The use of targeted genomic capture and massively parallel sequencing in diagnosis of Chinese Leukoencephalopathies

Abstract

Leukoencephalopathies are diseases with high clinical heterogeneity. In clinical work, it’s difficult for doctors to make a definite etiological diagnosis. Here, we designed a custom probe library which contains the known pathogenic genes reported to be associated with Leukoencephalopathies, and performed targeted gene capture and massively parallel sequencing (MPS) among 49 Chinese patients who has white matter damage as the main imaging changes, and made the validation by Sanger sequencing for the probands’ parents. As result, a total of 40.8% (20/49) of the patients identified pathogenic mutations, including four associated with metachromatic leukodystrophy, three associated with vanishing white matter leukoencephalopathy, three associated with mitochondrial complex I deficiency, one associated with Globoid cell leukodystrophy (or Krabbe diseases), three associated with megalencephalic leukoencephalopathy with subcortical cysts, two associated with Pelizaeus-Merzbacher disease, two associated with X-linked adrenoleukodystrophy, one associated with Zellweger syndrome and one associated with Alexander disease. Targeted capture and MPS enables to identify mutations of all classes causing leukoencephalopathy. Our study combines targeted capture and MPS technology with clinical and genetic diagnosis and highlights its usefulness for rapid and comprehensive genetic testing in the clinical setting. This method will also expand our knowledge of the genetic and clinical spectra of leukoencephalopathy.

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

“…In patients with an uncharacteristic and/or complex phenotype, the use of a directed capture of genes through the NGS technology reaffirmed the performance of these techniques for the diagnostic approach in these pathologies (Wang et al., ). This constituted a quick and effective instrument, allowing us to arrive at a definite etiology even when the clinical manifestation is not eloquent (Gordon, Letsou, & Bonkowsky, ), reducing costs by shortening the long process of complementary methods of study that patients are often subjected to (Córdoba, González Morón, Rodríguez‐Quiroga, & Kauffman, ).…”

High‐throughput custom capture sequencing identifies novel mutations in coloboma‐associated genes: Mutation in DNA‐binding domain of retinoic acid receptor beta affects nuclear localization causing ocular coloboma

“…Custom capture or targeted gene sequencing has been a cost‐effective approach to detect mutations in genes known to be associated with a specific disease condition (Aparisi et al, ; Bonachea et al, ; Patel et al, ; Rehm, ; Shang et al, ; Trujillano et al, ; X. Wang et al, ). Previous studies exploring mutations in coloboma‐associated genes have been limited to a subset of genes in affected families (Gonzalez‐Rodriguez et al, ; Williamson & FitzPatrick, ).…”

Novel West syndrome candidate genes in a Chinese cohort

“…Variants verified by Sanger sequencing were assessed with the HGMD pro database (http://www.hgmd.org). Candidate genes were searched in the OMIM database, and genes listed as causal genes for Mendelian diseases with genotypes fitting the recorded inheritance pattern were assessed for pathogenicity using the ACMG guidelines …”