Coffin–Siris syndrome

The estimated prevalence is 1/100,000 (GeneReviews, 2025). This figure is a rough estimate based on identified cases; the true prevalence is likely higher.

Coffin-Siris syndrome is inherited in an autosomal dominant manner. The recurrence risk for future offspring of an affected individual is 50%; the recurrence risk for siblings of an apparently sporadic proband is low but non-zero, reflecting the possibility of parental gonadal mosaicism. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified. In most affected individuals the pathogenic variant arises de novo.

The diagnosis of Coffin-Siris syndrome is established primarily through molecular genetic testing identifying a pathogenic variant in one of the implicated genes. No formal consensus diagnostic criteria have been established; clinical suspicion is based on the characteristic combination of developmental delay, fifth-digit nail hypoplasia and coarse facial features.

Main differential diagnoses include:

• Nicolaides-Baraitser syndrome: sparse scalp hair, prominent interphalangeal joints, severe intellectual disability and seizures; SMARCA2
• : synophrys, long eyelashes, growth restriction, hypertrichosis and upper-limb reduction defects; NIPBL and others
• Börjeson-Forssman-Lehmann syndrome: X-linked intellectual disability, obesity, gynaecomastia and narrow palpebral fissures; PHF6

• Establishing the molecular diagnosis confirms the clinical suspicion and provides a definitive aetiological classification.
• Identification of the causative variant enables specific and individualised surveillance and clinical management, forming the prerequisite for targeted medical care planned and adjusted by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing of asymptomatic at-risk relatives becomes possible and supports informed reproductive and family planning.

Schrier Vergano S, Santen G, Wieczorek D, et al. Coffin-Siris Syndrome. 2013 Apr 4 [Updated 2025 May 15]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. PMID: 23556151. Available from: