This study provided clinical and molecular information on 12 Korean patients with SSRIDDs. These 12 patients were recruited from the neurodevelopmental disorder cohort who underwent WES or CMA for elucidating the genetic cause of their condition. ARID1B, identified in eight patients, was the most frequently altered gene in this study. The remaining four patients harbored pathogenic variants or microdeletions in SMARCA4, SMARCB1, SMARCA2, and ARID2. The clinical diagnoses were CSS for 10 patients, ARID1B-related nonsyndromic ID for one patient, and NCBRS for one patient.
Among the patients in the neurodevelopmental disorder cohort, 2.13% had SSRIDDs (12/564, 2.13%). Unexplained ID due to SWI/SNF complex mutations was estimated to be up to 3%, and the data (2.13%) of this study supported this idea [20]. Hoyer et al. [3] reported that ARID1B mutations were identified in 0.9% of unexplained ID cases.
A definite genotype–phenotype correlation could not be established owing to the small number of patients. However, several phenotypic differences were found among various genotypes.
ARID1B mutations are considered to be the leading cause of CSS (68–83%) [7, 8, 21]. In this study, the pathogenic variants in ARID1B were identified in 66.7% of patients (8/12 patients). Clinical phenotypes associated with ARID1B alterations have been reported to be highly variable and not severe compared to phenotypes of other genotypes [22]. As the use of broad genetic tests such as WES is becoming widespread, individuals who may not fit the diagnosis of classic CSS but rather present with more inconclusive phenotypes are now being discovered. These patients with ARID1B-associated 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, hypoplastic/absent nail or distal phalanx of the fifth finger, and hypertrichosis [23].
For example, subject 3 was incidentally found to have a pathogenic variant in ARID1B during the evaluation of his mild DD. At the first examination, no dysmorphic features were noted in subject 3. However, the patient was reevaluated after identifying a pathogenic variant in ARID1B, and thick eyebrows and long eyelashes were noted. However, his phenotype was not sufficient to make a clinical diagnosis of CSS.
The patients with ARID1B-associated CSS in this study were likely to have a coarse face, hypertrichosis, thick eyebrows, large mouths, thick lips, long eyelashes, and micrognathia. Nail hypoplasia and/or a short distal phalanx of the fifth finger, which are known as cardinal CSS features, were identified in three patients (subjects 4, 6, and 7).
Previous studies [7, 8, 21] reported that a hypoplastic nail or a short distal phalanx of the fifth finger are present in 50%–68% of patients. According to a web-based survey (www.arid1bgene.com), which is an open collection of clinical information on patients with ARID1B mutations, the incidences of a hypoplastic fifth fingernail and short distal phalanx of the fifth finger were estimated to be 24.6% (42/171 patients) and 22.0% (37/168 patients), respectively. Previously reported high incidences (50–68%) of these abnormalities may reflect an ascertainment bias because ARID1B mutations were preferentially sought after among those with clinically diagnosed CSS [7, 8, 21]. In the present study, three (subjects 4, 6, and 7) out of seven patients with ARID1B-associated CSS (3/7 patients, 42.9%) exhibited nail and/or distal phalanx abnormalities, which corroborated the previously reported data (48%) [22].
The position of the pathogenic variants in ARID1B may not influence the severity of the clinical phenotypes. Santen et al. [24] found no relationship between the variant position on cDNA and clinical severity. For example, patients who had pathogenic variants in exon 20, at the 3′ terminal region of the gene, had severe ID [24]. Among the present cases, subject 8, who had a variant in exon 20, had short stature, moderate ID, and classical features of CSS.
Almost all patients with genetic alterations in SMARCA4 were reported to have hirsutism, thick eyebrows, long eyelashes, and a less coarse face [25]. Subject 9, with a pathogenic variant in SMARCA4, also exhibited these typical features.
The pathogenic variants in SMARCB1 lead to a severe form of CSS with various CNS anomalies and severe growth retardation [7, 8]. Subject 10 harbored a SMARCB1 variant in exon 8, which is a highly-conserved region and well-established causative domain for CSS [7, 8]. Considered small for gestational age at birth, the patient underwent gastrostomy due to severe feeding difficulties. Severe growth retardation and microcephaly were also observed. Brain magnetic resonance imaging at 6 months revealed partial agenesis of the corpus callosum.
Subject 11 had mild ID with a profound short stature. As previously described [19], the patient exhibited both RASopathy-related features (e.g., profound short stature, epicanthal folds, down slanting palpebral fissures, and webbed neck) and CSS-like phenotypes (e.g., thick eyebrows, thick upper lips, and a large mouth). CMA revealed a 3.7-Mb deletion at chromosome 12q12-13.11 causing complete deletion of ARID2. As one of the components in the SWI/SNF complex, ARID2 haploinsufficiency has been shown to be associated with CSS-like phenotypes [10]. A previous study demonstrated increased extracellular signal-regulated kinase (ERK) activation in ARID2 haploinsufficiency, suggesting an association between the SWI/SNF complex and RAS–MAPK pathway [19].
Subject 12, with the SMARCA2 variant, displayed 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 in this patient than in those with other types of SSRIDDs. Differential diagnosis is sometimes confusing because CSS and NCBRS are overlapping syndromes that share similar phenotypes. Moreover, the clinical diagnosis may change according to the results of molecular analysis [8, 13]. Molecular confirmation is thus required to make an accurate diagnosis between these two overlapping syndromes.
Similar to previous studies [13, 21], variants in ARID1B in this study were truncating (nonsense or splicing-site mutations), whereas those in SMARCA4, SMARCB1, and SMARCA2 were nontruncating (missense mutation). The ARID1B haploinsufficiency is a pathogenic mechanism that leads to CSS or ARID1B-related ID. Subject 5 with an exon 10–18 deletion in ARID1B also showed a CSS phenotype. AIRD2 haploinsufficiency seems to have caused a CSS-like phenotype as well as ID in subject 12. All variants in SMARCA4, SMARCB1, and SMARCA2 were missense mutations, implying that they may exert a gain-of-function or dominant-negative mechanism of pathogenicity [13, 21].
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 [26]. Furthermore, truncating and missense germline mutations in SMARCB1 and truncating germline mutations in SMARCA4 have been shown to lead to a cancer predisposition syndrome [27, 28]. Several cases with tumor formation were found among patients with SSRIDDs. Papillary thyroid cancer was reported in a patient with an interstitial 6q25 deletion, including ARID1B [29]. Moreover, a patient carrying an ARID1A pathogenic variant with hepatoblastoma was described previously in the literature [6]. van der Sluijs et al. [23] reported a boy with an ARID1B variant diagnosed with a Sertoli–Leydig cell tumor and a temporal glioneuronal tumor at 3 and 12 years, respectively. Longer observational periods are needed to conclude whether there is an association between SSRIDDs and cancer predisposition.
The limitation of this study should be noted. As a retrospective study, some clinical information was not available for some patients. The phenotypes among the patients were variable because of their varying ages. Thus, a longer observational period and larger patient population are needed to determine the complete clinical features and disease courses of these patients.