Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation

Dateki, Sumito; Nakatomi, Akiko; Watanabe, Satoshi; Shimizu, Hitomi; Inoue, Yukiko; Baba, Hideo; Yoshiura, Koh-ichiro; Moriuchi, Hiroyuki

doi:10.1038/jhg.2017.33

Cited by 34 publications

(44 citation statements)

References 18 publications

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“…ACAN-positive individuals with short stature and mild skeletal defects) have been reported in this study and in the literature (Table 5) [4][5][6][7][8][9][10]. .…”

supporting

confidence: 67%

“…Advanced BA:CA was only observed in 3/5 individuals with a pathogenic mutation; thus, two individuals had a BA equal or delayed with respect to the CA. To date, a total of 58 probands and 106 family members (total = 164 heterozygous ACAN‐ positive individuals with short stature and mild skeletal defects) have been reported in this study and in the literature (Table ) …”

Section: Discussionmentioning

confidence: 95%

“…Until recently, ACAN mutations had been observed in a few families with spondyloepiphyseal dysplasia, Kimberley type (SEDK, MIM 608361); spondyloepimetaphyseal dysplasia, aggrecan type (SEMD, MIM 612813); and osteochondritis dissecans (MIM 165800) . More recently, through the implementation of NGS, heterozygous ACAN mutations have been reported in individuals with a milder skeletal dysplasia, presenting with short stature and advanced bone age (BA) . This led to the creation of an International Aggrecan Consortium for the clinical and genetic evaluation of 103 ACAN heterozygotes from 20 families .…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Sentchordi-Montané

Aza‐Carmona

Benito‐Sanz

et al. 2018

Clinical Endocrinology

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“…ACAN-positive individuals with short stature and mild skeletal defects) have been reported in this study and in the literature (Table 5) [4][5][6][7][8][9][10]. .…”

supporting

confidence: 67%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Sentchordi-Montané

Aza‐Carmona

Benito‐Sanz

et al. 2018

Clinical Endocrinology

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“…yet unreported symptoms include a barrel-shaped chest (P1, P2, P3, P5 and P6) and a limited supination of the forearm (P1, P2 and P3). Some evidence for the response to growth hormone treatment was reported just recently 9,17,18 . Of the patients in this study, only patient P4 received growth hormone therapy improving his height from −3,2 SDS to −1,7 SDS.…”

Section: Resultsmentioning

confidence: 98%

“…To date, 27 different heterozygous mutations in ACAN have been reported to cause different entities of short stature ( Fig. 1d and Supplementary Table 2) 9, [16][17][18][19][20][21][22][23][24][25][26] . Eight of these mutations were frameshift variants, seven were missense variants, eleven were nonsense variants and one was a splice site variant.…”

Section: Resultsmentioning

confidence: 99%

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature

Sticht

Boppudi

et al. 2018

ESPE

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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

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Clinical and Molecular Spectrum of Nonsyndromic Early‐Onset Osteoarthritis

Ruault

Yauy

Fabre

et al. 2020

Arthritis & Rheumatology

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Objective. Osteoarthritis (OA) is the most common joint disease worldwide. The etiology of OA is varied, ranging from multifactorial to environmental to monogenic. In a condition called early-onset OA, OA occurs at an earlier age than is typical in the general population. To our knowledge, there have been no large-scale genetic studies of individuals with early-onset OA. The present study was undertaken to investigate causes of monogenic OA in individuals with nonsyndromic early-onset OA. Methods. The study probands were 45 patients with nonsyndromic early-onset OA who were referred to our skeletal disease center by skeletal dysplasia experts between 2013 and 2019. Criteria for early-onset OA included radiographic evidence, body mass index ≤30 kg/m 2 , age at onset ≤50 years, and involvement of ≥1 joint site. Molecular analysis was performed with a next-generation sequencing panel. Results. We identified a genetic variant in 13 probands (29%); the affected gene was COL2A1 in 11, ACAN in 1, and SLC26A2 in 1. After familial segregation analysis, 20 additional individuals were identified. The mean ± SD age at onset of joint pain was 19.5 ± 3.9 years (95% confidence interval 3-47). Eighteen of 33 subjects (55%) with nonsyndromic early-onset OA and a genetic variant had had at least 1 joint replacement (mean ± SD age at first joint replacement 41 ± 4.2 years; mean number of joint replacements 2.6 per individual), and 21 (45%) of the joint replacement surgeries were performed when the patient was <45 years old. Of the 20 patients age >40 years, 17 (85%) had had at least 1 joint replacement. Conclusion. We confirmed that COL2A1 is the main monogenic cause of nonsyndromic early-onset OA. However, on the basis of genetic heterogeneity of early-onset OA, we recommend next-generation sequencing for all individuals who undergo joint replacement prior to the age of 45 years. Lifestyle recommendations for prevention should be implemented. ClinicalTrials.gov identifier: NCT04267510.

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Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation

Cited by 34 publications

References 18 publications

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Heterozygous aggrecan variants are associated with short stature and brachydactyly: Description of 16 probands and a review of the literature

Genetic screening confirms heterozygous mutations in ACAN as a major cause of idiopathic short stature

Clinical and Molecular Spectrum of Nonsyndromic Early‐Onset Osteoarthritis

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