Novel PXDN biallelic variants in patients with microphthalmia and anterior segment dysgenesis

Zazo-Seco, Celia; Plaisancié, Julie; Bitoun, Pierre; Cortón, Marta; Arteche, Ana; Ayuso, Carmen; Schneider, Adele; Zafeiropoulou, Dimitra; Gilissen, Christian; Roche, Olivier; Fremont, Félix; Calvas, Patrick; Slavotinek, Anne; Ragge, Nicola; Chassaing, Nicolas

doi:10.1038/s10038-020-0726-x

Cited by 6 publications

(3 citation statements)

References 19 publications

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“…In a proband (patient 21) with severe bilateral sclerocornea ( Fig. 2c), glaucoma, and severe developmental delay, a previously reported 12,13 pathogenic homozygous frameshift variant was found in PXDN (c.4085_4086delAG, p.[Gln1362Argfs*22]) ( Fig. 3b).…”

Section: Likely Causative Variants In 54% Of Probands Including In 5mentioning

confidence: 75%

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Yousoof

Grigg

et al. 2020

Genetics in Medicine

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Purpose: Ocular anterior segment disorders (ASDs) are clinically and genetically heterogeneous, and genetic diagnosis often remains elusive. In this study, we demonstrate the value of a combined analysis protocol using phenotypic, genomic, and pedigree structure data to achieve a genetic conclusion. Methods: We utilized a combination of chromosome microarray, exome sequencing, and genome sequencing with structural variant and trio analysis to investigate a cohort of 41 predominantly sporadic cases. Results: We identified likely causative variants in 54% (22/41) of cases, including 51% (19/37) of sporadic cases and 75% (3/4) of cases initially referred as familial ASD. Two-thirds of sporadic cases were found to have heterozygous variants, which in most cases were de novo. Approximately one-third (7/22) of genetic diagnoses were found in rarely reported or recently identified ASD genes including PXDN, GJA8, COL4A1, ITPR1, CPAMD8, as well as the new phenotypic association of Axenfeld-Rieger anomaly with a homozygous ADAMTS17 variant. The remainder of the variants were in key ASD genes including FOXC1, PITX2, CYP1B1, FOXE3, and PAX6. Conclusions: We demonstrate the benefit of detailed phenotypic, genomic, variant, and segregation analysis to uncover some of the previously "hidden" heritable answers in several rarely reported and newly identified ocular ASD-related disease genes.

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Section: Likely Causative Variants In 54% Of Probands Including In 5mentioning

confidence: 75%

Revealing hidden genetic diagnoses in the ocular anterior segment disorders

Yousoof

Grigg

et al. 2020

Genetics in Medicine

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“…In family MA193, we identified the previously reported 1bp deletion (c.2568del; p.(Cys857Alafs*5)) which was reported [ 27 ] in a Pakistani family with corneal opacity and cataract. In a Caucasian family, a different variant with the same protein effect (c.2569delT; p.(Cys857Alafs*5)) showed unilateral microphthalmia [ 41 ]. Contradictory to both previous studies, all affected individuals from family MA193 manifest bilateral anophthalmia, suggesting the variant is responsible for a more severe phenotype in this family.…”

Section: Discussionmentioning

confidence: 99%

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

Basharat,

Rodenburg,

Rodríguez-Hidalgo

et al. 2023

Genes

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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.

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“…PXDNL and peroxidasin ( PXDN ) belong to the peroxidase-cyclooxygenase superfamily [ 38 ]. Mutations in PXDNL would cause congenital malformations in developing human embryo and laterality [ 39 ], whereas PXDN mutations would cause eye developmental glaucoma, microphthalmia, microcornea, and anterior segment dysgenesis in human and mice [ [40] , [41] , [42] , [43] ]. PXDNL could contribute to the development of angle closure and APAC through the changes in anatomical structures by forming complex with PXDN and antagonizing the peroxidase activity of PXDN [ 38 ].…”

Section: Discussionmentioning

confidence: 99%