The first 271 pediatric and adult diagnostic whole exome sequencing referrals: Results and recommendations

Abstract

Aims: To describe the results of diagnostic WES in childhood and adult Mendelian disorders, analysis methodologies and provide recommendations to maximize the utility of clinical referrals. Subjects and methods: Referrals were submitted from clinical geneticists and non-genetic physicians working with genetic counselors. Subjects included families with intellectual disabilities, epilepsy, immunodeficiencies, and a variety of other likely Mendelian disorders. Sequencing libraries were prepared using LifeTech DNA sample preparation kits and robotic instrumentation, and sequenced on an IonProton sequencer with 95% of the exome covered to >20× depth. Raw sequencing reads were aligned to the genome using TMAP with SNVs and indels identified using Torrent Suite. The variants were then filtered with the in-house genomic analysis pipeline including in house and external base frequency data, molecular, and clinical annotations. The genomic data were analyzed by clinical genomicists and reported by genomic pathologists. Results: The largest phenotype group, neurological disorders including intellectual disability, and early onset epilepsy, had likely causative pathogenic variants identified in 40%, which were skewed to de novo events. The majority of successful gene diagnoses were based on the analysis of family units (trios) and the involvement of experienced clinicians in the diagnostic process. The overall diagnostic rate was 30.4% with an additional 18% having a possible or novel finding.L6200019222018-01-03 <br />