Analysis of an NGS retinopathy panel detects chromosome 1 uniparental isodisomy in a patient with RPE65-related leber congenital amaurosis

Ophthalmic Genet. 2021 Oct;42(5):553-560. doi: 10.1080/13816810.2021.1938136. Epub 2021 Jun 22.


Purpose: This study aims to demonstrate the possibility of detecting segmental uniparental isodisomy (iUPD) using a next-generation sequencing gene panel by reporting a Leber congenital amaurosis (LCA) case caused by a homozygous pathogenic variant in RPE65 (c.1022 T > C:p.Leu341Ser) inherited exclusively from the proband's mother.Methods: Samples from the trio (proband, mother, and father) were sequenced with a next-generation sequencing (NGS) retinopathy gene panel (224 genes) and the VCF file containing all variants was used in order to determine single nucleotide variant (SNV) counts from each sample across all chromosomes.Results: Trio analysis showed that of 81 Chr1 inherited variants 41 were exclusively maternal, including 21 homozygous. The other 40 variants were common to both parents. On remaining autosomal chromosomes (Chr2-22) 645 inherited variants were found, 147 of them were exclusively maternal and 132 exclusively paternal. Based on these NGS data, it was possible to note that the proband's chromosomes 1 are more similar to his mother's chromosome 1 than his father's, suggesting the pathogenic homozygous variant found in this patient was inherited exclusively from the mother due to uniparental maternal isodisomy.Conclusions: This study presents a secondary analysis pipeline to identify responsible variants for a phenotype and the correct inheritance pattern, which is a critical step to the proper and accurate genetic counseling of all family members. In addition, this approach could be used to determine iUPD in different Mendelian disorders if the sequencing panel identifies variants spread throughout the genome.

Keywords: RPE65 gene; Uniparental isodisomy; diagnosis; gene panel; next-generation sequencing.

Publication types

  • Case Reports

MeSH terms

  • Adult
  • Chromosomes, Human, Pair 1 / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Leber Congenital Amaurosis / diagnosis*
  • Leber Congenital Amaurosis / genetics*
  • Male
  • Phenotype
  • Polymorphism, Single Nucleotide / genetics*
  • Retinal Dystrophies / diagnosis
  • Retinal Dystrophies / genetics*
  • Uniparental Disomy / genetics*
  • Whole Exome Sequencing
  • cis-trans-Isomerases / genetics*


  • retinoid isomerohydrolase
  • cis-trans-Isomerases