Braathen G J, Høyer H, Busk Ø L, Tveten K, Skjelbred C F, Russell M B
Head and Neck Research Group, Research Centre, Akershus University Hospital, Lørenskog, Oslo, Norway.
Institute of Clinical Medicine, Campus Akershus University Hospital, University of Oslo, Nordbyhagen, Oslo, Norway.
Acta Neurol Scand. 2016 Jul;134(1):67-75. doi: 10.1111/ane.12515. Epub 2015 Oct 12.
Charcot-Marie-Tooth disease (CMT) is a heterogeneous inherited neuropathy. The number of known CMT genes is rapidly increasing mainly due to next-generation sequencing technology, at present more than 70 CMT-associated genes are known. We investigated whether variants in the DCTN2 could cause CMT.
Fifty-nine Norwegian CMT families from the general population with unknown genotype were tested by targeted next-generation sequencing (NGS) for variants in DCTN2 along with 32 CMT genes and 19 other genes causing other inherited neuropathies or neuronopathies, due to phenotypic overlap. In the family with the DCTN2 variant, exome sequencing was then carried out on all available eight family members to rule out the presence of more potential variants.
Targeted NGS identified in one family a variant of DCTN2, c.337C>T, segregating with the phenotype in five affected members, while it was not present in the three unaffected members. The DCTN2 variant c.337C>T; p.(His113Tyr) was neither found in in-house controls nor in SNP databases. Exome sequencing revealed a singular heterozygous shared haplotype containing four genes, DCTN2, DNAH10, LRIG3, and MYO1A, with novel sequence variants. The haplotype was shared by all the affected members, while the unaffected members did not have it.
This is the first time a haplotype on chromosome 12 containing sequence variants in the genes DCTN2, DNAH10, LRIG3, and MYO1A has been linked to an inherited neuropathy in humans.
夏科-马里-图斯病（CMT）是一种异质性遗传性神经病变。由于新一代测序技术的应用，已知的CMT基因数量正在迅速增加，目前已知超过70个与CMT相关的基因。我们研究了动力蛋白2（DCTN2）基因变异是否会导致CMT。
对来自普通人群的59个基因型未知的挪威CMT家系进行靶向新一代测序（NGS），检测DCTN2以及32个CMT基因和19个其他导致其他遗传性神经病变或神经元病变的基因中的变异，原因是存在表型重叠。在发现DCTN2变异的家系中，随后对所有8名可用的家庭成员进行外显子组测序，以排除更多潜在变异的存在。
靶向NGS在一个家系中鉴定出DCTN2的一个变异，即c.337C>T，在5名患病成员中与表型共分离，而在3名未患病成员中不存在。DCTN2变异c.337C>T；p.(His113Tyr)在内部对照和单核苷酸多态性（SNP）数据库中均未发现。外显子组测序揭示了一个独特的杂合共享单倍型，包含四个基因，即DCTN2、DNAH10、LRIG3和MYO1A，带有新的序列变异。所有患病成员都共享该单倍型，而未患病成员则没有。
这是首次发现12号染色体上包含DCTN2、DNAH10、LRIG3和MYO1A基因序列变异的单倍型与人类遗传性神经病变相关联。
