TY - JOUR
T1 - Individuals with heterozygous variants in the Wnt-signalling pathway gene FZD5 delineate a phenotype characterized by isolated coloboma and variable expressivity
AU - Holt, Richard
AU - Goudie, David
AU - Verde, Alejandra Damián
AU - Gardham, Alice
AU - Ramond, Francis
AU - Putoux, Audrey
AU - Sarkar, Ajoy
AU - Clowes, Virginia
AU - Clayton-Smith, Jill
AU - Banka, Siddharth
AU - Cortazar Galarza, Laura
AU - Thuret, Gilles
AU - Ubeda Erviti, Marta
AU - Zurutuza Ibarguren, Ane
AU - Sáez Villaverde, Raquel
AU - Tamayo Durán, Alejandra
AU - Ayuso, Carmen
AU - Bax, Dorine A.
AU - Plaisancie, Julie
AU - Corton, Marta
AU - Chassaing, Nicolas
AU - Calvas, Patrick
AU - Ragge, Nicola K.
N1 - Funding Information:
The work was supported by the Baillie Gifford MACS (Microphthalmia, Anophthalmia, Coloboma Support).
Copyright:
© 2022 The Author(s). Published with licence by Taylor & Francis Group, LLC.
PY - 2023/1/25
Y1 - 2023/1/25
N2 - 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.
AB - 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.
KW - coloboma
KW - FZD5
KW - genetic testing
KW - microphthalmia
KW - patient care
KW - penetrance
KW - Wnt signalling pathway
UR - http://www.scopus.com/inward/record.url?scp=85147047753&partnerID=8YFLogxK
U2 - 10.1080/13816810.2022.2144905
DO - 10.1080/13816810.2022.2144905
M3 - Article
C2 - 36695497
AN - SCOPUS:85147047753
SN - 1381-6810
VL - 43
SP - 809
EP - 816
JO - Ophthalmic Genetics
JF - Ophthalmic Genetics
IS - 6
ER -