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Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity

2022; Taylor & Francis; Volume: 43; Issue: 6 Linguagem: Inglês

10.1080/13816810.2022.2144905

1744-5094

Richard Holt, David Goudie, Alejandra Damián Verde, Alice Gardham, Francis Ramond, Audrey Putoux, Ajoy Sarkar, Virginia Clowes, Jill Clayton‐Smith, Siddharth Banka, L. Cortazar Galarza, Gilles Thuret, Marta Ubeda Erviti, Ane Zurutuza Ibarguren, Raquel Sáez Villaverde, Alejandra Tamayo Durán, Carmen Ayuso, Dorine A. Bax, Julie Plaisancié, Marta Cortón, Nicolas Chassaing, Patrick Calvas, Nicola Ragge,

Craniofacial Disorders and Treatments

Background Anophthalmia, microphthalmia and coloboma are a genetically heterogenous spectrum of developmental eye disorders. Recently, variants in the Wnt-pathway gene Frizzled Class Receptor 5 (FZD5) have been identified in individuals with coloboma and rarely microphthalmia, sometimes with additional phenotypes and variable penetrance.Materials and Methods We identified variants in FZD5 in individuals with developmental eye disorders from the UK (including the DDD Study [www.ddduk.org/access.html]), France and Spain using whole genome/exome sequencing or customized NGS panels of ocular development genes.Results We report eight new families with FZD5 variants and ocular coloboma. Three individuals presented with additional syndromic features, two explicable by additional variants in other genes (SLC12A2 and DDX3X). In two families initially showing incomplete penetrance, re-examination of apparently unaffected carrier individuals revealed subtle ocular colobomatous phenotypes. Finally, we report two families with microphthalmia in addition to coloboma, representing the second and third reported cases of this phenotype in conjunction with FZD5 variants.Conclusions Our findings indicate FZD5 variants are typically associated with isolated ocular coloboma, occasionally microphthalmia, and that extraocular phenotypes are likely to be explained by other gene alterations.