A High Proportion of Novel ACAN Mutations and Their Prevalence in a Large Cohort of Chinese Short Stature Children

Abstract

Context: Aggrecan, encoded by the ACAN gene, is the main proteoglycan component in the extracellular cartilage matrix. Heterozygous mutations in ACAN have been reported to cause idiopathic short stature. However, the prevalence of ACAN pathogenic variants in Chinese short stature patients and clinical phenotypes remain to be evaluated.

Objective: We sought to determine the prevalence of ACAN pathogenic variants among Chinese short stature children and characterize the phenotypic spectrum and their responses to growth hormone therapies.

Patients and methods: Over 1000 unrelated short stature patients ascertained across China were genetically evaluated by next-generation sequencing-based test.

Result: We identified 10 novel likely pathogenic variants and 2 recurrent pathogenic variants in this cohort. None of ACAN mutation carriers exhibited significant dysmorphic features or skeletal abnormities. The prevalence of ACAN defect is estimated to be 1.2% in the whole cohort; it increased to 14.3% among those with advanced bone age and to 35.7% among those with both advanced bone age and family history of short stature. Nonetheless, 5 of 11 ACAN mutation carries had no advanced bone age. Two individuals received growth hormone therapy with variable levels of height SD score improvement.

Conclusion: Our data suggest that ACAN mutation is 1 of the common causes of Chinese pediatric short stature. Although it has a higher detection rate among short stature patients with advanced bone age and family history, part of affected probands presented with delayed bone age in Chinese short stature population. The growth hormone treatment was moderately effective for both individuals.

Keywords: ACAN mutation; genotype-phenotype correlation; growth hormone; prevalence; short stature.

Figure 1.

Schematic of the aggrecan proteoglycan and the locations of reported pathogenic variants and height SDS changes. The novel mutations identified in this study are highlighted in red, de novo variants are underlined. Abbreviations: CLD, C-type lectin domain; CRP, complement regulatory like domain; CS, chondroitin sulfate attachment domain; EGF1, 2, epidermal growth factor-like domain 1, 2; G1, globular domain 1; G2, globular domain 2; G3, globular domain 3; IGD, interglobular domain; KS, keratin sulfate attachment domain. #Early-onset osteoarthritis (OA). &Osteochondritis dissecans (OD).

Figure 2.

Pedigrees of affected families. Pedigrees of 12 families with ACAN pathogenic variants (NM_013227.3). Probands are denoted by arrows. Black indicates that the individual presented short stature (<−2 SD). Abbreviation: ?, unknown genotype or phenotype.

Figure 3.

Radiographs and growth charts of individuals carrying heterozygous ACAN variants. (A) Hand radiographs of some affected patients. Patients’ ID are indicated in the upper-right corner. (B) Growth charts of probands. The blue and red curves show boys and girls, respectively. The red dots represent 2 probands underwent GH treatment. The arrows indicated the starting date of the treatment.