Liu Lei, Li Xiaobo, Hu Zhengmao, Mao Xiao, Zi Xiaohong, Xia Kun, Tang Beisha, Zhang Ruxu
Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, China.
State Key Laboratory of Medical Genetics, Central South University, Changsha, China.
Neuromuscul Disord. 2017 Feb;27(2):193-199. doi: 10.1016/j.nmd.2016.11.008. Epub 2016 Nov 18.
IGHMBP2 mutations had been exclusively associated with spinal muscular atrophy with respiratory distress type I. However, increasing AR-CMT2S cases without respiratory failure caused by IGHMBP2 mutations have been reported in the past two years. We detected IGHMBP2 mutations in a cohort of Chinese CMT2 patients using genes panel testing, polymerase chain reaction and Sanger sequencing. We found four families with autosomal recessive IGHMBP2 mutations, and the frequency of IGHMBP2 mutations is 6.5% in CMT2 without dominant inheritance. We detected a homozygous variant c.1235 + 3A > G in Family 1, compound heterozygous variants c.1737C > A and c.2597_2598delAG in Family 2, compound heterozygous variants c.1489G > A and c.2356delG in Family 3, compound heterozygous variants c.1909C > T and c.1061-2A > G in Family 4. According to the standards and guidelines of the American College of Medical Genetics and Genomics, all the above variants were classified as pathogenic. Four mutations, c.1489G > A, c.2356delG, c.2597_2598delAG and c.1061-2A > G, are reported for the first time. The novel splice acceptor site mutation c.1061-2A > G resulted in deletion of 175 bp, and it was predicted to lead to a frameshift after codon 354 with a premature termination at codon 364. In conclusion, mutation screening of IGHMBP2 should be especially considered in AR-CMT2 and sporadic CMT2 patients.
IGHMBP2突变一直仅与I型伴有呼吸窘迫的脊髓性肌萎缩相关。然而，在过去两年中，越来越多由IGHMBP2突变引起的无呼吸衰竭的常染色体隐性遗传CMT2S病例被报道。我们通过基因panel检测、聚合酶链反应和桑格测序在中国CMT2患者队列中检测了IGHMBP2突变。我们发现了四个具有常染色体隐性IGHMBP2突变的家系，在无显性遗传的CMT2中IGHMBP2突变的频率为6.5%。我们在家族1中检测到纯合变体c.1235 + 3A > G，在家族2中检测到复合杂合变体c.1737C > A和c.2597_2598delAG，在家族3中检测到复合杂合变体c.1489G > A和c.2356delG，在家族4中检测到复合杂合变体c.1909C > T和c.1061-2A > G。根据美国医学遗传学与基因组学学会的标准和指南，上述所有变体均被分类为致病性变体。四个突变，c.1489G > A、c.2356delG、c.2597_2598delAG和c.1061-2A > G，首次被报道。新的剪接受体位点突变c.1061-2A > G导致175 bp的缺失，预计会导致密码子354之后的移码，并在密码子364处提前终止。总之，对于常染色体隐性遗传CMT2和散发性CMT2患者，应特别考虑进行IGHMBP2突变筛查。
