Novel pathogenic ACAN variants in non-syndromic short stature patients

Hu, Xuyun; Gui, Baoheng; Su, Jiasun; Li, Hongdou; Niu, Li; Yu, Tingting; Zhang, Qinle; Xu, Yufei; Li, Guoqiang; Chen, Yulin; Qing, Yanrong; Li, Chuan; Luo, Jingsi; Fan, Xin; Ding, Yu; Li, Juan; Wang, Jian; Wang, Xiumin; Chen, Shaoke; Shen, Yiping

doi:10.1016/j.cca.2017.04.004

Cited by 37 publications

(63 citation statements)

References 10 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: 66%

“…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: 66%

Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Two patients were enrolled in a study on short stature sequencing program (Hu et al, ). Peripheral blood samples were collected after parental consent.…”

Section: Methods and Resultsmentioning

confidence: 99%

Two Chinese Xia‐Gibbs syndrome patients with partial growth hormone deficiency

Cheng

Tang

et al. 2019

Molec Gen & Gen Med

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Background Heterozygous mutations in the AT‐hook DNA‐binding motif containing one (AHDC1, OMIM * 615790) gene cause an autosomal dominant multisystem developmental disorder known as Xia‐Gibbs syndrome (OMIM #615829). Xia‐Gibbs syndrome typically presented with global developmental delay, hypotonia, obstructive sleep apnea, seizures, delayed myelination, micrognathia, and other mild dysmorphic features. Methods Description of the clinical materials of two Chinese boys who were diagnosed with Xia‐Gibbs syndrome based on clinical presentations and next generation sequencing. Review of clinical features and AHDC1 mutations in previously reported Xia‐Gibbs syndrome patients together with our two new patients. Results The Xia‐Gibbs syndrome patients exhibited short stature, hypotonia, global developmental delay, speech delay, simian crease, and mild dysmorphic features. Next generation sequencing revealed de novo heterozygous variants in AHDC1 gene. In addition, laboratory test revealed partial growth hormone deficiency. Both patients underwent growth hormone replacement therapy for 24 and 9 months, respectively, and exhibited good response to the treatment. Conclusion This is the first report of Xia‐Gibbs syndrome patients to be treated with growth hormone. Review of previously reported Xia‐Gibbs syndrome patient indicated that short stature is a frequent feature of this condition, but its underlying cause needs to be further investigated.

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“…Phenotypic sequence analyses primarily focused on familial ISS cases with advanced bone age, it remains unknown whether ACAN mutations can be associated with other phenotypes. Hu et al recently identified three ACAN frameshift mutations in ISS patients with delayed or age-appropriate bone ages [19]. Second, patients 1-4 were born to parents with normal stature.…”

Section: Phenotypic Characteristics Of Patients With Sequence Variantsmentioning

confidence: 99%

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

et al. 2017

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Abstract. Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.

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Novel pathogenic ACAN variants in non-syndromic short stature patients

Cited by 37 publications

References 10 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

Two Chinese Xia‐Gibbs syndrome patients with partial growth hormone deficiency

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature

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