First Cornelia de Lange Syndrome Type 4 Caused by the Gonadal Mosaicism of RAD21 Deletion.

BACKGROUND: Cornelia de Lange syndrome (CdLS) currently has seven known causative genes, inherited in an autosomal or X-linked dominant pattern. Clinical features are variable, including dysmorphic facial features, intrauterine and/or postnatal growth retardation, multiple organ system malformations, and neurodevelopmental disorders. Type 4 of CdLS caused by RAD21 gene has a relatively mild phenotype. METHODS: Here, we report a pair of siblings from a Chinese family who both have similar dysmorphic facial features, cleft palate, spina bifida occulta, and limb phenotypes. Whole-genome sequencing (WGS) was performed to analyze the genetic basis of their condition. Gap-PCR was subsequently employed to map the breakpoints in the affected siblings' peripheral blood samples. Additionally, the copy number status of the parents and the father's sperm DNA were evaluated using Gap-PCR and digital PCR (dPCR). RESULTS: Through WGS analysis, a heterozygous deletion was found in the 8q23.3-8q24.11 region of both patients, which includes the full-length RAD21 gene. And we mapped the breakpoint with the peripheral blood samples of the affected siblings using Gap-PCR. The parents' peripheral blood had normal copy number. The father's sperm DNA was negative for the deletion by both Gap-PCR and dPCR, whereas the mother's peripheral blood was also negative, suggesting the deletion is likely due to maternal gonadal mosaicism. CONCLUSIONS: We report a pair of siblings with a complete loss of RAD21, with evidence supporting maternal gonadal mosaicism. This information will be helpful for genetic counseling for Type 4 of CdLS.