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PLoS One. 2017 Sep 27;12(9):e0185103. doi: 10.1371/journal.pone.0185103. eCollection 2017.

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

Author information

1
Consultorio y laboratorio de Neurogenética, Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, Buenos Aires, Argentina.
2
IBCN "Eduardo de Robertis", Facultad de Medicina, UBA-CONICET, Buenos Aires, Argentina.
3
Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Química Biológica, Buenos Aires, Argentina.
4
CONICET, Universidad de Buenos Aires, Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), Buenos Aires, Argentina.
5
Centro Universitario de Neurología "José María Ramos Mejía" y División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, Buenos Aires, Argentina.
6
Sección Neurofisiología y Epilepsia, Consultorio de Epilepsias Refractarias, Servicio de Neurología Infantil, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
7
Centro de Epilepsia, División Neurología, Hospital JM Ramos Mejía, Facultad de Medicina, UBA, Buenos Aires, Argentina.
8
Programa de Medicina de Precisión y Genómica Clínica, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, Universidad Austral-CONICET, Derqui, Argentina.

Abstract

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.

PMID:
28953922
PMCID:
PMC5617183
DOI:
10.1371/journal.pone.0185103
[Indexed for MEDLINE]
Free PMC Article

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