A number sign (#) is used with this entry because of evidence that blepharophimosis-impaired intellectual development syndrome (BIS) is caused by heterozygous mutation in the SMARCA2 gene (600014) on chromosome 9p24.

Heterozygous mutation in the SMARCA2 gene can also cause Nicolaides-Baraitser syndrome (NCBRS; 601358), which shows some overlapping features, but is considered to be a distinct phenotype.

Blepharophimosis-impaired intellectual development syndrome (BIS) is a congenital disorder characterized by a distinct facial appearance with blepharophimosis and global development delay. Affected individuals have delayed motor skills, sometimes with inability to walk, and impaired intellectual development with poor or absent speech; some patients show behavioral abnormalities. There are recognizable facial features, including epicanthal folds, sparse eyebrows, broad nasal bridge, short nose with downturned tip, and open mouth with thin upper lip. Other more variable features include distal skeletal anomalies, feeding difficulties with poor growth, respiratory infections, and hypotonia with peripheral spasticity (summary by Cappuccio et al., 2020).

Cappuccio et al. (2020) reported 14 patients with a recognizable neurodevelopmental syndrome who were ascertained through international collaboration after genomic sequencing. Reverse phenotyping was done in order to delineate the clinical features. The patients, who ranged from 3 to 19 years of age, had global developmental delay and variably impaired intellectual development, often with poor or absent speech and behavioral abnormalities. Most patients had delayed walking in the first years of life, although several never achieved independent ambulation. Many had hypotonia, sometimes with progression to peripheral spasticity. Three patients had seizures. Some had poor growth and feeding difficulties with gastroesophageal reflux. Six had microcephaly (down to -4.4 SD). All had a distinctive facial appearance with blepharophimosis, narrow palpebral fissures, epicanthal folds, sparse eyebrows and eyelashes, arched eyebrows, broad nasal bridge, and downturned nasal tip. Frontal bossing, tented upper vermilion of the lip, hypertelorism, long or short philtrum, abnormal ears, short nose with small nostrils and hypoplastic alae nasi, chin crease, broad and flat face, open mouth, and pinched nose were also observed. Many patients also had widely spaced teeth or enamel defects. Visual problems were common, including astigmatism, hyperopia, esotropia, myopia, and cortical visual impairment. Three males had cryptorchidism and 1 female had hypoplastic labia. Brain imaging, performed in only a few patients, showed variable anomalies, including enlarged ventricles, pontine hypoplasia, and nonspecific white matter signals. Almost all patients had variable skeletal defects, such as limb contractures, flat feet or foot deformities, long tapering fingers, and clinodactyly. About half of patients had recurrent respiratory infections. Cappuccio et al. (2020) proposed to name the disorder in these individuals 'blepharophimosis intellectual disability syndrome (BIS).'

The heterozygous mutations in the SMARCA2 gene that were identified in patients with BIS by Cappuccio et al. (2020) occurred de novo.

In 14 patients with BIS, Cappuccio et al. (2020) identified de novo heterozygous missense mutations in the SMARCA2 gene (see, e.g., 600014.0015-600014.0019). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not present in the gnomAD database. The mutations clustered in 2 regions located outside of the catalytic ATPase helicase domains. Some occurred in exons 8 or 9, corresponding to a region between the HSA and helicase ATP-binding domains, whereas others occurred in exon 19, mapping to the linker region located between DExx helicase ATP-binding and helicase C-terminal domains. Structural analysis of the variants using the yeast homolog (Snf2) showed that the residues mutated in BIS are on an alpha-helix that is likely at the interface with other members of the SWI/SNF complex. Introduction of mutations corresponding to E929V and R937L (600014.0018 and 600014.0019) in yeast showed no growth abnormalities, being similar to wildtype. RNA-seq transcriptome analysis of blood derived from 2 patients (patients 1 and 9) showed some differential gene expression profiles compared to cells from patients with NCBRS (601358). However, there was a close expression profile shared by BIS and NCBRS compared to controls. Cells from patients with BIS and NCBRS also showed some differences in methylation signature patterns. Additional functional studies of the variants were not performed. The authors concluded that SMARCA2 variants outside of the helicase domain result in a phenotypically and molecularly distinct disorder from NCBRS.