Compound heterozygous WDR19 variants associated with nephronophthisis, Caroli disease, refractory epilepsy and congenital bilateral central blindness: Case report

The WDR19 gene has been reported to be involved in nephronophthisis-related ciliopathies such as isolated nephronophthisis 13 (NPHP13), Sensenbrenner syndrome, Jeune syndrome, SeniorLoken syndrome, Caroli disease, retinitis pigmentosa and Asthenoteratospermia. In the present study, we provided the detailed clinical characteristics and genetic analysis of a patient with four variants in WDR19 and TG, reviewed a comprehensive mutation analysis in the WDR19-related ciliopathies, discussed the relationship between genotype and phenotype, and compared the allele frequencies (AFs) of WDR19 variants depending on the ethnic background. We used wholeexome sequencing (WES) combined with bioinformatics analysis to investigate the genetic variants of a 3-year-old boy with common features of WDR19-associated NPHP13 and Caroli disease, bilateral central blindness, refractory epilepsy, and elevated thyroid stimulating hormone. A novel splice-donor variant, c.98+1G > C, and a recurrent missense variant, c.3533G > A, were identified in the WDR19 gene. We used effective mRNA analysis to verify the effects on pre-mRNA processing and to assess the pathogenicity of the splice-site variant. The patient also harbored compound heterozygous variants of the TG gene (c.4889A > G, c.274+2T > G). Of note, using a review of an in-house database, we identified four additional likely pathogenic WDR19 variants and estimated the overall AF of WDR19 mutations to be 0.0025 in the southern Chinese population. Our findings have expanded the allelic spectrum of mutations in the WDR19 gene and broadened the clinical phenotype spectrum of WDR19-related ciliopathies. The results have also provided new insights into the clinical heterogeneity of the disorder, which would be useful in accurate genetic counseling for affected individuals and carrier screening in a general population.