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. 2025;165(2):51-56.
doi: 10.1159/000545736. Epub 2025 Jun 13.

ACAN Repeat Number Polymorphism in Patients with Idiopathic Short Stature

Sayuri Nakamura  1   2   3 , Yoko Kuroki  4   5   6 , Kyongsun Pak  7 , Tsutomu Kamimaki  8 , Takahiro Mochizuki  9 , Akira Ishiguro  2 , Maki Fukami  1   4
Affiliations

ACAN Repeat Number Polymorphism in Patients with Idiopathic Short Stature

Sayuri Nakamura et al. Cytogenet Genome Res. 2025.

Abstract

Introduction: Idiopathic short stature (ISS) refers to non-syndromic growth failure without chronic disorders. The molecular basis of ISS remains largely unknown. Although a variable number of tandem repeats (VNTR) of 57 nucleotides in ACAN is known to correlate with the height of people in the general population, the role of this genetic variant in the etiology of ISS has not been studied.

Methods: We studied 128 Japanese patients with ISS, including 63 patients with prenatal and postnatal growth failure (small-for-gestational age-SS [SGA-SS]), and 100 control individuals. To examine the repeat numbers of ACAN VNTR, we amplified the VNTR-containing genomic region and analyzed the PCR products by gel electrophoresis. The accuracy of the results was confirmed by long-read next-generation sequencing.

Results: The repeat numbers of the patient group were similarly distributed to those of the control group, and no patient had a very small number. Moreover, the repeat numbers of the shorter and longer alleles in each individual, as well as the average number of the two alleles, were comparable between the two groups. The height standard deviation scores obtained from 106 patients did not correlate with the repeat numbers. There was no difference in the repeat numbers between the SGA-SS or non-SGA ISS groups, and the control group.

Conclusion: The results of this study indicate that reduced repeat numbers of ACAN VNTR do not represent a monogenic cause or a major contributing factor for ISS. Our findings await further validation.

Keywords: Copy number polymorphism; Height; Repeat; Small-for-gestational age; Variable number of tandem repeats.

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Conflict of interest statement

M.F. was a member of the Editorial Board of this journal at the time of submission. The other authors declare no conflicts of interest to declare.

Figures

Fig. 1.
Fig. 1.
Representative results of repeat number analysis. a Agarose gel electrophoresis. The repeat numbers of cases 1–6 were assessed as 26/27, 26/26, 27/27, 27/28, 28/28, and 27/27, respectively. b Long-read NGS for cases 2, 3, and 5. Case 3 carried the same repeat number as the human reference genome (n = 27), while cases 2 and 5 had 26 and 28 repeats, respectively. c Distributions of repeat numbers of all alleles in the patient and control groups (the upper panel) and in the SGA-SS, non-SGA ISS, and control groups (the lower panel). d Correlation analysis between repeat numbers and height SDSs. No significant correlation was observed (Pearson correlation coefficient 0.112, p = 0.253).
Fig. 2.
Fig. 2.
Distribution of repeat numbers of two alleles in each individual. The results of the shorter and longer alleles and the average of the two alleles are shown.
See this image and copyright information in PMC

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