Identification of a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature

Abstract

Aggrecan is a proteoglycan in the extracellular matrix of growth plate and cartilaginous tissues. Aggrecanopathy has been reported as a genetic cause not only for severe skeletal dysplasia but also for autosomal dominant short stature with normal to advanced bone age. We report a novel heterozygous mutation of ACAN in a Korean family with proportionate short stature identified through targeted exome sequencing. We present a girl of 4 years and 9 months with a family history of short stature over three generations. The paternal grandmother is 143 cm tall (-3.8 as a Korean standard deviation score [SDS]), the father 155 cm (-3.4 SDS), and the index case 96.2 cm (-2.9 SDS). Evaluation for short stature showed normal growth hormone (GH) peaks in the GH provocation test and a mild delayed bone age for chronological age. This subject had clinical characteristics including a triangular face, flat nasal bridge, prognathia, blue sclerae, and brittle teeth. The targeted exome sequencing was applied to detect autosomal dominant growth palate disorder. The novel variant c.910G>A (p.Asp304Asn) in ACAN was identified and this variant was found in the subject's father using Sanger sequencing. This is the first case of Korean familial short stature due to ACAN mutation. ACAN should be considered for proportionate idiopathic short stature, especially in cases of familial short stature.

Identification of a heterozygous ACAN mutation in a 15-year-old boy with short stature who presented with advanced bone age: a case report and review of the literature

“…A heterozygous ACAN mutation has been reported as a major cause of idiopathic short stature and familial short stature. However, only one case of a young child without early advanced bone age, which is a typical manifestation of ACAN mutation, has been reported in Korea [ 5 ]. Here, we describe the case of an adolescent boy with severely short stature who harbored a heterozygous c.512C>T (p.Ala171Val) mutation of ACAN , which has not yet been reported to be associated with clinical manifestation.…”

Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review

“…Until November 1, 2021, we searched online databases (PubMed, Web of Science, and CNKI) for published papers with identified ACAN variants that cause clinical symptoms by "ACAN" or "aggrecan." Thirty-nine articles were collected to evaluate the affected individuals' genetic features, clinical manifestations, biochemical and radiologic characteristics, and response to therapy of rhGH and/or GnRHa (Crippa et al, 2018;Dateki et al, 2017;Deng, 2018;Florio et al, 2019;Freire et al, 2019;Fukuhara et al, 2019;Gkourogianni et al, 2017;Gleghorn et al, 2005;Hattori et al, 2017;Hauer et al, 2017;Hu et al, 2017;Kim et al, 2018Kim et al, , 2020Kim et al, , 2021Liang et al, 2020;Lin et al, 2021;Ma, 2021;Mancioppi et al, 2021;Nilsson et al, 2014;Quintos et al, 2015;Riera et al, 2021;Ristolainen et al, 2015;Sentchordi-Montane et al, 2018;Stattin et al, 2008;Stattin et al, 2010;Stavber et al, 2020;Tatsi et al, 2017;Tompson et al, 2009;Toscano et al, 2021;Uchida et al, 2020;van der Steen et al, 2017;Wang et al, 2020Wang et al, , 2021Wei et al, Data were expressed as the mean ± standard deviation (SD) for continuous variables confirmed to be normally distributed with equal variance and as numbers (percentages) for categorical variables. Heights in different groups were compared using the t-test of two independent samples.…”