Coffin-Siris Syndrome 4

A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-4 (CSS4) is caused by heterozygous mutation in the SMARCA4 gene (603254) on chromosome 19p13. The SMARCA4 gene is one of several genes encoding subunits of the SWI/SNF complex, also known as the BAF complex, which functions as a chromatin remodeling factor.

Description

Coffin-Siris syndrome is a congenital malformation syndrome characterized by developmental delay, intellectual disability, coarse facial features, feeding difficulties, and hypoplastic or absent fifth fingernails and fifth distal phalanges. Other more variable features may also occur. Patients with SMARCA4 mutations may have less coarse craniofacial appearances and fewer behavioral abnormalities than Coffin-Siris patients with mutations in other genes (summary by Kosho et al., 2014).

For a general phenotypic description and a discussion of genetic heterogeneity of Coffin-Siris syndrome, see CSS1 (135900).

Clinical Features

Tsurusaki et al. (2012) described 6 patients with Coffin-Siris syndrome. All 6 had developmental delay, 4 had hypotonia, and 4 of 5 examined had microcephaly. Two of the 6 had seizures, and 1 of 5 examined had a Dandy-Walker malformation. Five of the 6 had vision problems and half had hearing problems; all had absent or hypoplastic fifth fingernails or toenails; all were hirsute; and 3 of the 6 had sparse scalp hair. All had thick eyebrows and long eyelashes.

Molecular Genetics

In 6 patients with Coffin-Siris syndrome, Tsurusaki et al. (2012) identified an in-frame deletion (603254.0002) and 5 different missense mutations (603254.0003-603254.0007) in the SMARCA4 gene. In 5 cases the mutation was shown to have occurred de novo; in the sixth, parental DNA was not available.