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

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.

The odyssey of complex neurogenetic disorders: From undetermined to positive

“…Next Generation Sequencing (NGS) has become a widely used tool for obtaining genetic diagnosis in clinical medicine (Might & Wilsey, 2014). In particular, Whole‐exome sequencing (WES) and Targeted Gene Panel sequencing (TGPS) have shown excellent cost/benefit ratios (Cohen et al, 2020; Córdoba et al, 2018; González‐Morón et al, 2017; Perez Maturo et al, 2020) and are frequently used in the diagnostic workup of patients with neurogenetics disorders. These NGS‐based methods have diagnostic yields of 30–40%, substantially increasing the number of genetic diagnoses that may be amenable to disease‐specific medical management and opening the doors for precision medicine (Córdoba et al, 2018; Yang et al, 2013).…”

“…Targeted Gene Panel sequencing (TGPS) have shown excellent cost/ benefit ratios (Cohen et al, 2020;Córdoba et al, 2018;González-Morón et al, 2017;Perez Maturo et al, 2020) and are frequently used in the diagnostic workup of patients with neurogenetics disorders.…”

Genetics and genomic medicine in Argentina

“…These genomic services offer either precise molecular tests for (rare) Mendelian diseases (González‐Morón et al., 2017) ‐using both whole exome or panel‐based sequencing‐; evaluation of cancer risk ‐mainly based on BRCA1/2 genes analysis (OMIM 113705, NM_007300; OMIM 600185, NM_000059) (Israel, 2013); or Non Invasive Prenatal Testing (NIPT) (Vázquez et al., 2017) of chromosomal anomalies. Sequencing is either performed locally (currently there are between 10–20 next generation sequencers in health centers in the country) or outsourced abroad.…”

“…Nowadays genomics medicine is flooding Argentina, since most government supported initiatives from both Health and Science central agencies, private healthcare institutions and clinical diagnostic laboratories are offering genomic services, either supervised by healthcare professionals or with a direct to consumer sales model. These genomic services offer either precise molecular tests for (rare) Mendelian diseases (González‐Morón et al., ) ‐using both whole exome or panel‐based sequencing‐; evaluation of cancer risk ‐mainly based on BRCA1/2 genes analysis (OMIM 113705, NM_007300; OMIM 600185, NM_000059) (Israel, ); or Non Invasive Prenatal Testing (NIPT) (Vázquez et al., ) of chromosomal anomalies. Sequencing is either performed locally (currently there are between 10–20 next generation sequencers in health centers in the country) or outsourced abroad.…”

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development

“…Even though the diagnostic yield for some MCD groups displaying very defined features on brain imaging, such as lissencephaly (characterized by a smooth brain surface with absent gyri), can reach up to 80% (Di Donato et al, 2018), for the vast majority of cases of the remaining MCD spectrum the yield is much lower (Wiszniewski et al, 2018). Cases displaying this “missing heritability” are often reasoned to be caused by somatic mutations (Jamuar et al, 2014; Gonzalez-Moron et al, 2017), mosaicism (McMahon et al, 2015; Mirzaa et al, 2016; Zillhardt et al, 2016) or by non-genetic causes, such as viral infections (Bosnjak et al, 2011; Moore et al, 2017). However, as WES only interrogates the 1–2% of the human genome that encodes for proteins (Consortium, 2012), it is tempting to speculate that at least some of this missing heritability of MCD might be caused or influenced by genetic variation in the non-coding genome.…”