Previously we reported the identification of a homozygous COL27A1 (c.2089G>C; p.Gly697Arg) missense variant and proposed it as a founder allele in Puerto Rico segregating with Steel syndrome (STLS, MIM #615155); a rare osteochondrodysplasia characterized by short stature, congenital bilateral hip dysplasia, carpal coalitions, and scoliosis. We now report segregation of this variant in five probands from the initial clinical report defining the syndrome and an additional family of Puerto Rican descent with multiple affected adult individuals. We modeled the orthologous variant in murine Col27a1 and found it recapitulates some of the major Steel syndrome associated skeletal features including reduced body length, scoliosis, and a more rounded skull shape. Characterization of the in vivo murine model shows abnormal collagen deposition in the extracellular matrix and disorganization of the proliferative zone of the growth plate. We report additional COL27A1 pathogenic variant alleles identified in unrelated consanguineous Turkish kindreds suggesting Clan Genomics and identity-by-descent homozygosity contributing to disease in this population. The hypothesis that carrier states for this autosomal recessive osteochondrodysplasia may contribute to common complex traits is further explored in a large clinical population cohort. Our findings augment our understanding of COL27A1 biology and its role in skeletal development; and expand the functional allelic architecture in this gene underlying both rare and common disease phenotypes.

中文翻译：

---

钢铁综合症创始人等位基因的功能生物学和全球COL27A1致病等位基因的氏族基因组学衍生证据。

先前我们报道了纯合子COL27A1（c.2089G> C; p.Gly697Arg）错义变体的鉴定，并提出将其作为波多黎各与钢综合症隔离的创始人等位基因（STLS，MIM＃615155）；一种罕见的骨软骨发育不良，特征是身材矮小，先天性双侧髋关节发育不良，腕骨联合和脊柱侧弯。现在，我们从定义该综合征的初始临床报告和另外一个波多黎各人后裔家族中，有五个受影响的先证者隔离此变异体，其中有多个受影响的成年个体。我们对鼠Col27a1中的直系同源变体建模，发现它概括了一些主要的Steel综合征相关的骨骼特征，包括体长减少，脊柱侧弯和更圆的颅骨形状。体内小鼠模型的表征显示胶原异常沉积在细胞外基质中，并且生长板的增殖区混乱。我们报告了在无关的近亲土耳其亲戚中鉴定出的其他COL27A1致病变异等位基因，提示该族基因组学和后裔纯合性导致了该人群的疾病。在大量临床人群中进一步探讨了这种常染色体隐性骨软骨发育不良的携带者状态可能有助于常见复杂特征的假说。我们的发现增强了我们对COL27A1生物学及其在骨骼发育中的作用的了解；并扩展该基因在罕见和常见疾病表型中的功能等位基因结构。