ACAN biallelic variants in a girl with severe idiopathic short stature

• Published in: Journal of human genetics Vol. 67; no. 8; pp. 481 - 486
• Main Authors: Masunaga, Yohei, Ohkubo, Yumiko, Nishimura, Gen, Ueno, Taizo, Fujisawa, Yasuko, Fukami, Maki, Saitsu, Hirotomo, Ogata, Tsutomu
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.08.2022
• Subjects: Arthritis; Genetics; Genotype & phenotype; Growth hormones; Hospitals; mRNA turnover; Osteoarthritis; Pathogenicity; Pediatrics; Phenotypes
• ISSN: 1434-5161; 1435-232X; 1435-232X
• DOI: 10.1038/s10038-022-01030-3

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.