Isfahan University of Medical Sciences

Science Communicator Platform

Share By
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 Publisher Pubmed

Summary: Can one gene variant explain milder rare-disease signs? A case report links NIPBL start-loss to a milder Cornelia de Lange presentation; validation is needed. #RareDisease #Genetics

Mir A ; Abbasi Z ; Song Y ; Lee H ; Khajeh A ; Jahantigh M ; Hajigholami S ; Khedri S ; Tabatabaiefar M A
Authors

Source: Journal of Medical Case Reports Published:2026


Abstract

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. © The Author(s) 2026.
Related Docs
View other Related Docs
1. Molecular and Phenotypical Findings of a Novel De Novo Syngap1 Gene Variant in an 11-Year-Old Iranian Boy With Intellectual Disability, Lab Medicine (2024)
2. A Novel Homozygote Pathogenic Variant in the Diaph1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (Scbms): Report of a Family and Literature Review, Molecular Genetics and Genomic Medicine (2024)
3. Identification of Novel Likely Pathogenic Variant in Cdh23 Causing Non-Syndromic Hearing Loss, and a Novel Variant in Otogl in an Extended Iranian Family, Egyptian Journal of Medical Human Genetics (2024)
Experts (# of related papers)
View all Related Experts
Mohammad Amin Tabatabaiefar (13)
Hossein Khanahmad (2)
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
Other Related Docs
4. A Novel Mettl5 Variant Disrupting a Donor Splice Site Leads to Primary Microcephaly-Related Intellectual Disability in an Iranian Family: Clinical Features and Literature Review, Journal of Genetics (2023)
5. Clinical Characterizations and Molecular Genetic Study of Two Co-Segregating Variants in Pdzd7 and Pde6c Genes Leading Simultaneously to Non-Syndromic Hearing Loss and Achromatopsia, BMC Medical Genomics (2024)
6. A Novel De Novo Frameshift Variant in the Chd2 Gene Related to Intellectual and Developmental Disability, Seizures and Speech Problems, Molecular Genetics and Genomic Medicine (2024)
7. X-Linked Mental Retardation-Hypotonic Facies Syndrome: Exome Sequencing Identifies Novel Clinical Characteristics Associated With C.5182G>C Mutation in the Atrx Gene, Molecular Genetics and Genomic Medicine (2022)
8. Causative Variants Linked With Limb Girdle Muscular Dystrophy in an Iranian Population: 6 Novel Variants, Molecular Genetics and Genomic Medicine (2023)
9. Griscelli Syndrome Type 1: A Novel Pathogenic Variant, and Review of Literature, Molecular Genetics and Genomics (2023)
10. Genetic Heterogeneity in Cornelia De Lange Syndrome (Cdls) and Cdls-Like Phenotypes With Observed and Predicted Levels of Mosaicism, Journal of Medical Genetics (2014)
11. A Deleterious Frameshift Insertion Mutation in the Znf142 Gene Leads to Intellectual Developmental Disorder With Impaired Speech in Three Affected Siblings: Clinical Features and Literature Review, Molecular Genetics and Genomic Medicine (2023)
12. A Novel Pathogenic Variant in the Lrtomt Gene Causes Autosomal Recessive Non-Syndromic Hearing Loss in an Iranian Family, BMC Medical Genetics (2020)
13. Whole Exome Sequencing Revealed Variants in Four Genes Underlying X-Linked Intellectual Disability in Four Iranian Families: Novel Deleterious Variants and Clinical Features With the Review of Literature, BMC Medical Genomics (2023)
14. Molecular Diagnosis of Non-Syndromic Hearing Loss in Seven Iranian Families Using Whole-Exome Sequencing, BMC Medical Genomics (2026)
15. Comprehensive Review and Outline of Genotypes and Phenotypes of Arboleda-Tham Syndrome Spectrum: Insights From Novel Variants, Molecular Biology Reports (2025)
16. Mfsd8 Gene Mutations; Evidence for Phenotypic Heterogeneity, Ophthalmic Genetics (2019)
17. Familial Nonmedullary Thyroid Cancer: A Case Series in Iranian Patients With a Meta-Review of Case Series, Lab Medicine (2024)
18. Next-Generation Sequencing Reveals a Novel Pathological Mutation in the Tmc1 Gene Causing Autosomal Recessive Non-Syndromic Hearing Loss in an Iranian Kindred, International Journal of Pediatric Otorhinolaryngology (2019)
19. A Recurrent Homozygous Missense Dpm3 Variant Leads to Muscle and Brain Disease, Clinical Genetics (2022)
20. Limb-Girdle Muscular Dystrophy Type 2B (Lgmd2b) Caused by Pathogenic Splice and Missense Variants of Dysf Gene Among Iranians With Muscular Dystrophy, Advanced Biomedical Research (2023)