Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian Disorders

Abstract

BACKGROUND Whole-exome sequencing is a diagnostic approach for the identification of molecular defects in patients with suspected genetic disorders. METHODS We developed technical, bioinformatic, interpretive, and validation pipelines for whole-exome sequencing in a certified clinical laboratory to identify sequence variants underlying disease phenotypes in patients. RESULTS We present data on the first 250 probands for whom referring physicians ordered whole-exome sequencing. Patients presented with a range of phenotypes suggesting potential genetic causes. Approximately 80% were children with neurologic pheno-types. Insurance coverage was similar to that for established genetic tests. We identified 86 mutated alleles that were highly likely to be causative in 62 of the 250 patients, achieving a 25% molecular diagnostic rate (95% confidence interval, 20 to 31). Among the 62 patients, 33 had autosomal dominant disease, 16 had auto-somal recessive disease, and 9 had X-linked disease. A total of 4 probands received two nonoverlapping molecular diagnoses, which potentially challenged the clinical diagnosis that had been made on the basis of history and physical examination. A total of 83% of the autosomal dominant mutant alleles and 40% of the X-linked mutant alleles occurred de novo. Recurrent clinical phenotypes occurred in patients with mutations that were highly likely to be causative in the same genes and in different genes responsible for genetically heterogeneous disorders. CONCLUSIONS Whole-exome sequencing identified the underlying genetic defect in 25% of consecutive patients referred for evaluation of a possible genetic condition. (Funded by the National Human Genome Research Institute.)

Genetic landscape and novel disease mechanisms from a large LGMD cohort of 4656 patients

“…The 27% diagnostic yield included the 256 patients with one pathogenic and one VUS in the same LGMD gene since it is most likely these VUSs are likely pathogenic as the patients show clinical symptoms and no other variant was identified in the same or any other gene. The diagnostic yield of our study is slightly higher than some previous exome sequencing studies in neurological disorders, even with a substantial patient cohort recruited based on specific disease phenotypes 41, 42. This suggests the importance of using screening criteria of disease‐specific clinical information carefully to judge the type of NGS‐diagnostic testing for patient recruitment (fig.…”

Phenotypic expansion in DDX3X – a common cause of intellectual disability in females

“…Variants in DDX3X were identified by WES, performed according to previously described methods,5, 6, 13 either on a clinical basis at Baylor Genetics (Females 1–24, Males 1–2, Fetus 1) or on a research basis by the Baylor Hopkins Center for Mendelian Genomics (BHCMG, Females 25–27) or through the Centre de Génétique Humaine, Université de Franche‐Comté (Female 28). Deidentified reporting of aggregated demographic and molecular data for all clinically referred cases was approved by the Institutional Review Board at Baylor College of Medicine (BCM).…”

“…Although over 100 genes on the X chromosome were found to be associated with ID in males,2, 3 relatively less is known about X‐linked ID genes in females 4. Whole‐exome sequencing (WES) is finding de novo variants in X‐linked ID genes in females of all ages 5, 6, 7, 8. However, limited information is available regarding such cases.…”

Utility of whole‐exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care

“…The first of these was reported by the Baylor College of Medical Genetics Laboratory which demonstrated a 25% molecular diagnostic rate for 250 probands with varying indications (although 80% had a neurologic phenotype) 16. Interestingly, when they increased the number of patients to 2000, the diagnostic rate remained 25% 17.…”