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Updated: Sep 7, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Whole-Exome Sequencing in a Consanguinity-Enriched South Indian Retinitis Pigmentosa Cohort: Diagnostic Yield and
Sujay Jaju1,2, Jayashree Sivagnanam1, Parvathy Menon1
1P. Namperumalsamy Regional Research Centre, Aravind Eye Hospital, Coimbatore, Tamil Nadu, India.
Purpose:
To determine the molecular diagnostic yield, variant spectrum, inheritance architecture, and influence of consanguinity on whole-exome sequencing outcomes in a South Indian retinitis pigmentosa (RP) cohort.
Design:
Prospective, registry-based cohort study.
Subjects:
A total of 113 affected participants were enrolled through the Aravind Registry for Inherited Diseases of the Eye, including 109 unrelated probands and 4 affected relatives from already represented families. Primary analyses were restricted to the 109 unrelated probands.
Methods:
Whole-exome sequencing was performed using a clinical exome workflow. Variants were interpreted using American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria and cases were categorized as solved, possibly solved, inconclusive, or unsolved using prespecified inheritance-aware rules.
Main Outcome Measures:
Molecular diagnostic yield, distribution of implicated genes and variant classes, inheritance architecture, and diagnostic yield stratified by consanguinity status.
Results:
Among the 109 unrelated probands, mean age at testing was 39.3 ± 14.1 years and 58.7% were male. Whole-exome sequencing identified 186 distinct rare variants across 92 inherited retinal disease genes, including 26 pathogenic and 33 likely pathogenic variants. A molecular diagnosis was established in 50 of 109 probands (45.9%), including 42 solved and 8 possibly solved cases; 45 (41.3%) were inconclusive and 14 (12.8%) remained unsolved, including 4 (3.7%) in whom no candidate variant was identified. EYS, USH2A, and ADGRV1 were the most frequently implicated genes. Autosomal recessive (AR) disease predominated (44/50, 88.0%). Consanguineous AR cases were exclusively homozygous (17/17); notably, 68.0% of nonconsanguineous AR cases were also homozygous (P = 0.013). Diagnostic yield was higher in consanguineous probands (51.4% vs. 41.7%), without reaching significance. Recurrent alleles included an established South Asian founder variant (MFSD8 c.1361T>C) and candidate founder alleles in EYS (c.4321C>T) and ADGRV1 (c.14329C>T).
Conclusions:
Whole-exome sequencing established a molecular diagnosis in nearly half of this South Indian RP cohort and revealed a predominantly recessive, homozygosity-enriched architecture shaped by consanguinity. These findings define a region-specific variant landscape to support clinical interpretation, genetic counseling, and future trial enrollment in this underrepresented population.
Financial Disclosures:
The authors have no proprietary or commercial interest in any materials discussed in this article.
