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The testing strategy for genetic conditions has evolved in recent years. Initially, sequential single gene tests were the mainstay. This was followed by gene panels performed through targeted gene panel sequencing. Now, in many countries, ‘virtual panels’ are applied to whole exome sequencing (WES) or whole genome sequencing (WGS) as first-line tests, where multiple genes can be tested in parallel. Improved reliability and cost efficiency of WES or WGS, combined with advancing bioinformatic technology, mean that next-generation sequencing (NGS), which includes WES and WGS, is preferable. One exception is for diseases where there is a common genetic diagnosis, and a single gene test is still more cost-efficient, for example, Charcot-Marie-Tooth disease (CMT) type 1A. Another is where the pathogenic genetic defects are not easily detectable with NGS, including some complex copy number variants (CNVs; large deletions, duplications, rearrangements or translocations, for example, deletion of exon 7 and 8 of SMN1 in spinal muscular atrophy) or repeat expansions (e.g., amyotrophic lateral sclerosis caused by a repeat expansion in C9orf72). Many CNVs are now reliably detected by bioinformatic pipelines, but historical pipelines were less robust and CNVs were missed. For these reasons, multiplex ligation-dependent probe amplification (MLPA) is still commonly used as …
Contributors CJR: study design, acquisition, analysis and interpretation of data and drafting of manuscript. MP, RP, JMP: acquisition, analysis and interpretation of data and revision of manuscript. MMR: study design and revision of manuscript.
Funding CJR was supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1 and the National Institutes of Neurological Diseases and Stroke and Office of Rare Diseases (U54NS065712).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.