advertisement
Abstract #79119 Published in IGR 20-1
Parental Mosaicism in Causes Intra-Familial Variability: Implications for Genetic Counseling of Congenital Aniridia and Microphthalmia
Tarilonte M; Morín M; Ramos P; Galdós M; Blanco-Kelly F; Villaverde C; Rey-Zamora D; Rebolleda G; Muñoz-Negrete FJ; Tahsin-Swafiri S; Gener B; Moreno-Pelayo MA; Ayuso C; Villamar M; Corton MFrontiers in genetics 2018; 9: 479
Mutations in 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 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 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 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 cases, and even uncharacterized cases of aniridia and related developmental eye disorders, apparently lacking mutations.
Department of Genetics and Genomics, Instituto de Investigación Sanitaria de la Fundación Jiménez Díaz, University Hospital - Universidad Autónoma de Madrid, Madrid, Spain.
Full articleClassification:
9.1.3 Syndromes of Axenfeld, Rieger, Peters, aniridia (Part of: 9 Clinical forms of glaucomas > 9.1 Developmental glaucomas)