Resequencing (MIPS) of candidate genes for Keratoconus (2020)

In this study, we selected 34 candidate genes for KC based on previous Whole Exome Sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, ZEB1 and ZNF469. The top hit in the Fisher’s exact test was obtained for a common variant in the COL12A1 gene. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC. Besides the role for EDS genes, we also confirm the previously reported involvement of genetic variation in ZEB1 in KC.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001006825	The dataset consists of the BAM-files of 745 patients and 810 controls (retained after quality control) of a set of 34 candidate genes obtained after targeted enrichment via Molecular Inversion Probes (MIPS) technology. The sequencing was performed on the NextSeq 500 (Illumina, CA, USA) using custom sequencing and index primers in three 2 x 76 bp, dual indexed runs using a 150 cycles High-Output Illumina kit (Illumina, CA, USA). Alignment of the fastq reads to the human genome was performed using BWA (v0.7.4).	NextSeq 500	1555

Publications	Citations
Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes. Fransen E, Valgaeren H, Janssens K, Sommen M, De Ridder R, Vandeweyer G, Bisceglia L, Soler V, Hoischen A, Mortier G, Malecaze F, Koppen C, Van Camp G. Eur J Hum Genet 29: 2021 1745-1755	7