Coffin-Siris syndrome is a complex syndrome, the main symptoms of which are a developmental disorder of varying degree, muscular hypotonia and a characteristic appearance with full lips, a wide mouth, a broad nasal bridge and nose tip, thick eyebrows, long eyelashes and hypertrichosis with rather sparse scalp hair. Hypoplasia/aplasia of the end phalanx of the 5th finger or fingernail is also characteristic. Nail hypoplasia may also be present on other fingers or toes. Failure to thrive is seen in most infants and toddlers, about half have seizures, almost half have hearing loss that is often due to frequent airway infections, and about half have strabismus or ptosis. Heart defects and malformations of the kidneys and the urinary tract occur in about one third of cases.
Pathogenic heterozygous variants in 8 genes are causal: ARID1A, ARID1B, ARID2, SMARCA4, SMARCB1, SMARCE1, SOX11 and DPF2; pathogenic variants in ARID1B are most common at around 35-40%. In about 40% of patients with clinically suspected Coffin-Siris syndrome, no pathological variant can be detected in the above mentioned genes. The disease is inherited autosomal dominantly, although a pathogenic de novo variant is usually present in affected individuals. So far, deletions (especially in ARID1B) have been reported rarely. Due to the genetic heterogeneity, gene panel diagnostics of the mentioned genes can be useful where there is clinical suspicion of Coffin-Siris syndrome.
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