A de novo start-loss variant in the NIPBL gene causing mild type 1 Cornelia de Lange syndrome in an Iranian family: A Case Report

BACKGROUND: Cornelia de Lange syndrome is a rare congenital disorder marked by considerable clinical variability, including intellectual disability, growth retardation, distinctive facial features, limb abnormalities, and multisystem involvement. The condition is primarily linked to mutations in genes encoding components of the cohesin complex that are essential for chromosomal stability and gene regulation. We report a case of a mild type of Cornelia de Lange syndrome caused by a de novo mutation in an Iranian family. CASE PRESENTATION: We investigated a 19-year-old Iranian male individual presenting with developmental delay, borderline intellectual disability, dysmorphic facial features, and multisystem involvement. Whole-exome sequencing was performed to identify causative variants. A de novo heterozygous variant affecting the start codon of NIPBL (NM_133433.4:c.2T>A; NP_597677.2:p.Met1Lys) was identified. This variant was absent from population databases and predicted to disrupt normal translation initiation. Sanger sequencing and co-segregation analysis confirmed the genetic findings. In silico tools and population databases were utilized to assess variant pathogenicity. Clinically, the patient exhibited classical Cornelia de Lange syndrome features with relatively mild intellectual impairment compared with typical loss-of-function cases, consistent with the hypothesis of potential use of alternative start sites. CONCLUSION: This case shows a known NIPBL start-loss variant's correlation with a relatively mild clinical presentation and offers more genotype-phenotype evidence for it. This finding suggests a possible role for downstream translation initiation as a modifier of disease severity, although further functional validation is required. Comprehensive genetic analysis remains essential for accurate diagnosis, prognosis, and counseling in patients with Cornelia de Lange syndrome.