Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Department of Pediatrics, Shizuoka Saiseikai General Hospital, Shizuoka, Japan.
J Hum Genet. 2022 Aug;67(8):481-486. doi: 10.1038/s10038-022-01030-3. Epub 2022 Mar 22.
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.
虽然 ACAN 杂合功能丧失变异通常导致特发性身材矮小症（ISS）表型，但尚无报道描述 ACAN 双等位基因功能丧失变异引起的 ISS 表型。我们遇到了一位 4 岁 10 个月的日本女孩，身高 80.4cm（-5.2SD），体重 11.4kg（-1.9SD），头围 48.7cm（-0.6SD），臂展/身高比为 1.0（+1.1SD）。内分泌研究和骨骼检查未发现异常。全外显子组测序显示 ACAN 存在双等位基因罕见变异，即 NM_013227.4：c.4214delC：p.（Pro1405Leufs*3）来自身材矮小的父亲和祖父（分别为-2.9 和-2.0SD），以及 NM_013227.4：c.7124A>G：p.（Gln2375Arg）来自身材矮小的母亲和外祖母（分别为-2.1 和-3.0SD）。移码变异经历了无意义介导的 mRNA 衰变，错义变异被评估为具有高度致病性。结果首次表明，ACAN 双等位基因功能丧失变异可导致严重的 ISS 表型。
