passed away on 2019. Aldesia Provenzano and Andrea La Barbera contributed equally to this work. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00439-020-02231-6) contains supplementary material, which is available to authorized users. * Aldesia Provenzano [email protected] 1
Medical Genetics Unit, Department of Clinical and Experimental Biomedical Sciences “Mario Serio”, University of Florence, Florence, Italy
2
Department of Neurosurgery, “A. Meyer” Children Hospital of Florence, Florence, Italy
3
Medical Genetics Unit, “A. Meyer” Children Hospital of Florence, Florence, Italy
4
Department of Experimental and Clinical Medicine, Atherothrombotic D
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