The clinical utility of rapid exome sequencing in a consanguineous population.

BACKGROUND: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. METHODS: Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. RESULTS: A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. CONCLUSIONS: This work expands the diversity of environments in which RES has a demonstrable clinical utility.

Lethal variants in humans: lessons learned from a large molecular autopsy cohort.

BACKGROUND: Molecular autopsy refers to DNA-based identification of the cause of death. Despite recent attempts to broaden its scope, the term remains typically reserved to sudden unexplained death in young adults. In this study, we aim to showcase the utility of molecular autopsy in defining lethal variants in humans. METHODS: We describe our experience with a cohort of 481 cases in whom the cause of premature death was investigated using DNA from the index or relatives (molecular autopsy by proxy). Molecular autopsy tool was typically exome sequencing although some were investigated using targeted approaches in the earlier stages of the study; these include positional mapping, targeted gene sequencing, chromosomal microarray, and gene panels. RESULTS: The study includes 449 cases from consanguineous families and 141 lacked family history (simplex). The age range was embryos to 18 years. A likely causal variant (pathogenic/likely pathogenic) was identified in 63.8% (307/481), a much higher yield compared to the general diagnostic yield (43%) from the same population. The predominance of recessive lethal alleles allowed us to implement molecular autopsy by proxy in 55 couples, and the yield was similarly high (63.6%). We also note the occurrence of biallelic lethal forms of typically non-lethal dominant disorders, sometimes representing a novel bona fide biallelic recessive disease trait. Forty-six disease genes with no OMIM phenotype were identified in the course of this study. The presented data support the candidacy of two other previously reported novel disease genes (FAAH2 and MSN). The focus on lethal phenotypes revealed many examples of interesting phenotypic expansion as well as remarkable variability in clinical presentation. Furthermore, important insights into population genetics and variant interpretation are highlighted based on the results. CONCLUSIONS: Molecular autopsy, broadly defined, proved to be a helpful clinical approach that provides unique insights into lethal variants and the clinical annotation of the human genome.