Background

Primordial dwarfism (PD) is a group of genetically heterogeneous disorders related to developmental disabilities occurring in the uterus and prolongs during all stages of life, resulting in short stature, facial deformities and abnormal brain.

Objective

To determine the exact cause of the disease in two Vietnamese patients priory diagnosed with PD by severe pre-and postnatal growth retardation with marked microcephaly and some bone abnormalities.

Methods

Whole-exome sequencing was performed for the two patients and mutations in genes related to PD were screened. Sanger sequencing was applied to examine the mutations in the patients of their families.

Results

Three novel mutations in the PCNT gene which have not been reported previously were identified in the two patients. Of which, two frameshift mutations (p.Thr479Profs*6 and p.Glu2742Alafs*8) were detected in patient I and one stop-gained mutation (p.Gln1907*) was detected in the patient II. These mutations may result in a truncated PCNT protein, leading to an inactivated PACT domain corresponding to residue His3138–Trp3216 of PCNT protein. Therefore, the three mutations may cause a deficiency of protein functional activity and result in the phenotypes of primordial dwarfism in the two patients.

Conclusions

Clinical presentations in combination with genetic analyses supported an accurate diagnosis of the two patients with microcephalic osteodysplastic primordial dwarfism type II (MOPD II). In addition, these results have important implications for prenatal genetic screening and genetic counseling for the families.

中文翻译：

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越南小头骨发育不良原始侏儒症II型患者PCNT三个新突变的鉴定

背景

原始侏儒症 (PD) 是一组与子宫发育障碍相关的遗传异质性疾病，并在生命的各个阶段延长，导致身材矮小、面部畸形和大脑异常。

客观的

确定两名被诊断患有 PD 的越南患者的确切病因，该患者因严重的产前和产后生长迟缓伴明显的小头畸形和一些骨骼异常而被诊断出患有 PD。

方法

对这两名患者进行了全外显子组测序，并筛选了与 PD 相关的基因突变。桑格测序被用于检查其家属患者的突变。

结果

在这两名患者中发现了以前没有报道过的三个PCNT基因的新突变。其中，在患者I中检测到两个移码突变（p.Thr479Profs*6和p.Glu2742Alafs*8），在患者II中检测到一个停止突变（p.Gln1907*）。这些突变可能导致 PCNT 蛋白被截短，从而导致与 PCNT 蛋白的 His313​​8-Trp3216 残基相对应的失活 PACT 结构域。因此，这三个突变可能导致蛋白质功能活性的缺乏，并导致两名患者出现原始侏儒症的表型。

结论

临床表现与遗传分析相结合，支持对两名小头骨发育不良原始侏儒症 II 型 (MOPD II) 患者的准确诊断。此外，这些结果对家庭的产前遗传筛查和遗传咨询具有重要意义。