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ACAN biallelic variants in a girl with severe idiopathic short stature



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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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.


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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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).

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