Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders

Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains un...

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Publicado:	2017
Materias:	alanine arginine cysteine glycine proline serine acidosis agyria ambiguous genitalia amino acid sequence amino acid substitution Argentina Article ARX gene brain malformation chromosome breakage clinical article controlled study copy number variation corpus callosum agenesis DCX gene diagnostic value diarrhea disease association disease severity epilepsy exon family history feasibility study female FLNA gene frameshift mutation gene gene deletion gene frequency gene identification gene insertion gene targeting genetic variability genotype phenotype correlation germline mutation heart ventricle septum defect heterozygosity human hypothermia intellectual impairment karyotype macrogyria male missense mutation mosaicism mutational analysis neuronal migration disorder next generation sequencing nonsense mutation null allele PAFAH1B1 gene pathophysiology periventricular heterotopia personality disorder point mutation POMGNT1 gene POMT1 gene Sanger sequencing septum pellucidum agenesis sequence analysis sex difference somatic mutation spontaneous abortion stop codon subcortical heterotopia vermis hypoplasia white matter lesion X chromosome cohort analysis genetics genotype Malformations of Cortical Development, Group II phenotype young adult Cohort Studies DNA Copy Number Variations Female Genotype Germ-Line Mutation Humans Male Phenotype Young Adult
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v12_n9_p_GonzalezMoron http://hdl.handle.net/20.500.12110/paper_19326203_v12_n9_p_GonzalezMoron
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

