Argentinian clinical genomics in a leukodystrophies and genetic leukoencephalopathies cohort: Diagnostic yield in our first 9 years

Abstract

Introduction and objectives: Leukodystrophies and genetic leukoencephalopathiesconstitute a vast group of pathologies of the cerebral white matter. The large number of etiopathogenic genes and the frequent unspecificity on the clinical-radiological presentation generate remarkable difficulties in the diagnosis approach. Despite recent and significant developments, molecular diagnostic yield is still less than 50%. Our objective was to develop and explore the usefulness of a new diagnostic procedure using standardized molecular diagnostic tools, and next-generation sequencing techniques. Materials and methods:A prospective, observational, analytical study was conducted in a cohort of 46 patients, evaluated between May 2008 and December 2016, with a suspected genetic leukoencephalopathy or leukodystrophy. A diagnostic procedure was set up using classical monogenic tools in patients with characteristic phenotypes, and next-generation techniques in nonspecific ones.Results: Global diagnostic procedure yield was 57.9%, identifying the etiological pathogenesis in 22 of the 38 studied subjects. Analysis by subgroups, Sanger method, and next-generation sequencing showed a yield of 64%, and 46.1% respectively. The most common pathologies were adrenoleukodystrophy, cerebral autosomal-dominant arteriopathy with subcortical infarcts (CADASIL), and vanishing white matter disease. /journal/ahg 11 12 COHEN ET AL. Conclusions:Our results confirm the usefulness of the proposed diagnostic procedure expressed in a high diagnostic yield and suggest a more optimal cost-effectiveness in an etiological analysis phase. K E Y W O R D Sdiagnostic procedure, genetic leukoencephalopathies, leukodystrophies, next-generation sequencing

The odyssey of complex neurogenetic disorders: From undetermined to positive

“…Variant calls were generated using GATK3.6 or GATK4.1 haplotype caller following the so called best practices (van der Auwera et al, 2013). The output VCF file was annotated at various levels using Annovar (Wang, Li, & Hakonarson, 2010), with information from several databases as previously described by our group (Cohen et al, 2020; Córdoba et al, 2018). We classified variants according to the ACMG recommendations (Richards et al, 2015).…”

“…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.…”

OVERWHELMING GENETIC HETEROGENEITY AND EXHAUSTING MOLECULAR DIAGNOSTIC PROCESS IN CHRONIC AND PROGRESSIVE ATAXIAS: FACING IT UP WITH AN ALGORITHM, A GENE, A PANEL AT A TIME

“…Similarly, Sanger sequencing-based assays were used for the analyses of PRNP, NPC1, NPC2, CYP27A1, SCARB2 genes. Next generation sequencing assays were performed according to previous methods described by our group, TruSight One (Illumina INC) based multigene panel sequencing in [16] and exome sequencing in [17]. Bioinformatics procedures and variants interpretation was done as previously described by our group in [16, 17].…”

Genetic disorders with central nervous system white matter abnormalities: An update

“…Yield of a custom panel was noted to be 13.3% in a cohort of individuals with adult onset LD 53 . In an Argentinian cohort of individuals with genetic disorder with WMAs, a virtual panel analysis from exome data rendered a diagnostic yield of 46.1% 54 . Though whole genome sequencing (WGS) outweighs the diagnostic yield of ES, there is limited data on use of this technique as well for investigation of these disorders 5548 .…”