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

Dolores González-Morón,Sebastián Vishnopolska,Marta Córdoba,Marcelo Marti,Damián Consalvo,Sergio Alejandro Rodríguez-Quiroga,Marcelo Andrés Kauffman,Cecilia Vazquez-Dusefante,Silvia Kochen,Santiago Claverie,Nancy Medina,Walter Silva,Patricia Vega

doi:10.1371/journal.pone.0185103

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.

Highlights

Malformations of cortical development (MCD) are a major cause of intellectual disability and severe epilepsy
We presented clinical, neuroimaging and genetic data of a large cohort of neuronal migration disorders (NMD) patients followed in an academic neurogenetic tertiary center in Argentina
Our results expand the mutation spectrum causing this group of disorders and give new insights about the evolving role of somatic mutations in neurological diseases, especially for diagnostic purposes

Summary

Introduction

Malformations of cortical development (MCD) are a major cause of intellectual disability and severe epilepsy. Despite recent increase in our knowledge of NMD genetics, the identification of diseasecausing mutations in individual patients remains a challenge on clinical grounds, even in the Generation Sequencing (NGS) era. A high proportion of cases from NMD cohorts persists as genetically undefined [3]. Somatic mosaicism could be the mechanism underlying the aetiology of a third of these patients [4]. Their molecular diagnosis should be addressed to look for germline, but for somatic variants as well

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