Leveraging consanguinity in inherited retinal diseases uncovers missing genetic variation: rare novel disease genes and a multitude of novel pathogenic variants in known disease genes

Abstract

Purpose : It was our aim to leverage consanguinity in a cohort of 150 unrelated families of different ethnicities, segregating non-syndromic and syndromic inherited retinal disease (IRD) phenotypes, to uncover IRD-associated missing genetic variation.

Methods : We used a uniform integrative approach combining homozygosity mapping (HumanCytoSNP-12 BeadChip, Illumina), targeted next-generation sequencing and whole exome sequencing (WES) (SureSelectXT Human All Exon V5/V6 kit, Agilent; NextSeq 500 or HiSeq 3000, Illumina; CLC Genomics Workbench, Qiagen). In addition, copy number variants (CNVs) were assessed based on SNP chip (ViVar) and WES data (CoNIFER).

Results : We identified 111 unique likely pathogenic variants, 54 of which are novel, in 62 known IRD genes in 74% of the patients. Interestingly, we report the first autosomal recessive FBN2-associated IRD. Moreover, we uncovered homozygous mutations in seven novel candidate IRD genes in seven unrelated families, contributing to 5% of the IRD cohort. In three of them, ATP1B2, CEP162 and EML4, the likely primary genetic defect was found, while in four of them, EML2, ERICH6, PATJ and SPECC1, a pathogenic variant was found in combination with variants in other known IRD genes. In five of these (ATP1B2, CEP162, EML2, PATJ and SPECC1) loss-of-function alleles were found, while putative hypomorphic alleles were found in EML4 and ERICH6. Interrogation of previously generated exome or genome data revealed genetic defects in CEP162 and EML4 in two additional IRD families. Finally, we demonstrated the importance of structural variants in IRD, identifying CNVs in 8% of the cohort, including the first CNVs described in the PDE6G and C12ORF65 genes.

Conclusions : Overall, our study shows the power of genetic studies in consanguineous pedigrees to elucidate the underlying genetic cause of genetically heterogeneous diseases such as IRD. The exome-oriented approach focusing on different types of genetic variation revealed a high mutational load (76%). A causal genetic defect remained missing in 23% of our IRD cohort, assuming that non-coding mutations in known and novel genes significantly contribute to the overall genetic architecture of IRD and demonstrating that they require genome-oriented approaches.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.