This study has provided the clinical and molecular information of 12 Korean patients with SSRIDDs. These 12 patients were recruited from the neurodevelopmental disease cohort who underwent WES or CMA to decipher a causative gene for their condition. ARID1B, identified in eight patients, was the most frequently altered gene in this study. The remaining four patients harbored mutations or microdeletion in SMARCA4, SMARCB1, SMARCA2, and ARID2. The clinical diagnoses were CSS for 10 patients, ARID1B-related ID for one patient, and NCBRS for one patient.
The SSRIDDs proportion in the current cohort was 2.13% of the neurodevelopmental disorder (12/564, 2.13%). Unexplained ID due to the SWI/SNF complex mutations was estimated to be up to 3%, and the data (2.13%) of this study supports this idea . Hoyer et al.  reported that ARID1B mutations were identified in 0.9% of unexplained ID.
Accurate genotype–phenotype correlation was not possible due to the small number of patients. However, several phenotypic differences were found between genotypes.
ARID1B mutations are considered the leading cause of CSS (68–83%) [7, 8, 20]. In this study, the ARID1B mutation was 66.7% (8/12 patients). Clinical phenotypes associated with ARID1B mutations are highly variable and reported not to be severe compared with other genotypes . As broad genetic tests such as WES are becoming more widely used, individuals who may not fit the diagnosis of classic CSS but rather presented with more inconclusive phenotypes are now being discovered. These ARID1B-associated patients with ID are expanding the phenotypic spectrum of the ARID1B-related disorder. The major differences between ARID1B-ID and ARID1B-CSS are the presence of typical dysmorphic features including thick eyebrows, long eyelashes, small nails or absent fifth distal phalanx, and hypertrichosis .
For example, subject 3 was incidentally found to have an ARID1B mutation while evaluating his mild DD. At first, the patient was described as phenotypically normal without having any congenital anomaly with mild DD. The patient was reevaluated after identifying the nonsense mutation in ARID1B, and thick eyebrows and long eyelashes were noted. However, his phenotype was not sufficient to make a clinical diagnosis of CSS.
The ARID1B-CSS patients in this study are likely to have a coarse face (6/7 patients, 85.7%), hypertrichosis (6/7 patients, 85.7%), thick eyebrows (5/7 patients, 71.4%), large mouths (5/7 patients, 71.4%), thick lips (5/7 patients, 71.4%), long eyelashes (4/7 patients, 57.1%), and micrognathia (4/7 patients, 57.1%). Nail hypoplasia and short fifth finger are known as cardinal CSS features. However, only two patients (2/8 patients, 25%) with the ARID1B mutation showed hypoplasia of the fifth finger and nail hypoplasia was noted in three patients (3/8 patients, 37.5%).
Previous studies [7, 8, 20] reported that the fifth finger and nail anomalies are present in 50–68% of patients. According to a web-based survey (www.arid1bgene.com), which is an open collection of clinical information of patients with ARID1B mutations, the frequency of a hypoplastic fifth fingernail and short distal phalanx of the fifth finger was estimated as 24.6% (42/171 patients) and 22.0% (37/168 patients), respectively. Previous high frequency of the fifth finger and nail abnormalities may reflect ascertainment bias because ARID1B mutations were preferentially sought in the clinically diagnosed CSS group [7, 8, 20]. Moreover, Mannino et al.  also reported the short fifth digital phalanges and/or nail hypoplasia in only 48% of the subjects.
The position of the mutation in ARID1B may not influence the severity of the clinical phenotypes. Santen et al.  found no relationship between the mutation position on cDNA and clinical severity. For example, patients who had mutations in exon 20, the 3′ terminal region of the gene, showed severe ID . In the current cases, subject 8, having mutation in exon 20, also showed a short stature, moderate ID, and a classical feature of CSS.
Almost all patients with SMARCA4 were reported as having hirsutism, thick eyebrows, long eyelashes, and a less coarse face . Subject 9, with a SMARCA4 mutation, also exhibited these typical features.
SMARCB1 mutation leads to a severe form of CSS with various CNS anomalies and severe growth retardation [7, 8]. Subject 10 harbored a SMARCB1 mutation in exon 8, which is a highly-conserved region and well-established causative CSS domain [7, 8]. Born small for gestational age, the patient had gastrostomy due to severe feeding difficulties. Microcephaly and low body weight were observed as well. Partial agenesis of the corpus callosum was demonstrated by the brain magnetic resonance imaging at 6 months old.
Subject 11 had mild mental retardation with a profound short stature. As previously described , the patient had overlapping phenotypes including RASopathy-associated features (e.g., profound short stature, epicanthal folds, down slanting palpebral fissures, and webbed neck) and CSS-like features (e.g., thick eyebrows, thick upper lips, and large mouths). Chromosomal microarray revealed 3.7-Mb deletion at chromosome 12q12-13.11 encompassing ARID2. As one component of the SWI/SNF complex, ARID2 haploinsufficiency is associated with CSS-like phenotypes . In a previous study, an increased extracellular signal-regulated kinase (ERK) activation in ARID2 haploinsufficiency was demonstrated, suggesting the association between the SWI/SNF complex and RAS–MAPK pathway .
Subject 12, with the SMARCA2 mutation, showed the typical features of NCBRS (e.g., coarse face with hypertrichosis, thick eyebrows, thick lips, long eyelashes, nail hypoplasia, and microcephaly) but did not have prominent interphalangeal joints. Cognitive dysfunction was more severe than those with other types of SSRIDDs. Differential diagnosis is sometimes confusing because CSS and NCBRS are overlapping syndromes that share similar phenotypes. Moreover, changes in clinical diagnosis exist according to molecular results [8, 13]. Molecular confirmation is required to make an accurate diagnosis between these two overlapping syndromes.
Similar to previous studies [13, 20], ARID1B mutations in this study were truncating mutations (nonsense or splicing site mutations), whereas those in SMARCA4, SMARCB1, and SMARCA2 were nontruncating mutations (missense mutation). The ARID1B haploinsufficiency is a pathogenic mechanism leading to CSS or ARID1B-related ID because subject 5 with exons 10–18 deletion in ARID1B also showed CSS phenotypes. AIRD2 haploinsufficiency seems to cause CSS-like phenotypes as well as ID in subject 12. All variants of SMARCA4, SMARCB1, and SMARCA2 were missense mutations, implying that they may exert gain of function or dominant negative mechanism of pathogenicity [13, 20].
The SWI/SNF complex components were initially recognized as tumor-suppressor genes associated with oncogenesis. Inactivating mutations in several SWI/SNF components have recently been identified in a wide variety of tumors, including rhabdoid and lung cancer tumors . Furthermore, truncating and missense germline mutations in SMARCB1 and truncating germline mutations in SMARCA4 have been shown to lead to a cancer predisposition syndrome [26, 27]. Several cases with tumor formation exist in patients with SSRIDDs. Papillary thyroid cancer was reported in a patient with interstitial 6q25 deletion, including ARID1B . Moreover, a patient carrying an ARID1A mutation presented with hepatoblastoma in previous literature . van der Sluijs et al.  reported a boy with ARID1B mutation diagnosed with a Sertoli–Leydig cell tumor and a temporal glioneuronal tumor at 3 and 12 years, respectively. Longer observations are needed to conclude the association of SSRIDDs and cancer predisposition.
The limitation of this study should be noted. As a retrospective study, clinical information was not available in some patients. The phenotypes among the patients were variable because of the varying ages. Thus, longer observation and larger number of patients are needed to determine the whole clinical features and courses of these patients.