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Observational Study
. 2023 Jul:251:90-103.
doi: 10.1016/j.ajo.2023.02.025. Epub 2023 Mar 10.

Commercial Gene Panels for Congenital Anterior Segment Anomalies: Are They All the Same?

Maria Fernanda Villalba  1 , Chris Michael Li  2 , Parastou Pakravan  2 , Guney Bademci  3 , Ta Chen Peter Chang  4
Affiliations
Observational Study

Commercial Gene Panels for Congenital Anterior Segment Anomalies: Are They All the Same?

Maria Fernanda Villalba et al. Am J Ophthalmol. 2023 Jul.

Abstract

Purpose: We compared next generation sequencing multigene panels (NGS-MGP) from 5 commercial laboratories to inform ophthalmologists' decision making in diagnostic genetic testing for congenital anterior segment anomalies (CASAs).

Design: Comparison of commercial genetic testing panels.

Methods: This observational study gathered publicly available information on NGS-MGP from 5 commercial laboratories for the following: cataracts, glaucoma, anterior segment dysgenesis (ASD), microphthalmia-anophthalmia-coloboma (MAC), corneal dystrophies, and Axenfeld-Rieger syndrome (ARS). We compared gene panel composition, consensus rate (genes covered by all the panels per condition, "concurrent"), dissensus rate (genes covered by only 1 panel per condition, "standalone"), and intronic variant coverage. For individual genes, we compared publication history and association with systemic conditions.

Results: Altogether, cataract, glaucoma, corneal dystrophies, MAC, ASD, and ARS panels tested 239, 60, 36, 292, and 10 discrete genes, respectively. The consensus rate varied between 16% and 50%, and the dissensus rate varied between 14% and 74%. After pooling concurrent genes from all conditions, 20% of these genes were concurrent in 2 or more conditions. For both cataract and glaucoma, concurrent genes had significantly stronger correlation with the condition than standalone genes.

Conclusions: The genetic testing of CASAs using NGS-MGPs is complicated, owing to their number, variety, and phenotypic and genetic overlap. Although the inclusion of additional genes, such as the standalone ones, might increase diagnostic yield, these genes are also less well studied, indicating uncertainty over their role in CASA pathogenesis. Rigorous prospective diagnostic yield studies of NGS-MGPs will aid in making decisions of panel selection for the diagnosis of CASAs.

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Conflict of interest statement

Conflict of interest: None of the authors has any conflicts of interest to disclose. None of the authors possess financial interest in the commercial laboratory providers described in this study.

Figures

Figure 1.
Figure 1.. Visualizing the degree of overlap between condition-specific genetic testing panels from different laboratories.
For each condition, Venn diagrams show the number of genes in each combinatorial overlap between up to five genetic testing panels from Invitae, GeneDx, Blueprint Genetics, Prevention Genetics, and/or Fulgent Genetics. A. Cataract. B. Glaucoma. C. Corneal dystrophies. D. Microphthalmia, anophthalmia, and coloboma (MAC). E. Anterior segment dysgenesis (ASD). F. Axenfeld-Rieger Syndrome (ARS). Per condition, the total number of discrete genes after combining the available panels is shown below the respective Venn diagram.
Figure 2.
Figure 2.. Consensus and dissensus of genetic testing panels per condition.
Conditions are grouped by the number of genetic testing panels available: A. Cataract (left) and glaucoma (right), 5 tests. B. Corneal dystrophies (left) and microphthalmia, anophthalmia, and coloboma (MAC, right), 4 tests. C. Anterior segment dysgenesis (ASD), 3 tests. D. Axenfeld-Rieger Syndrome (ARS), 2 tests. Concurrent genes are those that are included in all panels (gold, consensus) and standalone genes are those that are included in only one panel (violet, dissensus). Genes included in more than one but not all panels are given intermediate colors varying depending on the number of total panels for the condition (blue, teal, or green). The rates of concurrence and dissensus are determined by the proportion of concurrent and standalone genes, respectively, to the total number of discrete genes and shown as a percentage. For each condition, available genetic panels are combined to determine the total number of discrete genes tested (italicized text).
Figure 3.
Figure 3.. Multi-overlapping concurrent genes between conditions.
Left: Per condition, concurrent genes from each condition (gold) were combined, yielding a list of 115 discrete concurrent genes across all conditions (middle). Right: Each of the 115 genes was analyzed for “multi-overlap”, defined as having a concurrent status in two or more different conditions (right, red). The Prevention Genetics “congenital cataracts panel” and “comprehensive cataracts panel” contribute the same concurrent genes for consideration of multi-overlap.
See this image and copyright information in PMC

References

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Supplementary concepts