Laboratory of Molecular and Cellular Screening Processes (LPCMC), LR15CBS07, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia.
Medical Genetic Department, Hedi Chaker Hospital, Sfax, Tunisia.
Am J Med Genet A. 2021 Apr;185(4):1081-1090. doi: 10.1002/ajmg.a.62065. Epub 2021 Jan 6.
Pathogenic variants in Steroid 5 alpha reductase type 3 (SRD5A3) cause rare inherited congenital disorder of glycosylation known as SRD5A3-CDG (MIM# 612379). To date, 43 affected individuals have been reported. Despite the development of various dysmorphic features in significant number of patients, facial recognition entity has not yet been established for SRD5A3-CDG. Herein, we reported a novel SRD5A3 missense pathogenic variant c.460 T > C p.(Ser154Pro). The 3D structural modeling of the SRD5A3 protein revealed additional transmembrane α-helices and predicted that the p.(Ser154Pro) variant is located in a potential active site and is capable of reducing its catalytic efficiency. Based on phenotypes of our patients and all published SRD5A3-CDG cases, we identified the most common clinical features as well as some recurrent dysmorphic features such as arched eyebrows, wide eyes, shallow nasal bridge, short nose, and large mouth. Based on facial digital 2D images, we successfully designed and validated a SRD5A3-CDG computer based dysmorphic facial analysis, which achieved 92.5% accuracy. The current work integrates genotypic, 3D structural modeling and phenotypic characteristics of CDG-SRD5A3 cases with the successful development of computer tool for accurate facial recognition of CDG-SRD5A3 complex cases to assist in the diagnosis of this particular disorder globally.
类固醇 5α 还原酶 3 型（SRD5A3）中的致病变异导致罕见的遗传性糖基化缺陷疾病，称为 SRD5A3-CDG（MIM#612379）。迄今为止，已有 43 例受影响的个体被报道。尽管许多患者都出现了多种发育异常特征，但尚未为 SRD5A3-CDG 建立面部识别实体。在此，我们报道了一种新型的 SRD5A3 错义致病性变异 c.460T>C p.(Ser154Pro)。SRD5A3 蛋白的 3D 结构建模揭示了额外的跨膜α-螺旋，并预测 p.(Ser154Pro)变异位于潜在的活性部位，并能够降低其催化效率。基于我们患者的表型和所有已发表的 SRD5A3-CDG 病例，我们确定了最常见的临床特征以及一些反复出现的发育异常特征，如拱形眉毛、大眼睛、浅鼻梁、短鼻子和大嘴巴。基于面部数字 2D 图像，我们成功设计并验证了一种基于计算机的 SRD5A3-CDG 畸形面部分析，其准确率达到 92.5%。目前的工作整合了 CDG-SRD5A3 病例的基因型、3D 结构建模和表型特征，以及用于准确识别 CDG-SRD5A3 复杂病例的计算机工具的成功开发，以协助在全球范围内诊断这种特殊疾病。
