Detection of Large Structural Variants Causing Inherited Retinal Diseases

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Next-generation sequencing (NGS) identifies disease-causing mutations in 60-85% of inherited retinal disease (IRD) patients.
• A significant portion of IRD cases remain genetically unsolved, suggesting other mutation types exist.

Purpose of the Study:

• To investigate the genetic cause of autosomal dominant retinitis pigmentosa (adRP) in families with elusive genotypes.
• To identify novel genetic mechanisms underlying inherited retinal diseases.

Main Methods:

• Retinal-targeted-capture NGS and whole-exome NGS were used to screen for mutations.
• Linkage mapping was performed in large families.
• 10X Genomics Chromium sequencing was employed for linked-read, phase-known chromosomal analysis.

Main Results:

• A balanced translocation between chromosomes 2 and 4 was identified in all affected individuals of one adRP family.
• The translocation involved 35 Mb of chromosome 2 and 73 Mb of chromosome 4, with a breakpoint near the LRAT gene.
• The translocation was absent in unaffected individuals and associated with a history of miscarriages.

Conclusions:

• The balanced translocation is the likely cause of adRP in this family, potentially through LRAT gene dysregulation.
• Large structural variants, undetectable by conventional sequencing, may explain a substantial fraction of unsolved IRD cases.
• Balanced translocations should be considered in IRD families with a history of miscarriages.