De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes
De novo single-nucleotide and copy number variation in discordant monozygotic twins reveals disease-related genes
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DOI：
10.1038/s41431-019-0376-7
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发表时间：
2019-03
影响因子：
5.2
通讯作者：
Nirmal Vadgama;A. Pittman;M. Simpson;N. Nirmalananthan;R. Murray;T. Yoshikawa;Peter De Rijk;E. Rees;G. Kirov;D. Hughes;Tomas W. Fitzgerald;M. Kristiansen;K. Pearce;Eliza Cerveira;Qihui Zhu;Chengsheng Zhang;Charles Lee;J. Hardy;J. Nasir
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文献类型：
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作者：
Nirmal Vadgama;A. Pittman;M. Simpson;N. Nirmalananthan;R. Murray;T. Yoshikawa;Peter De Rijk;E. Rees;G. Kirov;D. Hughes;Tomas W. Fitzgerald;M. Kristiansen;K. Pearce;Eliza Cerveira;Qihui Zhu;Chengsheng Zhang;Charles Lee;J. Hardy;J. Nasir
最近的研究表明，单卵双胞胎（MZ）之间的遗传差异。为了检验早期双胞胎后突变事件与表型不一致相关的假设，我们使用全外显子组测序研究了13对双胞胎（n= 26）的队列，这些双胞胎对的各种临床表型不一致，并筛选拷贝数变异（CNV）。我们鉴定了PLCB 1的一个新生变异体，PLCB 1是一个参与奶牛乳中脂磷水解的基因，与乳糖酶非持久性相关，以及线粒体复合物I基因MT-ND 5的一个变异体，与肌萎缩侧索硬化症（ALS）相关。我们还在另一对与ALS不一致的MZ双胞胎中发现了多个基因（TMEM 225 B，KBTBD 3，TUBGCP 4，TFIP 11）的体细胞变异。基于双胞胎之间的不一致性可以通过具有可变的遗传或表达性的共同变异来解释的假设，我们筛选了双胞胎样本中已知的共同致病变异，并在双胞胎中发现了一种罕见的缺失ARHGAP 11B，表现为典型人格障碍或精神分裂症。对两对双胞胎进行亲子三人分析，以评估父母来源的变异与疾病易感性的潜在关联。我们发现了一个8岁男性双胞胎共有的RASD 2的新生变异体，他们被怀疑诊断为自闭症谱系障碍（ASD），表现为不同的特征。在这些双胞胎中也发现了新生CNV重复，即CD 38基因，该基因以前与ASD有关。在抽动秽语综合征不一致的双胞胎中，在AADAC中检测到父系遗传的停止损失变异，AADAC是该疾病的已知候选基因。
Recent studies have demonstrated genetic differences between monozygotic (MZ) twins. To test the hypothesis that early post-twinning mutational events associate with phenotypic discordance, we investigated a cohort of 13 twin pairs (n= 26) discordant for various clinical phenotypes using whole-exome sequencing and screened for copy number variation (CNV). We identified a de novo variant inPLCB1, a gene involved in the hydrolysis of lipid phosphorus in milk from dairy cows, associated with lactase non-persistence, and a variant in the mitochondrial complex I geneMT-ND5associated with amyotrophic lateral sclerosis (ALS). We also found somatic variants in multiple genes (TMEM225B, KBTBD3, TUBGCP4, TFIP11) in another MZ twin pair discordant for ALS. Based on the assumption that discordance between twins could be explained by a common variant with variable penetrance or expressivity, we screened the twin samples for known pathogenic variants that are shared and identified a rare deletion overlappingARHGAP11B, in the twin pair manifesting with either schizotypal personality disorder or schizophrenia. Parent–offspring trio analysis was implemented for two twin pairs to assess potential association of variants of parental origin with susceptibility to disease. We identified a de novo variant inRASD2shared by 8-year-old male twins with a suspected diagnosis of autism spectrum disorder (ASD) manifesting as different traits. A de novo CNV duplication was also identified in these twins overlappingCD38, a gene previously implicated in ASD. In twins discordant for Tourette’s syndrome, a paternally inherited stop loss variant was detected inAADAC, a known candidate gene for the disorder.