Coffin-Siris Syndrome 3

A number sign (#) is used with this entry because of evidence that Coffin-Siris syndrome-3 (CSS3) is caused by heterozygous mutation in the SMARCB1 gene (601607) on chromosome 22q11. The SMARCB1 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 SMARCB1 mutations may have more severe neurodevelopmental deficits including severe intellectual disability, brain structural abnormalities, and no expressive words, as well as scoliosis (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) identified SMARCB1 mutations in 4 patients with Coffin-Siris syndrome. All had developmental delay and hypotonia; 2 of 3 examined had microcephaly, 2 of 3 had a small cerebellum; 2 of the 4 had seizures, and neither of 2 examined had Dandy-Walker malformation. Three of the 4 had hearing loss. All 4 had absent or hypoplastic fifth finger or toenails, sparse scalp hair, thick eyebrows, and long eyelashes. Three of 3 examined had abnormal delayed dentition, 2 of 3 had nonfunctioning or absent tear duct, and 3 of the 4 were hirsute. All 4 were described as having a coarse facial appearance with broad nose, wide mouth, thick lips, abnormal ears, and a high palate. All 4 had short stature, 3 of the 4 had spinal anomalies, and all had feeding problems. Absent hypoplastic fifth phalanx of the hand and the foot and delayed bone age were found in 1 patient examined for these. Other phenotypic features were more variable. Two patients for whom pictures were presented, while dysmorphic, did not resemble each other.

In studies of large cohorts of patients with CSS, Wieczorek et al. (2013) and Santen et al. (2013) found that those with CSS3 had the most severe phenotype compared to patients with other forms of CSS. In addition to the typical facial gestalt, hypertrichosis, and hypoplastic or absent fifth finger- and toenails associated with hypoplasia of other nails, these patients had poor overall growth, short stature, microcephaly, severe developmental delay, and feeding problems. Many patients also had seizures, congenital heart defects, hearing impairment, small cerebellum, and abnormal corpus callosum.

Molecular Genetics

In 4 patients with Coffin-Siris syndrome, Tsurusaki et al. (2012) identified a heterozygous missense mutation in the SMARCB1 gene in 1 (601607.0013) and the same single-codon deletion (601607.0012) in 3. Germline heterozygous truncating mutations in SMARCB1 have been reported in individuals with rhabdoid tumor predisposition syndrome-1 (609322), and various types of mutations in SMARCB1 have been reported in the germline of individuals with familial and sporadic schwannomatosis (162091). The SMARCB1 mutations resulting in CSS3 were nontruncating, implying that they exert gain-of-function or dominant-negative effects (excluding haploinsufficiency as a cause).

In a patient with a syndromic form of mental retardation, Kleefstra et al. (2012) detected a missense mutation in the SMARCB1 gene (R37H; 601607.0014). The patient was 1 of 9 patients with syndromic mental retardation who shared core features of Kleefstra syndrome (610253) but who were phenotypically heterogeneous otherwise.

Using a combination of whole-exome sequencing, next-generation sequencing of 23 SWI/SNF complex genes, and molecular karyotyping, Wieczorek et al. (2013) identified mutations in 28 (60%) of 46 patients with a clinical phenotype consistent with Coffin-Siris syndrome or Nicolaides-Baraitser syndrome (NCBRS; 601358), which shows similar features. Only 2 patients had mutations in the SMARCB1 gene, including 1 with an initial diagnosis of NCBRS, suggesting that these syndromes may represent a phenotypic spectrum rather than 2 distinct disorders. Functional studies of the variants and studies of patient cells were not performed.

Santen et al. (2013) identified heterozygous pathogenic mutations in the SMARCB1 gene in 4 unrelated patients with CSS3. The mutations were shown to have occurred de novo in the 3 patients for whom parental DNA was available. Three patients carried the same mutation (K364del; 601607.0012). The patients were ascertained from a large cohort of 63 patients with a clinical diagnosis of CSS who were screened for mutations in the 6 genes of the BAF complex. Functional studies of the variants and studies of patient cells were not performed.