Reanalysis of exome sequencing data of intellectual disability samples: Yields and benefits

Abstract

Recently, with the advancement in next generation sequencing (NGS) along with the improvement of bioinformatics tools, whole exome sequencing (WES) has become the most efficient diagnostic test for patients with intellectual disability (ID). This study aims to estimate the yield of a reanalysis of ID negative exome cases after data reannotation. Total of 50 data files of exome sequencing, representing 50 samples were collected. The inclusion criteria include ID phenotype, and previous analysis indicated a negative result (no abnormality detected). These files were pre-processed and reannotated using ANNOVAR tool. Prioritized variants in the 50 cases studied were classified into three groups, (1) disease-causative variants (2) possible disease-causing variants and (3) variants in novel genes. Reanalysis resulted in the identification of pathogenic/likely pathogenic variants in six cases (12%). Thirteen cases (26%) were classified as having possible disease-causing variants. Candidate genes requiring future functional studies were detected in seven cases (14%). Improvement in bioinformatics tools, update in the genetic databases and literature, and patients' clinical phenotype update were the main reasons for identification of these variants in this study.

The Responsibility to Recontact Research Participants after Reinterpretation of Genetic and Genomic Research Results

“…As a result of ongoing improvements in analytical methods and bioinformatic analyses, resequencing of an original specimen or reanalysis of raw sequence data might lead to a newly detected variant that was missed as a result of factors such as poor coverage or limitations in variantdetection algorithms and filtration. [6][7][8][9][10][11][12][13][14][15][16] The above situations might or might not justify an effort on the part of the research team to recontact a participant to disclose new information. In addition, recontact might be considered appropriate if there is a change in a research project's threshold of what types of variants should be disclosed at all, such that variants that were uniformly not disclosed in the past later meet criteria for disclosure after a participant had originally received his or her results.…”

“…Should the study's principal investigator change in an ongoing study (such as a longitudinal study), ultimate responsibility for recontact is transferred in the same way as for responsibility of other study functions. 6. The ASHG recommends that, when there is a strong recommendation for recontact, the recontact should occur within 6 months of the reinterpretation.…”

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

“…Among these methods, reanalysis of the exome is the most accessible and inexpensive. Multiple studies with predominantly Caucasian individuals have shown that the diagnostic rate of reanalysis ranges from 6 to 47% [10][11][12][13][14][15][16][17][18][19][20][21][22][23] . Stark et al has estimated that 18months is the most cost-effective time point to perform reanalysis 19 .…”

The Polyadenosine RNA Binding Protein ZC3H14 is Required in Mice for Proper Dendritic Spine Density

“…ZC3H14 (Zinc Finger CCCH-Type Containing 14) is an evolutionarily conserved, ubiquitously expressed polyadenosine RNA-binding protein (Leung et al, 2009). Mutations in the ZC3H14 gene cause an autosomal-recessive, non-syndromic form of intellectual disability (Al-Nabhani et al, 2018; S. Kelly et al, 2012; Pak et al, 2011).…”