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 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.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin remodeling genes / Aldesia Provenzano, Andrea La Barbera, Mirko Scagnet, Angelica Pagliazzi, Giovanna Traficante, Marilena Pantaleo, Lucia Tiberi, Debora Vergani, Nehir Kurtas, Silvia Guarducci, Sara Bargiacchi, Giulia Forzano, Rosangela Artuso, Viviana Palazzo, Ada Kura, Flavio Giordano, Daniele di Feo, Marzia Mortilla, Claudio De Filippi, Gianluca Mattei, Livia Garavelli, Betti Giusti, Lorenzo Genitori, Orsetta Zuffardi & Sabrina Giglio. - In: HUMAN GENETICS. - ISSN 1432-1203. - ELETTRONICO. - (2020), pp. 0-0.

Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin remodeling genes

Aldesia Provenzano
;
Andrea La Barbera;Angelica Pagliazzi;Lucia Tiberi;Debora Vergani;Nehir Kurtas;Sara Bargiacchi;Giulia Forzano;Rosangela Artuso;Viviana Palazzo;Ada Kura;Flavio Giordano;Daniele di Feo;Marzia Mortilla;Claudio De Filippi;Gianluca Mattei;Betti Giusti;Sabrina Giglio
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 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.
2020
0
0
Goal 3: Good health and well-being for people
Aldesia Provenzano, Andrea La Barbera, Mirko Scagnet, Angelica Pagliazzi, Giovanna Traficante, Marilena Pantaleo, Lucia Tiberi, Debora Vergani, Nehir Kurtas, Silvia Guarducci, Sara Bargiacchi, Giulia Forzano, Rosangela Artuso, Viviana Palazzo, Ada Kura, Flavio Giordano, Daniele di Feo, Marzia Mortilla, Claudio De Filippi, Gianluca Mattei, Livia Garavelli, Betti Giusti, Lorenzo Genitori, Orsetta Zuffardi & Sabrina Giglio
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1215634
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