Whole Genome Sequencing Solves an Atypical Form of Bardet–Biedl Syndrome: Identification of Novel Pathogenic Variants of BBS9

Autor: Emilia Stellacci, Marcello Niceta, Alessandro Bruselles, Emilio Straface, Massimo Tatti, Mattia Carvetta, Cecilia Mancini, Serena Cecchetti, Mariacristina Parravano, Lucilla Barbano, Monica Varano, Marco Tartaglia, Lucia Ziccardi, Viviana Cordeddu
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: International Journal of Molecular Sciences, Vol 25, Iss 15, p 8313 (2024)
Druh dokumentu: article
ISSN: 1422-0067
1661-6596
DOI: 10.3390/ijms25158313
Popis: Bardet–Biedl syndrome (BBS) is a rare recessive multisystem disorder characterized by retinitis pigmentosa, obesity, postaxial polydactyly, cognitive deficits, and genitourinary defects. BBS is clinically variable and genetically heterogeneous, with 26 genes identified to contribute to the disorder when mutated, the majority encoding proteins playing role in primary cilium biogenesis, intraflagellar transport, and ciliary trafficking. Here, we report on an 18-year-old boy with features including severe photophobia and central vision loss since childhood, hexadactyly of the right foot and a supernumerary nipple, which were suggestive of BBS. Genetic analyses using targeted resequencing and exome sequencing failed to provide a conclusive genetic diagnosis. Whole-genome sequencing (WGS) allowed us to identify compound heterozygosity for a missense variant and a large intragenic deletion encompassing exon 12 in BBS9 as underlying the condition. We assessed the functional impact of the identified variants and demonstrated that they impair BBS9 function, with significant consequences for primary cilium formation and morphology. Overall, this study further highlights the usefulness of WGS in the diagnostic workflow of rare diseases to reach a definitive diagnosis. This report also remarks on a requirement for functional validation analyses to more effectively classify variants that are identified in the frame of the diagnostic workflow.
Databáze: Directory of Open Access Journals
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