Deep intronic NIPBL splice site variant in a patient with a mild presentation of classic Cornelia de Lange syndrome phenotype

Furquim, I., Seyama, R., Nunes, B. C., Melaragno, M. I., Kim, C. A., Matsumoto, N. (2025). Deep intronic NIPBL splice site variant in a patient with a mild presentation of classic Cornelia de Lange syndrome phenotype (Version 1) [DataSet]. GestaltMatcher Database.

We report a 9-year-old male, first living child of a Brazilian non-consanguineous couple after a miscarriage, who presents classic Cornelia de Lange Syndrome (CdLS) phenotype. He exhibits synophrys, thick eyebrows, an upturned nasal tip, a long and smooth philtrum, thin upper lip vermilion, hirsutism, global developmental delay, and prenatal growth retardation. Features also include ankyloglossia, syndactyly, inguinal hernia, and abnormal external genitalia. He required hospitalization due to bronchiolitis and had bilateral herniorrhaphy, orchiopexy, phimosis, and frenectomy surgeries. He can speak sentences, recognize letters and numbers, and perform basic daily activities independently (e.g., showering, eating, etc.). Although whole exome sequencing showed no clinically relevant variants (Aoi et al. 2019, 10.1038/s10038-019-0643-z), RNA sequencing revealed a novel heterozygous deep intronic variant in intron 21 of the NIPBL gene (Seyama et al. 2022, 10.1016/j.ygeno.2022.110468). RT-PCR showed a cryptic 117 bp exon inclusion in intron 21, which induced a premature stop codon. Variants in the NIPBL gene are the most frequent among CdLS patients, usually leading to severe cases. However, the patient’s phenotype is mild compared to other patients with NIPBL variants, as he can perform daily activities independently, has preserved speech, and does not have severe malformations. In summary, this case highlights the importance of continuing the investigation after inconclusive WES results in patients with classic CdLS phenotype and suggests that splice site NIPBL variants might be associated with milder phenotypes.