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spelling	paper:paper_19326203_v12_n9_p_GonzalezMoron2023-06-08T16:30:43Z Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders alanine arginine cysteine glycine proline serine acidosis agyria ambiguous genitalia amino acid sequence amino acid substitution Argentina Article ARX gene brain malformation chromosome breakage clinical article controlled study copy number variation corpus callosum agenesis DCX gene diagnostic value diarrhea disease association disease severity epilepsy exon family history feasibility study female FLNA gene frameshift mutation gene gene deletion gene frequency gene identification gene insertion gene targeting genetic variability genotype phenotype correlation germline mutation heart ventricle septum defect heterozygosity human hypothermia intellectual impairment karyotype macrogyria male missense mutation mosaicism mutational analysis neuronal migration disorder next generation sequencing nonsense mutation null allele PAFAH1B1 gene pathophysiology periventricular heterotopia personality disorder point mutation POMGNT1 gene POMT1 gene Sanger sequencing septum pellucidum agenesis sequence analysis sex difference somatic mutation spontaneous abortion stop codon subcortical heterotopia vermis hypoplasia white matter lesion X chromosome cohort analysis genetics genotype Malformations of Cortical Development, Group II phenotype young adult Cohort Studies DNA Copy Number Variations Female Genotype Germ-Line Mutation Humans Male Malformations of Cortical Development, Group II Phenotype Young Adult Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations. © 2017 González-Morón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2017 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v12_n9_p_GonzalezMoron http://hdl.handle.net/20.500.12110/paper_19326203_v12_n9_p_GonzalezMoron
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	alanine arginine cysteine glycine proline serine acidosis agyria ambiguous genitalia amino acid sequence amino acid substitution Argentina Article ARX gene brain malformation chromosome breakage clinical article controlled study copy number variation corpus callosum agenesis DCX gene diagnostic value diarrhea disease association disease severity epilepsy exon family history feasibility study female FLNA gene frameshift mutation gene gene deletion gene frequency gene identification gene insertion gene targeting genetic variability genotype phenotype correlation germline mutation heart ventricle septum defect heterozygosity human hypothermia intellectual impairment karyotype macrogyria male missense mutation mosaicism mutational analysis neuronal migration disorder next generation sequencing nonsense mutation null allele PAFAH1B1 gene pathophysiology periventricular heterotopia personality disorder point mutation POMGNT1 gene POMT1 gene Sanger sequencing septum pellucidum agenesis sequence analysis sex difference somatic mutation spontaneous abortion stop codon subcortical heterotopia vermis hypoplasia white matter lesion X chromosome cohort analysis genetics genotype Malformations of Cortical Development, Group II phenotype young adult Cohort Studies DNA Copy Number Variations Female Genotype Germ-Line Mutation Humans Male Malformations of Cortical Development, Group II Phenotype Young Adult
spellingShingle	alanine arginine cysteine glycine proline serine acidosis agyria ambiguous genitalia amino acid sequence amino acid substitution Argentina Article ARX gene brain malformation chromosome breakage clinical article controlled study copy number variation corpus callosum agenesis DCX gene diagnostic value diarrhea disease association disease severity epilepsy exon family history feasibility study female FLNA gene frameshift mutation gene gene deletion gene frequency gene identification gene insertion gene targeting genetic variability genotype phenotype correlation germline mutation heart ventricle septum defect heterozygosity human hypothermia intellectual impairment karyotype macrogyria male missense mutation mosaicism mutational analysis neuronal migration disorder next generation sequencing nonsense mutation null allele PAFAH1B1 gene pathophysiology periventricular heterotopia personality disorder point mutation POMGNT1 gene POMT1 gene Sanger sequencing septum pellucidum agenesis sequence analysis sex difference somatic mutation spontaneous abortion stop codon subcortical heterotopia vermis hypoplasia white matter lesion X chromosome cohort analysis genetics genotype Malformations of Cortical Development, Group II phenotype young adult Cohort Studies DNA Copy Number Variations Female Genotype Germ-Line Mutation Humans Male Malformations of Cortical Development, Group II Phenotype Young Adult Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
topic_facet	alanine arginine cysteine glycine proline serine acidosis agyria ambiguous genitalia amino acid sequence amino acid substitution Argentina Article ARX gene brain malformation chromosome breakage clinical article controlled study copy number variation corpus callosum agenesis DCX gene diagnostic value diarrhea disease association disease severity epilepsy exon family history feasibility study female FLNA gene frameshift mutation gene gene deletion gene frequency gene identification gene insertion gene targeting genetic variability genotype phenotype correlation germline mutation heart ventricle septum defect heterozygosity human hypothermia intellectual impairment karyotype macrogyria male missense mutation mosaicism mutational analysis neuronal migration disorder next generation sequencing nonsense mutation null allele PAFAH1B1 gene pathophysiology periventricular heterotopia personality disorder point mutation POMGNT1 gene POMT1 gene Sanger sequencing septum pellucidum agenesis sequence analysis sex difference somatic mutation spontaneous abortion stop codon subcortical heterotopia vermis hypoplasia white matter lesion X chromosome cohort analysis genetics genotype Malformations of Cortical Development, Group II phenotype young adult Cohort Studies DNA Copy Number Variations Female Genotype Germ-Line Mutation Humans Male Malformations of Cortical Development, Group II Phenotype Young Adult
description	Neuronal migration disorders are a clinically and genetically heterogeneous group of malformations of cortical development, frequently responsible for severe disability. Despite the increasing knowledge of the molecular mechanisms underlying this group of diseases, their genetic diagnosis remains unattainable in a high proportion of cases. Here, we present the results of 38 patients with lissencephaly, periventricular heterotopia and subcortical band heterotopia from Argentina. We performed Sanger and Next Generation Sequencing (NGS) of DCX, FLNA and ARX and searched for copy number variations by MLPA in PAFAH1B1, DCX, POMT1, and POMGNT1. Additionally, somatic mosaicism at 5% or higher was investigated by means of targeted high coverage NGS of DCX, ARX, and PAFAH1B1. Our approach had a diagnostic yield of 36%. Pathogenic or likely pathogenic variants were identified in 14 patients, including 10 germline (five novel) and 4 somatic mutations in FLNA, DCX, ARX and PAFAH1B1 genes. This study represents the largest series of patients comprehensively characterized in our population. Our findings reinforce the importance of somatic mutations in the pathophysiology and diagnosis of neuronal migration disorders and contribute to expand their phenotype-genotype correlations. © 2017 González-Morón et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
title	Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
title_short	Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
title_full	Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
title_fullStr	Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
title_full_unstemmed	Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders
title_sort	germline and somatic mutations in cortical malformations: molecular defects in argentinean patients with neuronal migration disorders
publishDate	2017
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v12_n9_p_GonzalezMoron http://hdl.handle.net/20.500.12110/paper_19326203_v12_n9_p_GonzalezMoron
_version_	1768545209809895424

Germline and somatic mutations in cortical malformations: Molecular defects in Argentinean patients with neuronal migration disorders

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