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ACAN biallelic variants in a girl with severe idiopathic short stature

Journal of Human Genetics volume 67, pages 481–486 (2022)Cite this article

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Abstract

Although ACAN heterozygous loss-of-function variants often cause idiopathic short stature (ISS) phenotype, there is no report describing ISS phenotype caused by ACAN biallelic loss-of-function variants. We encountered a 4 1/12-year-old Japanese girl with a height of 80.4 cm (−5.2 SD), a weight of 11.4 kg (−1.9 SD), a head circumference of 48.7 cm (−0.6 SD), and an arm span/height ratio of 1.0 (+1.1 SD). Endocrine studies and bone survey showed no abnormal findings. Whole exome sequencing revealed biallelic rare variants in ACAN, i.e., NM_013227.4:c.4214delC:p.(Pro1405Leufs*3) derived from her father and paternal grandfather with short stature (−2.9 and −2.0 SD, respectively) and NM_013227.4:c.7124 A>G:p.(Gln2375Arg) inherited from her mother and maternal grandmother with short stature (−2.1 and −3.0 SD, respectively). The frameshift variant underwent nonsense mediated mRNA decay, and the missense variant was assessed to have high pathogenicity. The results imply for the first time that ACAN biallelic loss-of-function variants can cause severe ISS phenotype.

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Acknowledgements

We are grateful to the patient and her family members for their cooperation. We would like to thank Ms. Fumiko Kato, Ms. Aya Kitamoto, and Mr. Naoki Adachi for their support in molecular analyses.

Funding

This work was supported by the grants from Japan Agency for Medical Research and Development (AMED) (JP19ek0109297 to HS and JP21ek0109549 to TO).

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Author notes

  1. These authors contributed equally: Yohei Masunaga, Yumiko Ohkubo.

Authors and Affiliations

  1. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Yohei Masunaga, Yasuko Fujisawa & Tsutomu Ogata

  2. Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan

    Yumiko Ohkubo, Taizo Ueno & Tsutomu Ogata

  3. Center for Intractable Diseases, Saitama Medical University Hospital, Saitama, Japan

    Gen Nishimura

  4. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

    Maki Fukami & Tsutomu Ogata

  5. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Hirotomo Saitsu & Tsutomu Ogata

  6. Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan

    Tsutomu Ogata

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  1. Yohei Masunaga
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  3. Gen Nishimura
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Contributions

YM, YF, MF and HS performed molecular studies. YO, GN, TU and TO obtained clinical data and blood samples. TO designed the study, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Tsutomu Ogata.

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Masunaga, Y., Ohkubo, Y., Nishimura, G. et al. ACAN biallelic variants in a girl with severe idiopathic short stature. J Hum Genet 67, 481–486 (2022). https://doi.org/10.1038/s10038-022-01030-3

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