Expanding Genetic and Phenotypic Understanding of Cornelia de Lange Syndrome: New Insights and Future Directions

Cornelia de Lange syndrome (CdLS) is a rare neurodevelopmental disorder characterized by distinctive facial features, growth restriction, skeletal and limb anomalies, developmental delay, intellectual disability, speech and language impairment, executive dysfunction, and behavioral difficulties. Although advances in genomic technologies have identified an expanding range of CdLS-associated cohesin and chromatin-related genes—including NIPBL, SMC1A, SMC3, HDAC8, and BRD4—substantial gaps remain in defining the full cognitive, neurological, behavioral, and medical spectrum of the condition. Clinical heterogeneity and phenotypic overlap with other chromatinopathies can complicate diagnosis, prognosis, and clinical management. Recent studies indicate that disease presentation and severity may vary according to the underlying molecular cause, emphasizing the importance of integrating genetic and detailed phenotypic characterization. At the same time, preclinical studies of chromatinopathies are informing the development of therapies that may address epigenomic dysregulation. However, limited genotype–phenotype data and the lack of reliable, validated outcome measures continue to impede the design of genotype-informed interventions and future human clinical trials.

This Research Topic aims to advance understanding of the genetic, molecular, neurological, cognitive, behavioral, and clinical diversity of CdLS. It will examine how variation in CdLS-associated genes contributes to differences in disease presentation, severity, developmental trajectories, and treatment needs. Contributions may also address convergent biological pathways, mechanisms of epigenomic dysregulation, and clinical domains that could serve as robust endpoints in therapeutic studies. By integrating findings from clinical, genetic, molecular, and translational research, the Research Topic seeks to support improved diagnostic strategies, earlier and more individualized intervention, genotype-informed care, and the development of precision medicine approaches for individuals with CdLS.

To gather further insights into genotype–phenotype relationships and translational opportunities in CdLS, this Research Topic will focus on human studies, clinical characterization, molecular mechanisms, preclinical models, and outcome measurement, while recognizing the diversity of genes and phenotypes associated with the syndrome. We welcome articles addressing, but not limited to, the following themes:
- Genotype–phenotype associations across NIPBL, SMC1A, SMC3, HDAC8, BRD4, and other CdLS-associated genes
- Cognitive, language, neurological, behavioral, and psychiatric profiles
- Growth, skeletal, limb, craniofacial, sensory, gastrointestinal, and other systemic features
- Clinical heterogeneity, disease severity, and developmental trajectories
- Genetic testing, molecular diagnosis, variant interpretation, and differential diagnosis
- Cohesin biology, chromatin regulation, and epigenomic mechanisms
- Animal and cellular models of CdLS and related chromatinopathies
- Convergent molecular pathways and potential therapeutic targets
- Development and validation of clinical, cognitive, behavioral, and patient-reported outcome measures
- Genotype-informed clinical management, intervention, and precision medicine
- Translational strategies for advancing candidate therapies toward clinical trials

The Research Topic welcomes original research, systematic reviews, case reports, and perspective articles. Please ensure your manuscript aligns with our article type guidelines, as specified here (https://www.frontiersin.org/journals/genetics/for-authors/article-types), paying particular attention to the case report guidelines. Further information about our case report acceptance criteria can be found here (https://www.frontiersin.org/journals/genetics/sections/genetics-of-common-and-rare-diseases/about).

Dr. David Litwack owns shares of ELi Lilly, which were awarded to him during his employment at the company. Dr. Grados has received travel support from the CDL-USA Foundation.