Brachydactyly type A1 (BDA1) is an autosomal dominant disorder characterized by uniform shortening of the middle phalanges in all digits. It is associated with variants in the Indian Hedgehog (IHH) gene, which plays a key role in endochondral ossification. To date, heterozygous pathogenic IHH variants involving several codons, which are restricted to a specific region of the N-terminal active fragment of IHH, have been reported. The purpose of this study was to identify the pathogenic variant in a Japanese family with BDA1 and to evaluate its pathogenesis with regard to previous reports. The proband, a 9-year-old boy, his siblings, and his father had shortened digits and a short stature of variable severity. Based on physical examinations, radiographic findings and family history, they were diagnosed with BDA1. This family is the first case of an isolated malformation in Japan. Sanger sequencing of IHH was performed on these individuals and on the proband’s unaffected mother. The significance of the variants was assessed using three-dimensional analysis methods. Sanger sequencing showed a novel IHH heterozygous variant, NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del].. These two residues are located outside the cluster region considered a hotspot of pathogenic variants. Three-dimensional modelling showed that S182 and K183 are located on the same surface as other residues associated with BDA1. Analysis of residue interactions across the interface between IHH and its interacting receptor protein revealed the presence of hydrogen bonds between them. We report a novel variant, NM_002181.4:c.544_549delTCAAAG (p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] in a Japanese family with BDA1. Indeed, neither variations in codons 182 or 183 nor with such two-amino-acid deletions in IHH have been reported previously. Although these two residues are located outside the cluster region considered a hotspot of pathogenic variants, we speculate that this variant causes BDA1 through impaired interactions between IHH and target receptor proteins in the same manner as other pathogenic variants located in the cluster region. This report expands the genetic spectrum of BDA1.

中文翻译：

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日本 A1 型短指症家系 IHH 中 2 个氨基酸缺失

A1 型短指（BDA1）是一种常染色体显性遗传疾病，其特征是所有手指的中指骨均匀缩短。它与印度刺猬 (IHH) 基因的变体有关，该基因在软骨内骨化中起关键作用。迄今为止，已经报道了涉及多个密码子的杂合致病性 IHH 变体，这些密码子仅限于 IHH 的 N 末端活性片段的特定区域。本研究的目的是确定日本 BDA1 家族的致病性变异，并根据之前的报道评估其发病机制。先证者是一个 9 岁的男孩，他的兄弟姐妹和他的父亲都有缩短的手指和不同严重程度的身材矮小。根据体格检查、影像学检查结果和家族史，他们被诊断为 BDA1。这个家庭是日本首例孤立性畸形病例。对这些个体和先证者未受影响的母亲进行了 IHH 的 Sanger 测序。使用三维分析方法评估变体的重要性。Sanger测序显示了一种新的IHH杂合变体，NM_002181.4:c.544_549delTCAAAG(p.Ser182Lys183del) [NC_000002.12:g.219057461_219057466del]。这两个残基位于被认为是致病变异热点的簇区域之外。三维建模显示 S182 和 K183 与 BDA1 相关的其他残基位于同一表面。对 IHH 与其相互作用的受体蛋白之间界面上的残基相互作用的分析揭示了它们之间存在氢键。我们报告了一个新的变体，NM_002181.4:c.544_549delTCAAAG (p. Ser182Lys183del) [NC_000002.12:g.219057461_219057466del] 在带有 BDA1 的日本家庭中。事实上，以前既没有报道过 IHH 中密码子 182 或 183 的变异，也没有这种两个氨基酸缺失的报道。尽管这两个残基位于被认为是致病变异热点的簇区域之外，但我们推测该变异通过 IHH 和靶受体蛋白之间的相互作用受损导致 BDA1，其方式与位于簇区域中的其他致病变异相同。本报告扩展了 BDA1 的遗传谱。尽管这两个残基位于被认为是致病变异热点的簇区域之外，但我们推测该变异通过 IHH 和靶受体蛋白之间的相互作用受损导致 BDA1，其方式与位于簇区域中的其他致病变异相同。本报告扩展了 BDA1 的遗传谱。尽管这两个残基位于被认为是致病变异热点的簇区域之外，但我们推测该变异通过 IHH 和靶受体蛋白之间的相互作用受损导致 BDA1，其方式与位于簇区域中的其他致病变异相同。本报告扩展了 BDA1 的遗传谱。