Expanding the phenotypic spectrum of CC2D2A-related ciliopathies: a rare homozygous nonsense variant in a patient with suspected nephronophthisis

Autor: Sentell, Zachary T., Nurcombe, Zachary W., Mougharbel, Lina, Anastasio, Natascia, Rivière, Jean-Baptiste, Babayeva, Sima, Goodyer, Paul R., Torban, Elena, Kitzler, Thomas M.
Zdroj: European Journal of Human Genetics: EJHG; 20240101, Issue: Preprints p1-6, 6p
Abstrakt: Biallelic pathogenic variants in the gene CC2D2Acause a spectrum of ciliopathies, including Joubert and Meckel syndrome, which frequently involve the kidney; however, no cases of isolated renal disease (i.e., nephronophthisis) have yet been reported. In an adult with a clinical presentation consistent with nephronophthisis, next-generation sequencing identified a rare homozygous nonsense variant in CC2D2A(c.100 C > T; p.(Arg34*)). Tissue-specific expression data and promoter activity analysis demonstrates that this variant primarily affects a transcript isoform predominant in the kidneys but does not affect the transcript isoforms predominant in other tissues typically involved in CC2D2A-related ciliopathies (e.g., cerebellum, liver). Expression analysis of patient-specific cDNA in MDCK cells demonstrates partial translation re-initiation downstream of p.(Arg34*) as a possible escape mechanism from nonsense mediated decay. These data provide mechanistic insights in support of this novel genotype-phenotype association.
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