CUL3-Related Neurodevelopmental Disorder: Expanding the Prenatal Phenotype
Yoel Gofin1,2,3, Tania Dery1, Tamar Tenne1
1Genetics Institute, Meir Medical Center, Kfar Saba, Israel.
Insights
Pathogenic CUL3 variants cause neurodevelopmental disorders. Cerebellar hypoplasia is a newly identified prenatal sonographic marker, aiding in early diagnosis and genetic counseling for CUL3-related conditions.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Prenatal Diagnosis
Background:
- Pathogenic variants in the CUL3 gene are associated with a neurodevelopmental disorder.
- The prenatal phenotype of this disorder is not fully characterized.
Purpose of the Study:
- To expand the spectrum of prenatal sonographic findings in CUL3-related neurodevelopmental disorders.
- To improve prenatal diagnosis and genetic counseling for affected families.
Main Methods:
- A multi-center case series of seven new cases with pathogenic CUL3 variants.
- Integration of new data with a literature review of 18 previously reported prenatal cases.
- Exome sequencing was used to identify pathogenic CUL3 variants.
Main Results:
- Intrauterine growth restriction and increased nuchal translucency are common but nonspecific findings.
- Cerebellar hypoplasia was identified as a novel sonographic marker in three new cases.
- Other observed anomalies included cardiac defects, abnormal brain sulcation, and skeletal abnormalities.
Conclusions:
- Cerebellar hypoplasia is proposed as a significant sonographic marker for CUL3-related neurodevelopmental disorders.
- The identification of cerebellar hypoplasia should increase suspicion for CUL3 variants.
- This finding supports exome sequencing and aids in the clinical interpretation of CUL3 variants.
Objective:
Pathogenic 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.
Methods:
This 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.
Results:
Our 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.
Conclusion:
This 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.
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