Cornelia de Lange syndrome

The estimated prevalence is 1/50,000 (Barisic et al., 2008). Older national estimates ranged from 1/10,000 to 1/100,000, and milder phenotypes are likely under-recognised.

CdLS is inherited in an autosomal dominant manner. Approximately 99% of probands with autosomal-dominant CdLS carry a de novo pathogenic variant, with familial recurrence being rare. When both parents are clinically unaffected, the empirical recurrence risk to siblings remains low but non-zero owing to germline mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established clinically using consensus criteria. The defines cardinal and suggestive features with a scoring system to distinguish classic from non-classic CdLS. Meeting these criteria constitutes the clinical diagnosis of CdLS.

Main differential diagnoses include:

• KBG syndrome: developmental delay/intellectual disability that is typically milder than in CdLS, with macrodontia and few congenital defects; ANKRD11.
• Bohring-Opitz syndrome: facial resemblance to CdLS especially in infants, but with usually more severe feeding intolerance, high myopia, prominent globes, and the characteristic ‘BOS posture’; ASXL1.
• EP300-: developmental delay, short stature, hypertrichosis, full eyebrows, long lashes and micrognathia overlap CdLS, but prominent nose and broad thumbs (less marked than in CREBBP-RSTS) point away from CdLS; EP300.

• Establishing the molecular diagnosis confirms the clinical suspicion and identifies the underlying pathogenic variant, providing a definitive aetiological diagnosis.
• Knowledge of the underlying variant supports specific, individualised surveillance and clinical management aligned to the implicated gene, serving as a prerequisite for targeted medical care delivered by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing of at-risk relatives and carrier testing within the family are technically possible following genetic counselling.

• Deardorff MA, Noon SE, Krantz ID. Cornelia de Lange Syndrome. 2020 Oct 15. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. PMID: 20301283. Available from:
• Barisic I, Tokic V, Loane M, Bianchi F, Calzolari E, Garne E, et al. Descriptive epidemiology of Cornelia de Lange syndrome in Europe. American journal of medical genetics. Part A. 2008;146A(1):51-9. doi: 10.1002/ajmg.a.32016. PMID: .
• Kline AD, Moss JF, Selicorni A, Bisgaard AM, Deardorff MA, Gillett PM, et al. Diagnosis and management of Cornelia de Lange syndrome: first international consensus statement. Nature reviews. Genetics. 2018;19(10):649-666. doi: 10.1038/s41576-018-0031-0. PMID: . PMCID: PMC7136165.