Ribosomal RNA processing impairments in a B cell immunodeficient patient with WDR75 variants.

Ribosomopathies are rare genetic disorders associated with abnormalities in the production and function of ribosomes. We describe here our study of a patient presenting with hypogammaglobulinemia and autism spectrum disorder. Genetic analyses revealed compound-heterozygous variants in the WDR75 gene. WDR75 encodes a component of the SSU processome, a large ribonucleoprotein complex involved in the early stages of small ribosomal subunit assembly. Functional studies in cells derived from the patient and a cell line modified by CRISPR/Cas9 showed altered processing of pre-rRNA (A0 cleavage) and increased expression of p21, suggesting a predisposition to nucleolar stress and partial activation of the p53 pathway. While these observations do not prove causality between genotype and phenotype, they suggest a possible association between WDR75 genetic variants and nuclear stress, which may contribute to the clinical presentation.