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Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia

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Tarilonte, María & Morín, Matías & Ramos, Patricia & Galdós, Marta & Blanco Kelly, Fiona & Villaverde, Cristina & Rey Zamora, Dolores & Rebolleda, Gema & Muñoz Negrete, Francisco J. & Tahsin Swafiri, Saoud & Gener, Blanca & Moreno Pelayo, Miguel Angel & Ayuso, Carmen & Villamar, Manuela & Corton, Marta (2018-10 ) .Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia.

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Tarilonte, María & Morín, Matías & Ramos, Patricia & Galdós, Marta & Blanco Kelly, Fiona & Villaverde, Cristina & Rey Zamora, Dolores & Rebolleda, Gema & Muñoz Negrete, Francisco J. & Tahsin Swafiri, Saoud & Gener, Blanca & Moreno Pelayo, Miguel Angel & Ayuso, Carmen & Villamar, Manuela & Corton, Marta. 2018-10 .Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia.

https://hdl.handle.net/20.500.12080/39723
dc.contributor.author Tarilonte, María
dc.contributor.author Morín, Matías
dc.contributor.author Ramos, Patricia
dc.contributor.author Galdós, Marta
dc.contributor.author Blanco Kelly, Fiona
dc.contributor.author Villaverde, Cristina
dc.contributor.author Rey Zamora, Dolores
dc.contributor.author Rebolleda, Gema
dc.contributor.author Muñoz Negrete, Francisco J.
dc.contributor.author Tahsin Swafiri, Saoud
dc.contributor.author Gener, Blanca
dc.contributor.author Moreno Pelayo, Miguel Angel
dc.contributor.author Ayuso, Carmen
dc.contributor.author Villamar, Manuela
dc.contributor.author Corton, Marta
dc.date.accessioned 2024-02-12T14:38:34Z
dc.date.available 2024-02-12T14:38:34Z
dc.date.created 2018-10
dc.date.issued 2018-10
dc.identifier.uri https://hdl.handle.net/20.500.12080/39723
dc.description.abstract Mutations in PAX6 are involved in several developmental eye disorders. These disorders have considerable phenotypic variability, ranging from panocular forms of congenital aniridia and microphthalmia to isolated anomalies of the anterior or posterior segment. Here, we describe 3 families with variable inter-generational ocular expression of aniridia, iris coloboma, or microphthalmia, and an unusual transmission of PAX6 mutations from an unaffected or mildly affected parent; all of which raised suspicion of gonosomal mosaicism. We first identified two previously known nonsense mutations and one novel likely pathogenic missense variant in PAX6 in probands by means of targeted NGS. The subsequent segregation analysis by Sanger sequencing evidenced the presence of highly probable mosaic events in paternal blood samples. Mosaicism was further confirmed by droplet digital PCR analysis in several somatic tissues of mosaic fathers. Quantification of the mutant allele fraction in parental samples showed a marked deviation from 50%, with a range between 12 and 29% depending on cell type. Gonosomal mosaicsm was definitively confirmed in one of the families thanks to the availability of a sperm sample from the mosaic father. Thus, the recurrence risk in this family was estimated to be about one-third. This is the first report confirming parental PAX6 mosaicism as a cause of disease recurrence in aniridia and other related phenotypes. In addition, we demonstrated that post-zygotic mosaicism is a frequent and underestimated pathogenic mechanism in aniridia, explaining intra-familial phenotypic variability in many cases. Our findings may have substantial implications for genetic counseling in congenital aniridia. Thus, we also highlight the importance of comprehensive genetic screening of parents for new sporadic cases with aniridia or related developmental eye disease to more accurately assess recurrence risk. In conclusion, somatic and/or gonosomal mosaicism should be taken into consideration as a genetic factor to explain not only families with unaffected parents despite multiple affected children but also variable expressivity, apparent de novo cases, and even uncharacterized cases of aniridia and related developmental eye disorders, apparently lacking PAX6 mutations. es_ES
dc.format application/pdf es_ES
dc.language eng es_ES
dc.rights CC-BY es_ES
dc.rights.uri http://creativecommons.org/licenses/by/4.0/deed.es es_ES
dc.title Parental Mosaicism in PAX6 Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia es_ES
dc.type info:eu-repo/semantics/article es_ES
dc.rights.accessrights info:eu-repo/semantics/openAccess es_ES
dc.identifier.location N/A es_ES


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