Exome sequences versus sequential gene testing in the UK highly specialised Service for Limb Girdle Muscular Dystrophy

Abstract

BackgroundLimb girdle muscular dystrophies are a group of rare and genetically heterogeneous diseases that share proximal weakness as a common feature; however they are often lacking very specific phenotypic features to allow an accurate differential diagnosis based on the clinical signs only, limiting the diagnostic rate using phenotype driven genetic testing. Next generation sequencing provides an opportunity to obtain molecular diagnoses for undiagnosed patients, as well as identifying novel genetic causes of muscle diseases. We performed whole exome sequencing (WES) on 104 affected individuals from 75 families in who standard gene by gene testing had not yielded a diagnosis. For comparison we also evaluated the diagnostic rate using sequential gene by gene testing for 91 affected individuals from 84 families over a 2 year period.ResultsPatients selected for WES had undergone more extensive prior testing than those undergoing standard genetic testing and on average had had 8 genes screened already. In this extensively investigated cohort WES identified the genetic diagnosis in 28 families (28/75, 37%), including the identification of the novel gene ZAK and two unpublished genes. WES of a single affected individual with sporadic disease yielded a diagnosis in 13/38 (34%) of cases. In comparison, conventional gene by gene testing provided a genetic diagnosis in 28/84 (33%) families. Titinopathies and collagen VI related dystrophy were the most frequent diagnoses made by WES. Reasons why mutations in known genes were not identified previously included atypical phenotypes, reassignment of pathogenicity of variants, and in one individual mosaicism for a COL6A1 mutation which was undetected by prior direct sequencing.ConclusionWES was able to overcome many limitations of standard testing and achieved a higher rate of diagnosis than standard testing even in this cohort of extensively investigated patients. Earlier application of WES is therefore likely to yield an even higher diagnostic rate. We obtained a high diagnosis rate in simplex cases and therefore such individuals should be included in exome or genome sequencing projects. Disease due to somatic mosaicism may be increasingly recognised due to the increased sensitivity of next generation sequencing techniques to detect low level mosaicism.Electronic supplementary materialThe online version of this article (10.1186/s13023-017-0699-9) contains supplementary material, which is available to authorized users.

Molecular diagnosis of muscular diseases in outpatient clinics

“…1 Therefore, genetic testing is increasingly used and can be obtained in a noninvasive manner. Across different countries such as Canada, the United States, China, Korea, Germany, the United Kingdom, Egypt, Poland, Australia, and Japan, gene panel sequencing has a yield varying from 16% to 65%, [2][3][4][5][6][7] depending on subgroups of patients' selection, whereas exome sequencing has a yield in between 13% and 69% [8][9][10][11][12][13][14][15] in different settings. Its superiority over gene panel, in diagnosing common etiologies, remains to be quantified.…”

Meeting Patients’ Right to the Correct Diagnosis: Ongoing International Initiatives on Undiagnosed Rare Diseases and Ethical and Social Issues

“…NGS, and in particular WES, has proved to have a high diagnostic utility and to be cost effective in undiagnosed patients. It allows to the dramatic reduction in both the number of tests and the time required to arrive at an accurate diagnosis, thus reducing the significant financial and psychological burdens associated with prolonged investigation [ 61 , 62 , 63 , 64 ].…”

Diagnostic Utility of Whole Exome Sequencing in the Neuromuscular Clinic

“…8,9 Published diagnostic rates of gene panel testing and WES in pediatric and neuromuscular populations range from 13 to 70% where the highest success rates are attributed to more comprehensive testing. [7][8][9][10][11][12][13][14][15][16] Here we sought to assess the impact of WES, which has only become widely available as a clinically reimbursed diagnostic method over the past 4 years, on the rate of successful molecular diagnosis within a single neuromuscular clinic.…”