Abstract
Short stature is a common pediatric disorder affecting 3% of the population. However, the clinical variability and genetic heterogeneity prevents the identification of the underlying cause in about 80% of the patients. Recently, heterozygous mutations in the ACAN gene coding for the proteoglycan aggrecan, a main component of the cartilage matrix, were associated with idiopathic short stature. To ascertain the prevalence of ACAN mutations and broaden the phenotypic spectrum in patients with idiopathic short stature we performed sequence analyses in 428 families. We identified heterozygous nonsense mutations in four and potentially disease-causing missense variants in two families (1.4%). These patients presented with a mean of −3.2 SDS and some suggestive clinical characteristics. The results suggest heterozygous mutations in ACAN as a common cause of isolated as well as inherited idiopathic short stature.
Highlights
Short stature is defined as a height of at least two standard deviations below the population specific age- and sex-related average[1]
Systematic data is present about the frequency of heterozygous ACAN mutations in patients with idiopathic short stature in a larger cohort of mostly European decent
We systematically analyzed 428 families to establish the prevalence of heterozygous mutations in ACAN in idiopathic short stature
Summary
The most common underlying monogenic cause are defects, deletions and mutations, of the SHOX gene attributing for 2.4% of patients with idiopathic short stature[11]. To identify the proportion of heterozygous defects in ACAN we analyzed 428 patients with idiopathic short stature and identified potential disease causing mutations in 6 patients (1.4%) (Fig. 1, Table 1). Four of them were truncating variants including one frameshift variant leading to a premature termination codon. The missense variant p.(Cys51Gly) in patient P1 is located at an evolutionary highly conserved position and has a CADD score of 18.27 suggesting a deleterious effect on the protein. This missense variant affects the region coding for
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