Abstract
BackgroundHuman height is a complex trait with a strong genetic basis. Recently, a significant association between rare copy number variations (CNVs) and short stature has been identified, and candidate genes in these rare CNVs are being explored. This study aims to evaluate the association between mutations in ARID1B gene and short stature, both the syndromic and non-syndromic form.ResultsBased on a case-control study of whole genome chromosome microarray analysis (CMA), three overlapping CNVs were identified in patients with developmental disorders who exhibited short stature. ARID1B, a causal gene for Coffin Siris syndrome, is the only gene encompassed by all three CNVs. A following retrospective genotype-phenotype analysis based on a literature review confirmed that short stature is a frequent feature in those Coffin-Siris syndrome patients with ARID1B mutations. Mutation screening of ARID1B coding regions was further conducted in a cohort of 48 non-syndromic short stature patients,andfour novel missense variants including two de novo mutations were found.ConclusionThese results suggest that haploinsufficient mutations of ARID1B are associated with syndromic short stature including Coffin-Siris syndrome and intellectual disability, while rare missense variants in ARID1B are associated with non-syndromic short stature. This study supports the notion that mutations in genes related to syndromic short stature may exert milder effect and contribute to short stature in the general population.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-1898-1) contains supplementary material, which is available to authorized users.
Highlights
Human height is a complex trait with a strong genetic basis
We propose that the ARID1B gene, which is the only gene intercepted by three copy number variations (CNVs), is a novel short stature gene
Short stature is a frequent feature associated with patients with ARID1B mutations A total of 70 patients with mutations in ARID1B have been described in the literature and Decipher database, many of whom have CoffinSiris syndrome
Summary
A significant association between rare copy number variations (CNVs) and short stature has been identified, and candidate genes in these rare CNVs are being explored. This study aims to evaluate the association between mutations in ARID1B gene and short stature, both the syndromic and non-syndromic form. Human height is a quantitative trait that follows a Gaussian distribution. Individuals with short stature include those at the tail of the normal distribution (not necessary associated with any disorders) as well as individuals with rare disorders that restrict growth. We focus on a recurrent CNV detected in patients with short stature. We propose that the ARID1B gene, which is the only gene intercepted by three CNVs, is a novel short stature gene.
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