Molecular diagnostic experience of whole-exome sequencing in adult patients

Abstract

PurposeWhole exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of whole exome sequencing in adults.MethodsWe performed a retrospective analysis of consecutive WES reports for adults from a diagnostic laboratory. Phenotype composition was determined using Human Phenotype Ontology terms.ResultsMolecular diagnoses were reported for 17.5% (85/486) of adults, lower than a primarily pediatric population (25.2%; p=0.0003); the diagnostic rate was higher (23.9%) in those 18–30 years of age compared to patients over 30 years (10.4%; p=0.0001). Dual Mendelian diagnoses contributed to 7% of diagnoses, revealing blended phenotypes. Diagnoses were more frequent among individuals with abnormalities of the nervous system, skeletal system, head/neck, and growth. Diagnostic rate was independent of family history information, and de novo mutations contributed to 61.4% of autosomal dominant diagnoses.ConclusionEarly WES experience in adults demonstrates molecular diagnoses in a substantial proportion of patients, informing clinical management, recurrence risk and recommendations for relatives. A positive family history was not predictive, consistent with molecular diagnoses often revealed by de novo events, informing the Mendelian basis of genetic disease in adults.

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

“…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.…”

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

“…The diagnostic yield in less restrictive adult and pediatric populations series ranged from 17 to 30% (Yang et al, 2014;Valencia et al, 2015;Posey et al, 2015).…”

Parental DNA sequence is critical family history in clinical genomics

“…The exception to biparental samples is the ascertainment of a de novo event in the mitochondrial DNA, which can be determined with supporting maternal DNA evidence alone. Despite a clear opportunity to increase the diagnostic yield of this expensive clinical test by submitting trio samples, 3,4 only about half of the proband samples received by Posey et al 5 were accompanied by biparental samples. These observations prompt the question "What is the ideal family history data set for patient care in the era of genomic medicine?…”

“…It should give us pause to learn that at a leading clinical laboratory the molecular diagnosis rate for WES decreased from 25% in the general cohort to 10% among samples from the probands over 30 years of age. 2,5 What underlies the reduction in diagnostic yield to 10%? Certainly consideration should be given to whether and how biologic factors or case selection biases could contribute to the inverse correlation between age and diagnosis.…”

“…That analysis notwithstanding, a clear contributor to the diminished molecular diagnoses in the older patient group is the paucity of diagnoses supported by trio analysis ( Table 1). 5 Laboratories are appropriately cautious when attributing disease to novel missense variants; however, this attribution can be made with much greater confidence in the setting of three findings: the novel missense variant is in a plausible gene, it is shown through trio analysis to be de novo, and the parental medical history is negative for the phenotype in question. In the cohort reported by Posey et al, 5 all 13 novel autosomal-dominant missense variants were in patients under the age of 30, and 11 of those 13 had parental samples to inform the interpretation as de novo.…”