Pilot study of EVIDENCE: High diagnostic yield and clinical utility of whole exome sequencing using an automated interpretation system for patients with suspected genetic disorders

Abstract

2 AbstractsPurpose: We developed an automated interpretation system for the whole process of Whole exome sequencing (WES) including raw data processing, variant calling, variant interpretation, and measurement of phenotypic similarity between the patient and each disease. This study was to investigate diagnostic yield and clinical utility of our new system that assists clinicians with diagnosis of patients with suspected genetic disorders. Methods: WES was performed a total of 194 patients (age range 0-68 years) with suspected genetic disorder. The patient inclusion criteria were delayed development within age of 5 months, multiple congenital anomalies with dysmorphic features, strongly suggestive features of monogenic disorder or genetically heterogeneous disorder, or not diagnosed despite performing genetic investigation. Results: WES reported 180 variants, of which 110 variants were confirmed by segregation analysis and 94 patients (48.4%) were diagnosed with 89 genetic disorders. There was no difference of diagnostic rate (48.9 %, 71/145 vs. 46.9%, 23/49, P > 0.05) and duration of the diagnostic odyssey (2.8 ± 3.3 vs. 4.1 ± 5.1, P= 0.293) between group with and without genetic test before WES. There was no significant difference in the distribution of clinical symptoms between the patients who were diagnosed with and without genetic disorder. Forty four percent of total patients filled only 9% of total symptom principal component analysis (PCA) space, and the remaining 56% of patients filled the other 91% of symptom PCA space. The two groups had similar genetic variant diversities (P = 0.899). ConclusionThis study showed improved diagnostic yield (48.4%) in patients with clinical heterogeneity by using automating variant interpretation. Diverse genetic variations were also observed in patients with similar symptoms. This study highlights the utility of automated 3 interpretation system of WES to clarify differential diagnosis in patients with suspected genetic disorder.

Proteins Structure Models in the Evaluation of Novel Variant (C.472_477del) in the MOCS2 Gene

“…The captured genomic regions (exons of approx. 22,000 genes) were sequenced using a NovaSeq platform (Illumina, San Diego, CA, USA) and aligned to the reference sequence (NCBI genome assembly GRCh37; accessed in February 2009), as previously described [ 7 ]. The mean depth of coverage was 100-fold, with 99.2% coverage higher than 10-fold.…”

Effects of long-term growth hormone therapy in a girl with Floating-Harbor syndrome

“…Variant calling, annotation, and prioritization were performed as previously described. 9) Variants with minor allele frequencies <0.05% for dominant disease association or 2% for recessive disease association were analyzed using population genome databases, such as the 1,000 genomes site (http://phase3browser.1000genomes.org), the Exome Variant Server (http://evs.gs.washington.edu/EVS/), and ExAC (http://exac.broadinstitute.org/).…”

Case Report of a Juvenile Patient with Autism Spectrum Disorder with a Novel Combination of Copy Number Variants in ADGRL3 (LPHN3) and Two Pseudogenes

“…In the EVIDENCE database, 23 we found 15 pathogenic, 20,110 VUS, and 426 likely benign entries for ADGLR3 ( https://3billion.io/gene/ADGRL3/ ). Of these, phenotype entries for 14 patients have been reported in the following classes with the respective frequencies: Abnormalities of the nervous system 57.1%, abnormalities of head or neck 42.9%, abnormalities of the musculoskeletal system 28.6%, abnormalities of the cardiovascular system 14.3%, abnormalities of the eye 14.3%, constitutional symptoms 7.1%, and growth abnormalities 7.1%.…”