Molecular diagnosis based on comprehensive genetic testing in 800 Chinese families with non‐syndromic inherited retinal dystrophies

Abstract

Importance Inherited retinal dystrophies (IRDs) are a group of monogenic diseases, one of the leading causes of blindness. Background Introducing a comprehensive genetic testing strategy by combining single gene Sanger sequencing, next‐generation sequencing (NGS) including whole exome sequencing (WES), and a specific hereditary eye disease enrichment panel (HEDEP) sequencing, to identify the disease‐causing variants of 800 Chinese probands affected with non‐syndromic IRDs. Design Retrospective analysis. Participants Eight hundred Chinese non‐syndromic IRDs probands and their families. Methods A total of 149 patients were subjected to Sanger sequencing. Of the 651 patients subjected to NGS, 86 patients underwent WES and 565 underwent HEDEP. Patients that likely carried copy number variations (CNVs) detected by HEDEP were further validated by multiplex ligation‐dependent probe amplification (MLPA) or quantitative fluorescence PCR (QF‐PCR). Main Outcome Measures The diagnostic rate. Results (Likely) pathogenic variants were determined in 481 cases (60.13% detection rate). The detection rates of single gene Sanger sequencing, WES and HEDEP were 86.58%, 31.40% and 56.99%, respectively. Approximately 11.64% of 481 cases carried autosomal dominant variants, 72.97% carried AR variants and 15.39% were found to be X‐linked. CNVs were confirmed by MLPA or QF‐PCR in 17 families. Fourteen genes that each caused disease in 1% or more of the cohort were detected, and these genes were collectively responsible for disease in almost one half (46.38%) of the families. Conclusions and Relevance Sanger sequencing is ideal to detect pathogenic variants of clinical homogeneous diseases, whereas NGS is more appropriate for patients without an explicit clinical diagnosis.

Genome-Wide Disease Screening in Early Human Embryos with Primary Template-Directed Amplification

“…3A). This included a known gene conversion event in vWF (V1279I) 13 that increases the risk of bleeding, SDHB S163P that has been shown to cause cancer predisposition 14 , and APC R534Q which increases risk for clotting 15,16 . In addition, embryo S4 has autosomal recessive alpha−actinin−3 deficiency, which is associated with increased aerobic metabolism in skeletal muscle (Fig.…”

Genetic Testing of Inherited Retinal Disease in Australian Private Tertiary Ophthalmology Practice

“…Obtaining a history of consanguinity in patients with an IRD may assist in selecting appropriate genes for screening and interpreting whole-genome sequencing results. 29 In the current cohort, 3.5% of the patients reported consanguinity, which is mid-range between reported Chinese (<1%) 34 and Norwegian (6%) 31 IRD patient cohorts. However, our results are less than those reported in Brazil (>10%), 35 Spain (11%), 22 and Iran (76%).…”

Comprehensive Molecular Analysis of DMD Gene Increases the Diagnostic Value of Dystrophinopathies: A Pilot Study in a Southern Italy Cohort of Patients

“…Recently, it has been proposed that the high sequence coverage, unusual of NGS applications, may be used to estimate the presence of copy number variations (CNVs) often associated with GRs [24,25]. In this way, NGS may be able to allow, in a single analytic procedure, the complete diagnosis of a disease of interest by detecting both SNVs and GRs [26].…”