Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
Department of Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
Eur J Med Genet. 2022 May;65(5):104492. doi: 10.1016/j.ejmg.2022.104492. Epub 2022 Mar 23.
Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare metabolic disease mainly characterized by psychomotor disability, visual impairment, and variable eye malformations caused by bi-allelic pathogenic variants in SRD5A3. So far, only 23 distinct mutations were described. Exome sequencing in 32-year old monozygotic male twins revealed only the heterozygous splice variant c.562+3delG in SRD5A3, but no second variant. The twins presented with psychomotor deficit and a complex eye disease including retinal dystrophy, pallor of the papilla, nystagmus, and strabismus suggestive of SRD5A3-CDG. Only when applying exome-based copy number analysis, we identified as a second compound heterozygous variant a previously not reported tandem duplication of exons 2-4 in SRD5A3. Next to the typical skeletal anomalies of SRD5A3-CDG such as kyphosis and scoliosis, extension deficits of the proximal interphalangeal (PIP) joints IV were observed. Since similar contractures were described once in a patient with SRD5A3-CDG, we suggest that this rare symptom is possibly associated with SRD5A3-CDG. Our findings further expand the mutational and clinical spectrum of SRD5A3-CDG and emphasize the importance of an intragenic copy number analysis in patients with strong clinical suspicion of SRD5A3-CDG and only one detectable sequence variant.
类固醇 5α-还原酶 3 型先天性糖基化障碍（SRD5A3-CDG）是一种罕见的代谢疾病，主要表现为精神运动障碍、视力损害和各种眼部畸形，由 SRD5A3 的双等位基因致病性变异引起。到目前为止，已经描述了 23 种不同的突变。对 32 岁同卵双胞胎男性进行外显子组测序，仅发现 SRD5A3 中的杂合剪接变异 c.562+3delG，而没有第二种变异。这对双胞胎表现出精神运动缺陷和复杂的眼部疾病，包括视网膜营养不良、视乳头苍白、眼球震颤和斜视，提示为 SRD5A3-CDG。只有应用外显子组拷贝数分析，我们才确定了第二个复合杂合变异，即 SRD5A3 中以前未报道的外显子 2-4 的串联重复。除了 SRD5A3-CDG 的典型骨骼异常，如脊柱后凸和脊柱侧凸外，还观察到近端指间关节（PIP）IV 的伸展不足。由于在一名 SRD5A3-CDG 患者中曾描述过类似的挛缩，我们建议这种罕见的症状可能与 SRD5A3-CDG 有关。我们的发现进一步扩展了 SRD5A3-CDG 的突变和临床谱，并强调了在具有强烈 SRD5A3-CDG 临床怀疑且仅检测到一种可检测序列变异的患者中进行基因内拷贝数分析的重要性。
