期刊
HUMAN MUTATION
卷 43, 期 12, 页码 2234-2250出版社
WILEY-HINDAWI
DOI: 10.1002/humu.24489
关键词
cost-effective; high-throughput; macular diseases; smMIPs; targeted gene sequencing
资金
- HRCI HRB Joint Funding Scheme [2020-007]
- Stichting Oogfonds Nederland [UZ 2020-17]
- Pro Retina Deutschland
- Stichting tot Verbetering van het Lot der Blinden
- Stichting voor Ooglijders
- Stichting Blindenhulp
- Retina Australia
- Australian National Health and Medical Research Council [MRF1142962]
- Retina South Africa
- South African Medical Research Council
- University of Campania Luigi Vanvitelli
- SOLVE-RET
Macular degenerations (MDs), a subgroup of retinal disorders, are characterized by central vision loss. This study used smMIPs sequencing to investigate the genetic factors influencing MDs and identified new variants and genetic associations.
Macular degenerations (MDs) are a subgroup of retinal disorders characterized by central vision loss. Knowledge is still lacking on the extent of genetic and nongenetic factors influencing inherited MD (iMD) and age-related MD (AMD) expression. Single molecule Molecular Inversion Probes (smMIPs) have proven effective in sequencing the ABCA4 gene in patients with Stargardt disease to identify associated coding and noncoding variation, however many MD patients still remain genetically unexplained. We hypothesized that the missing heritability of MDs may be revealed by smMIPs-based sequencing of all MD-associated genes and risk factors. Using 17,394 smMIPs, we sequenced the coding regions of 105 iMD and AMD-associated genes and noncoding or regulatory loci, known pseudo-exons, and the mitochondrial genome in two test cohorts that were previously screened for variants in ABCA4. Following detailed sequencing analysis of 110 probands, a diagnostic yield of 38% was observed. This established an ''MD-smMIPs panel, enabling a genotype-first approach in a high-throughput and cost-effective manner, whilst achieving uniform and high coverage across targets. Further analysis will identify known and novel variants in MD-associated genes to offer an accurate clinical diagnosis to patients. Furthermore, this will reveal new genetic associations for MD and potential genetic overlaps between iMD and AMD.
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