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other·ophthalmology, pediatric ophthalmology, ocular immunology, biomedical research, research methods·PMC10454697

Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients

Genes · 11 authors, 5 centres

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TL;DR

This study combined targeted *FOXE3* gene testing followed by genome sequencing to diagnose seven consanguineous families with anophthalmia/microphthalmia, achieving a 100% diagnostic solve rate by identifying pathogenic variants in *FOXE3*, *PXDN*, and *VSX2* genes.

Full summary

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The study included seven consanguineous Pakistani families affected by anophthalmia and microphthalmia with an unknown molecular cause. The diagnostic approach used targeted Sanger sequencing of the *FOXE3* gene, followed by genome sequencing for unsolved cases. This strategy provided a genetic diagnosis for all seven families. Targeted *FOXE3* sequencing solved four families, identifying two previously reported pathogenic variants. Genome sequencing solved the remaining three families, identifying a known *PXDN* variant, a novel 13bp deletion in *VSX2*, and a novel deep intronic splice variant in *PXDN*. An in vitro splice assay confirmed the splice variant caused a severe defect. The study demonstrates the utility of this combined, cost-effective approach for genetic diagnosis. Limitations include the small cohort size and the unavailability of detailed phenotypic data from OCT, ERG, or MRI scans.

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

100% · A

ORIGINAL PAPER

PMC10454697

Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients

Genes

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ABSTRACT

Anophthalmia and microphthalmia (A/M) are among the most severe congenital developmental eye disorders. Despite the advancements in genome screening technologies, more than half of A/M patients do not receive a molecular diagnosis. We included seven consanguineous families affected with A/M from Pakistani cohort and an unknown molecular basis. Single gene testing of FOXE3 was performed, followed by genome sequencing for unsolved probands in order to establish a genetic diagnosis for these families. All seven families were provided with a genetic diagnosis. The identified variants were all homozygous, classified as (likely) pathogenic and present in an A/M-associated gene. Targeted FOXE3 sequencing revealed two previously reported pathogenic FOXE3 variants in four families. In the remaining families, genome sequencing revealed a known pathogenic PXDN variant, a novel 13bp deletion in VSX2 , and one novel deep intronic splice variant in PXDN . An in vitro splice assay was performed for the PXDN splice variant which revealed a severe splicing defect. Our study confirmed the utility of genome sequencing as a diagnostic tool for A/M-affected individuals. Furthermore, the identification of a novel deep intronic pathogenic variant in PXDN highlights the role of non-coding variants in A/M-disorders and the value of genome sequencing for the identification of this type of variants.

CITATION EXPORT

Rabia Basharat, Kim Rodenburg, María Rodríguez-Hidalgo et al.. Combined Single Gene Testing and Genome Sequencing as an Effective Diagnostic Approach for Anophthalmia and Microphthalmia Patients. Genes. (2023). https://doi.org/10.3390/genes14081573

AUTHORS

11 · 5 CENTRES

Rabia Basharat, Kim Rodenburg, María Rodríguez-Hidalgo, Afeefa Jarral, Ehsan Ullah, Jordi Corominas, Christian Gilissen, Syeda Tatheer Zehra, Usman Hameed, Muhammad Ansar, Suzanne E. de Bruijn

1Department of Biochemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
2Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands
3Department of Neuroscience, Biodonostia Health Research Institute, 20014 Donostia-San Sebastián, Spain
4Department of Biotechnology, Mirpur University of Science and Technology (MUST), Mirpur 10250, AJK, Pakistan
5Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA

EDITOR / REVIEWER

Shi Song Rong