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. Short stature is defined as a height of at least two standard deviations below the population specific age-and sex-related average 1. It might occur either with regular body proportions or disproportionate, the latter observed in most forms of skeletal dysplasias affecting the growth of distinct bones 1,2. The longitudinal growth of the bones is mainly regulated by the configuration of the growth plate 3. The growth plate is embedded between epi-and metaphysis and is composed of the resting, proliferative and hypertrophic zone. The resting zone consists of the chondrocyte progenitor cells 3-5. These undergo cell division in the proliferative zone, differentiate to chondrocytes and terminate proliferation in the hypertrophic zone. Osteoblasts, osteoclasts and blood vessels transform the newly formed cartilage into bone. Aggrecan is the main proteoglycan of the extracellular matrix of the growth plate cartilage 6. Mutations in ACAN, which encodes for aggrecan, are associated with growth defects ranging from mild idiopathic short stature to severe skeletal dysplasias [MIM: 165800, 612813, 608361] (Fig. 1d) 7. Biallelic mutations lead to spondyloepimetaphyseal dysplasia comprising severe short stature with a final adult height between 66 and 71 cm, brachydactyly and characteristic clinical findings [MIM: 612813] 8. Parents carrying heterozygous mutations present with a final height of 150-152 cm without further dysmorphic findings 8. Although different in their entity, all described phenotypes caused by mutations in the ACAN gene include reduced height of the patients. This phenotypic spectrum suggests a dosage effect. Recently, the phenotypic spectrum arising from heterozygous mutations in ACAN was evaluated in 103 patients from 20 selected families 9. Currently, no