Identification of a novel de novo NONO variants causing X-linked syndromic intellectual developmental disorder-34 in...

This study aimed to confirm the pathogenicity of a novel de novo nonsense variant (c.214C > T, p.Gln72*) in NONO in a male fetus with multisystem anomalies and to expand the prenatal phenotypic spectrum of NONO-related disorders.

A male fetus presenting with noncompaction cardiomyopathy, corpus callosum hypoplasia, mild ventriculomegaly, and relative macrocephaly was analyzed. Trio Exome sequencing (trio-ES) was performed on fetal and parental DNA. Candidate variants were validated by Sanger sequencing, and functional studies, including RT-qPCR and Western blot, were used to evaluate the variant's effect on NONO protein.

Trio-ES identified a de novo hemizygous nonsense variant in NONO exon 4 (c.214C > T, p.Gln72*), absent in parental genomes and population databases. Sanger sequencing confirmed the variant in fetus. Functional assays (RT-qPCR, Western blot) confirmed truncated protein degradation and NONO loss-of-function (LoF), supporting its pathogenicity. These results expand the prenatal phenotype of NONO-related disorders to encompass cardiac and neurostructural anomalies.

This study functionally validates the pathogenicity of the NONO c.214C > T variant and identifies novel prenatal features. The findings highlight the value of trio-ES combined with functional studies in diagnosing rare multisystem fetal conditions, thereby improving prenatal diagnostic accuracy and broadening the understanding of phenotypic variability associated with NONO LoF variants.