Clinical application of exome sequencing in undiagnosed genetic conditions

Abstract

BackgroundThere is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.MethodsThe authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.ResultsThis undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).ConclusionsThis study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.

Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing

“…8 In fact, a much higher rate of ~50% was seen in a different pilot study in which more stringent predetermined criteria were applied for selecting patients suitable for ES. 9 From an Review economic perspective, a recent study has shown that, compared with multiple single-gene or low-throughput testing, ES has the potential to provide a significant cost benefit for patients who remain undiagnosed after a few traditional approaches. 2 ES has shown success most often in cases in which it does not rely on a priori knowledge of the genetic condition.…”

The shifting model in clinical diagnostics: how next-generation sequencing and families are altering the way rare diseases are discovered, studied, and treated

“…That being said, parents can offer observations and ideas, and we can push for solutions. Nineteen months after the initial report by Need et al, 2 five viable approaches to treatment are under active consideration, thanks to relentless digging by afflicted families. One parent found a compound that seems to have measurably raised the quality of life in one NGLY1 child.…”

“…Two new developments in genetics promise to dramatically shorten the time to reach a successful diagnosis: next-generation sequencing (NGS) and family engagement through social media. The very speed with which Need et al 2 and Enns et al 1 were published suggests a new model for clinicians and researchers. In this model, families, patients, and scientists work jointly to find new patients, confirm or refute hypotheses, exchange clinical information, enhance collaboration methods, and support research toward understanding and treatment.…”

“…They felt the family could understand this uncertainty (as many families can) and that sharing the NGLY1 suspicion would make the family partners in the discovery efforts. Following a demonstration in a molecular biology laboratory that the mutations found in the child eliminated the protein associated with the NGLY1 gene (this does not happen in the general population), Need et al 2 shared their nomination of NGLY1 as a likely (but by no means certain) cause of the condition.Until very recently, the fragmented distribution of patients across institutions hindered the discovery of new rare diseases. Clinicians working with a single, isolated patient could steadily eliminate known disorders but do little more.…”

Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes

“…The number of patients diagnosed through research and clinical exome sequencing has increased exponentially since the inception of the technology in 2008 and the introduction of the clinical test in 2011 (NIH Health Consensus Conference Statement, 2001;Worthey et al 2011;Dixon-Salazar et al 2012;Need et al 2012;Sailer et al 2012;Hanchard et al 2013;Shamseldin et al 2013). Exome sequencing has been instrumental in discovering the pathogenic etiology in patients in whom traditional molecular methods were uninformative and is uniquely useful in overcoming limitations posed by traditional molecular diagnostic strategies in the identification of oligogenic findings.…”