Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data Reanalysis.

Recent advances in next generation sequencing (NGS) have positioned whole exome sequencing (WES) as an efficient first-tier method in genetic diagnosis. However, despite the diagnostic yield of 35%-50% in intellectual disability (ID) many patients still remain undiagnosed due to inherent limitations and bioinformatic short-comings. In this study, we reanalyzed WES data from 159 Iranian families showing recessively inherited ID.

Clinical application of next generation sequencing for Mendelian disease diagnosis in the Iranian population.

Next-generation sequencing (NGS) has been proven to be one of the most powerful diagnostic tools for rare Mendelian disorders. Several studies on the clinical application of NGS in unselected cohorts of Middle Eastern patients have reported a high diagnostic yield of up to 48%, correlated with a high level of consanguinity in these populations. We evaluated the diagnostic utility of NGS-based testing across different clinical indications in 1436 patients from Iran, representing the first study of its kind in this highly consanguineous population.

Guidelines for clinical interpretation of variant pathogenicity using RNA phenotypes.

Over the last 5 years, RNA sequencing (RNA-seq) has been established and is increasingly applied as an effective approach complementary to DNA sequencing in molecular diagnostics. Currently, three RNA phenotypes, aberrant expression, aberrant splicing, and allelic imbalance, are considered to provide information about pathogenic variants. By providing a high-throughput, transcriptome-wide functional readout on variants causing aberrant RNA phenotypes, RNA-seq has increased diagnostic rates by about 15% over whole-exome sequencing.

RNA sequencing role and application in clinical diagnostic.

Although whole-exome sequencing and whole-genome sequencing has tremendously improved our understanding of the genetic etiology of human disorders, about half of the patients still do not receive a molecular diagnosis. The high fraction of variants with uncertain significance and the challenges of interpretation of noncoding variants have urged scientists to implement RNA sequencing (RNA-seq) in the diagnostic approach as a high throughput assay to complement genomic data with functional evidence. RNA-seq data can be used to identify aberrantly spliced genes, detect allele-specific expression, and identify gene expression outliers.

Novel Mutation in in Two Iranian Consanguineous Families with Syndromic Intellectual Disability and Facial Dysmorphism.

Background: Recently, we have reported mutations in LARP7 gene, leading to neurodevelopmental disorders (NDDs), the most frequent cause of disability in children with a broad phenotype spectrum and diverse genetic landscape.

Methods: Here, we present two Iranian patients from consanguineous families with syndromic intellectual disability, facial dysmorphism, and short stature.

Results: Whole-exome sequencing (WES) revealed a novel homozygous stop-gain (c.

Whole-Transcriptome Analysis Reveals Dysregulation of Actin-Cytoskeleton Pathway in Intellectual Disability Patients.

A significant level of genetic heterogeneity has been demonstrated in intellectual disability (ID). More than 700 genes have been identified in ID patients. To identify molecular pathways underlying this heterogeneity, we applied whole-transcriptome analysis using RNA-Seq in consanguineous families with ID.