Hoyer et al. (2012) reported 8 unrelated patients with mental retardation. All patients presented with moderate to severe psychomotor retardation, and most showed evidence of muscular hypotonia. In many patients, expressive speech was reported to be more severely ... Hoyer et al. (2012) reported 8 unrelated patients with mental retardation. All patients presented with moderate to severe psychomotor retardation, and most showed evidence of muscular hypotonia. In many patients, expressive speech was reported to be more severely affected than receptive function. Although there was no distinct recognizable facial gestalt, common findings included short stature, abnormal head shape and low-set, posteriorly rotated, and abnormally shaped ears, downslanting palpebral fissures, a bulbous nasal tip, a thin upper lip, minor teeth anomalies, and brachydactyly or single palmar creases. Only 1 patient had autistic features. In 5 patients with a multiple congenital anomaly syndrome classified as Coffin-Siris syndrome (CSS; 135900), Tsurusaki et al. (2012) identified different mutations in the ARID1B gene. All 5 patients had developmental delay and absent or hypoplastic fifth fingernails/toenails with absent/hypoplastic fifth phalanx of the hand; all had hirsutism and a coarse facial appearance with flat nasal bridge, broad nose, and thick lips. Frequent infections were reported in all 5 patients. By exome sequencing, Santen et al. (2012) identified 3 de novo truncating mutations in the ARID1B gene (614556) in individuals with syndromic mental retardation who had received a clinical diagnosis of CSS. All 3 patients had moderate to severe intellectual disability and severe speech delay. All had coarse facial features with thick eyebrows and low frontal hairline; hypertrichosis was also present in all. Two had fifth finger brachydactyly; one of these and the other patient without brachydactyly had a hypoplastic nail on the fifth finger. Two had agenesis of the corpus callosum and one had partial agenesis. Three additional subjects with deletions involving ARID1B had some facial similarities with the patients carrying truncation mutations but lacked hypoplastic or absent fingernails or toenails. Santen et al. (2012) noted that few affected individuals in published reports fulfill the complete spectrum of the CSS phenotype, and it is a subject of debate whether all individuals with CSS represent the same entity.
Hoyer et al. (2012) performed Sanger sequencing of candidate genes, including ARID1B, in a region on chromosome 6q25 that was deleted in a patient with mental retardation (see 612863). A total of 8 mutations in the ARID1B gene ... Hoyer et al. (2012) performed Sanger sequencing of candidate genes, including ARID1B, in a region on chromosome 6q25 that was deleted in a patient with mental retardation (see 612863). A total of 8 mutations in the ARID1B gene (see, e.g., 614556.0001-614556.0005) were found in 8 (0.9%) of 887 individuals with mental retardation. All mutations were in the heterozygous state, occurred de novo, and resulted in haploinsufficiency of the ARID1B gene. Given the known function of ARID1B, the findings indicated that chromatin-remodeling defects are an important contributor to neurodevelopmental disorders. In 5 patients with multiple congenital anomalies and mental retardation, Tsurusaki et al. (2012) identified 4 nonsense or frameshift mutations in ARID1B (e.g., 614556.0006, 614556.0007), which encodes a subunit of the SWI/SNF complex. Three of these mutations occurred de novo. One of the patients carried a microdeletion involving ARID1B. In a total of 20 affected individuals with a similar constellation of clinical features, Tsurusaki et al. (2012) identified germline mutations in one of 6 SWI/SNF subunit genes. By exome sequencing, Santen et al. (2012) identified 3 de novo truncating mutations in the ARID1B gene (614556.0008-614556.0010) in individuals with syndromic mental retardation. Array-based copy number variation analysis in 2,000 individuals with intellectual disability revealed an additional 3 subjects with a deletion affecting ARID1B.