CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype.

objectivePathogenic variants of the CUL3 gene are known to cause a neurodevelopmental disorder with a partially described prenatal phenotype. This study further characterizes and expands the spectrum of prenatal sonographic findings associated with the disorder to improve prenatal diagnosis and counseling.

methodsThis multi-center case series adds seven new cases from 5 pedigrees with pathogenic CUL3 variants identified through exome sequencing. We analyzed the new data and integrated the findings with a comprehensive review of 18 prenatal cases in the literature.

resultsOur analysis of a combined cohort of 25 prenatal cases confirms that intrauterine growth restriction and increased nuchal translucency are frequent, nonspecific findings. The most significant novel finding in our series was cerebellar hypoplasia, which was identified in three of the new cases. Other findings included cardiac anomalies, abnormal sulcation, and skeletal abnormalities.

conclusionThis study expands on the known prenatal phenotype of CUL3-related neurodevelopmental disorders, proposing cerebellar hypoplasia as a new sonographic marker. The presence of cerebellar hypoplasia should significantly raise suspicion for a CUL3-related neurodevelopmental disorder. This finding provides a strong rationale for pursuing exome sequencing and serves as critical evidence for the clinical interpretation of CUL3 variants.