METHODS: A boy with CPSKF1B was recruited and subjected to a comprehensive clinical and imaging evaluation. Genetic detection with whole-exome sequencing (WES) was performed on the patient and extended family members to identify the causative variation. A series of in silico and in vitro investigations were carried out to verify the pathogenicity of the two variants of the identified compound heterozygous variation.
RESULTS: The patient exhibited moderate CPSKF1B symptoms including multiarticular contractures, webbed neck, and spondylocarpotarsal fusion. WES detected a compound heterozygous MYH3 variation consisting of two variants, namely NM_002470.4: c.3377A>G; p. (E1126G) and NM_002470.4: c.5161-2A>C. It was indicated that the NM_002470.4: c.3377A>G; p. (E1126G) variant mainly impaired the local hydrogen bond formation and impacted the TGF-B pathway, while the NM_002470.4: c.5161-2A>C variant could affect the normal splicing of pre-mRNA, resulting in the appearance of multiple abnormal transcripts.
CONCLUSIONS: The findings of this study expanded the mutation spectrum of CPSKF1B, provided an important basis for the counseling of the affected family, and also laid a foundation for the functional study of MYH3 mutations.
方法:招募一名患有CPSKF1B的男孩,并进行全面的临床和影像学评估。对患者和扩展家庭成员进行全外显子组测序(WES)的遗传检测,以鉴定致病变异。进行了一系列计算机模拟和体外研究,以验证已鉴定的复合杂合变异的两个变异体的致病性。
结果:患者出现中度CPSKF1B症状,包括多关节挛缩,网状脖子,和脊骨融合术.WES检测到由两个变体组成的复合杂合MYH3变异,即NM_002470.4:c.3377A>G;p.(E1126G)和NM_002470.4:c.5161-2A>C.表明NM_002470.4:c.3377A>G;p。(E1126G)变体主要损害局部氢键形成并影响TGF-B途径,而NM_002470.4:c.5161-2A>C变异体可影响pre-mRNA的正常剪接,导致多个异常转录物的出现。
结论:这项研究的发现扩展了CPSKF1B的突变谱,为受影响家庭的咨询提供了重要依据,为MYH3突变的功能研究奠定了基础。