PMC:4574214 / 12993-19554 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PMC/sourceid/4574214","sourcedb":"PMC","sourceid":"4574214","source_url":"https://www.ncbi.nlm.nih.gov/pmc/4574214","text":"Discussion\nHigh resolution array CGH enables the detection of small CNVs involving one gene or part of a gene. This approach allowed for the identification of candidate short stature genes. We scanned the whole genome for single CNVs in individual patients or overlapping CNVs with a single gene in the region of overlap in patients with short stature. We paid particular attention to de novo CNVs only present in patients and not in a control population. By this approach, we identified a chromatin-remodeling gene ARID1B as a novel short stature gene. ARID1B was the only gene in the region of overlap involving two deletions and one duplication. The two deletions were de novo. ARID1B has been identified as one of the causal genes for Coffin-Siris syndrome and it has also been associated with syndromic intellectual disability [10]. While growth retardation was mentioned as one of the features of Coffin-Sirissyndrome [11], this feature is currently under appreciated [12]. We then performed a comprehensive case review of the clinical features of all individuals carrying mutation in ARID1B regardless of their associated syndromes (Table 1). This genotype-driven approach revealed a significant association between short stature and mutations in ARID1B. Next, we further explored the possible contribution of ARID1B mutations to non-syndromic short stature by screening 48 short stature patients who did not have developmental delay or intellectual disability. As a result, we identified four novel missense variants in ARID1B including two de novo variants. The likelihood of a chance finding of two de novo variants in the same gene in 48 individuals is extremely small, indicating that these variants are likely causal of the patients’ short stature. Collectively, our data support the notion that ARID1B mutations cause growth retardation in syndromic patients and may also contribute to non-syndromic short stature.\n\nCoffin-Siris syndrome and short stature\nRecently, loss of function mutations in ARID1B were identified as causative for Coffin-Siris syndrome, a rare genetic condition characterized by growth deficiency, developmental delay, severe speech impairment, intellectual disability, and specific physical features including microcephaly, coarse facial features, hypertrichosis, hypoplastic or absent fifth fingernails or toenails and hypoplasia or agenesis of the corpus callosum [13]. Our patient A exhibited many features of Coffin-Siris but was not noted to have hypoplastic or absent fifth fingernails or toenails. Our patient B showed typical signs of Coffin-Siris syndrome but not patient C. All three patients exhibited short stature. We performed a comprehensive review on published cases with loss-of-function mutations in ARID1B (Table 1). Based on the available clinical information from the published literature, all patients showed developmental delay (70/70) and language impairment (63/63). Most of patients exhibited hypertonia (49/56), seizures (16/52), agenesis of corpus callosum (23/47), autism or autistic features (9/42) as well as dysmorphic features: low-set or abnormal-shaped ears (42/47), prominent nose (41/55), various eye-related features (51/64), hypertrichosis (38/51), coarse face/abnormal head shape (16/18), low hair line (9/11), and spinal/skeletal anomalies (10/12). Patients ascertained with Coffin-Siris syndrome also exhibited dysplastic nails.\nCase review data showed that 34 % of patients with ARID1B mutations had short stature defined as height below -2 SD. The majority (90 %) had a height Z-score below -1 and none of the patients had above average height. The average Z score among patients for whom height data was available is -1.86. Thus, growth retardation and short stature is a common feature associated with mutations in ARID1B and Coffin-Siris syndrome.\nCoffin-Siris syndrome is a nucleosome remodeling complex (SWI/SNF-SWI) disorder. Mutations in other genes involved with the SWI/SNF complex such as ARID1A, SMARCA2, SMARCA4, SMARCB1 and SMARCE1 are also responsible for Coffin-Siris syndrome [12]. Recent genotype-phenotype analysis indicated that short stature is a prominent feature in patients carrying mutations in those other SWI/SNF genes [14] as well. Among all the Coffin-Siris syndrome patients detected with mutations in those BAF-complex-related-genes (BRG1/brm-associated factor), 21 % of them (9/43) showed short stature. Additionally, 24 % of Coffin-Siris patients without identified mutations presented with short stature. Thus short stature is a common feature of Coffin-Siris syndrome.\n\nARID1B and non-syndromic short stature\nWe identified four novel missense variants among 48 individuals with idiopathic short stature not associated with developmental delay. These variants were not reported in 1000 genomes project database, dbSNP database, the ESP6500 dataset or ExAC database. Functional predictions suggest deleterious effect on protein for all four variants, although two of the variants were found in family members without short stature. All four variants were absent from 1100 ethnically matched controls. We found significantly fewer deleterious novel missense variants in age, gender, and ethnicity-matched controls than in short stature patients. Importantly, two of the variants were de novo changes not detected in parents and non-affected siblings. All four patients carrying ARID1B mutation showed no signs of Coffin-Siris syndrome, or developmental or mental deficits. ARID1B de novo mutations have been shown to contribute to the heritable complex traits, such as autism spectrum disorders (ASDs), although the effect size may be small [15]. We have not established the causal relationship between these mutations and short stature, but we postulate that ARID1B is also involved with idiopathic short stature in a similar manner.\nAlmost all 70 syndromic individuals carried loss-of-function ARID1B mutations which include genic deletions (n = 27), genic duplications (n = 2), nonsense mutations (n = 14), frame shift mutations (n = 21) and a translocation (n = 1). On the other hand, all variants identified in non-syndromic short stature are missense variants. Based on this finding, we postulate that while complete loss of the ARID1B gene product causes a syndrome that involves developmental delay, intellectual disability, dysmorphism and short stature, missense mutations may cause isolated short stature without developmental defects. Further testing of more non-syndromic short stature patient is warranted to validate such hypothesis.\n","divisions":[{"label":"Title","span":{"begin":0,"end":10}},{"label":"Section","span":{"begin":1930,"end":4583}},{"label":"Title","span":{"begin":1930,"end":1969}},{"label":"Section","span":{"begin":4585,"end":6560}},{"label":"Title","span":{"begin":4585,"end":4623}}],"tracks":[{"project":"2_test","denotations":[{"id":"26376624-1865473-10040323","span":{"begin":925,"end":927},"obj":"1865473"},{"id":"26376624-23815551-10040324","span":{"begin":975,"end":977},"obj":"23815551"},{"id":"26376624-22711679-10040325","span":{"begin":2404,"end":2406},"obj":"22711679"},{"id":"26376624-23815551-10040326","span":{"begin":4074,"end":4076},"obj":"23815551"},{"id":"26376624-23929686-10040327","span":{"begin":4227,"end":4229},"obj":"23929686"},{"id":"26376624-25086666-10040328","span":{"begin":5654,"end":5656},"obj":"25086666"}],"attributes":[{"subj":"26376624-1865473-10040323","pred":"source","obj":"2_test"},{"subj":"26376624-23815551-10040324","pred":"source","obj":"2_test"},{"subj":"26376624-22711679-10040325","pred":"source","obj":"2_test"},{"subj":"26376624-23815551-10040326","pred":"source","obj":"2_test"},{"subj":"26376624-23929686-10040327","pred":"source","obj":"2_test"},{"subj":"26376624-25086666-10040328","pred":"source","obj":"2_test"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"2_test","color":"#ec9d93","default":true}]}]}}