The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome.
The mitochondrial genome as a modifier of autism versus cancer phenotypes in PTEN hamartoma tumor syndrome.
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DOI：
10.1016/j.xhgg.2023.100199
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发表时间：
2023-07-13
期刊：
影响因子：
--
通讯作者：
Eng, Charis
中科院分区：
文献类型：
--
作者：
Wei, Ruipeng;Yehia, Lamis;Ni, Ying;Eng, Charis
癌症和自闭症谱系障碍/发育迟缓(ASD/DD)是具有生殖系PTEN变异(PTEN错构瘤肿瘤综合征，PHTS)个体的两种常见临床表型。新兴的研究表明，基因组和代谢因子可能在PHTS中作为ASD/DD与癌症的修饰物。最近，我们发现在这些PHTS患者中，拷贝数变异与ASD/DD与癌症相关。我们还发现，在10%的PHTS患者中出现的线粒体复合体II变体可以改变乳腺癌风险和甲状腺癌组织学。这些研究表明，线粒体途径可能是PHTS表型发育的重要因素。然而，线粒体基因组(MtDNA)在PHTS中从未被系统研究过。因此，我们研究了从498名PHTS患者的全基因组测序数据中提取的mtDNA图谱，其中包括164名ASD/DD患者(仅PHTS-ASD/DD)，184名癌症患者(PHTS-Only癌症)，132名既不是ASD/DD也不是癌症(PHTS-Non)的患者，以及18名同时患有ASD/DD和癌症(PHTS-ASD癌症)的患者。我们发现，单纯PTS-ASD/DD组的线粒体DNA拷贝数显著高于单纯PTS-癌组(p=9.2x×10−3；在H单倍组中p=4.2x×10−3)。PHTS-NON组(仅PHTS-ASD/DD组和PHTS-NON组)的线粒体DNA变异负担也高于PHTS-癌症组(PHTS-癌症和PHTS-ASD/癌症组；p=4.6x×10−2)；PHTS-NON组(仅PHTS-ASD/DD组和PHTS-ASD/癌症组；p=0.03×10−2)也显示出更高的变异负担。我们的研究表明，线粒体DNA是ASD/DD与PHTS癌症表型发展之间的一种修饰物。癌症和自闭症谱系障碍/发育迟缓(ASD/DD)在带有生殖系PTEN变异(PHTS)的个体中似乎是不同的表型。我们研究了线粒体DNA(MtDNA)在PHTS中的分布，并证明了不同表型在拷贝数和变异负荷上的差异，从而作为ASD/DD与PHTS癌症之间的修饰物。
Cancer and autism spectrum disorder/developmental delay (ASD/DD) are two common clinical phenotypes in individuals with germline PTEN variants (PTEN hamartoma tumor syndrome, PHTS). Burgeoning studies have shown that genomic and metabolomic factors may act as modifiers of ASD/DD versus cancer in PHTS. Recently, we showed copy number variations to be associated with ASD/DD versus cancer in these PHTS individuals. We also found that mitochondrial complex II variants occurring in 10% of PHTS individuals modify breast cancer risk and thyroid cancer histology. These studies suggest that mitochondrial pathways could act as important factors in PHTS phenotype development. However, the mitochondrial genome (mtDNA) has never been systematically studied in PHTS. We therefore investigated the mtDNA landscape extracted from whole-genome sequencing data from 498 PHTS individuals, including 164 with ASD/DD (PHTS-onlyASD/DD), 184 with cancer (PHTS-onlyCancer), 132 with neither ASD/DD nor cancer (PHTS-neither), and 18 with both ASD/DD and cancer (PHTS-ASDCancer). We demonstrate that PHTS-onlyASD/DD has significantly higher mtDNA copy number than PHTS-onlyCancer group (p = 9.2 × 10−3 in all samples; p = 4.2 × 10−3 in the H haplogroup). PHTS-neither group has significantly higher mtDNA variant burden than PHTS-ASDCancer group (p = 4.6 × 10−2); the PHTS-noCancer group (PHTS-onlyASD/DD and PHTS-neither groups) also shows higher variant burden than the PHTS-Cancer group (PHTS-onlyCancer and PHTS-ASD/Cancer groups; p = 3.3 × 10−2). Our study implicates the mtDNA as a modifier of ASD/DD versus cancer phenotype development in PHTS. Cancer and autism spectrum disorder/developmental delay (ASD/DD) are seemingly disparate phenotypes in individuals with germline PTEN variants (PHTS). We investigated the mitochondrial DNA (mtDNA) landscape in PHTS and demonstrate differences in copy number and variant burden according to phenotype, thus serving as a modifier of ASD/DD versus cancer in PHTS.
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下一代测序在自闭症谱系障碍中线粒体DNA分析。
DOI：
10.1002/aur.1792
发表时间：
2017-08
期刊：
Autism research : official journal of the International Society for Autism Research
影响因子：
--
作者：
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Brkanac Z
DOI：
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发表时间：
2015-11
期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
4.7
作者：
Klein, Steven;Sharifi-Hannauer, Pantea;Martinez-Agosto, Julian A.
通讯作者：
Martinez-Agosto, Julian A.
影响因子：
14.9
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通讯作者：
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影响因子：
14.9
作者：
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通讯作者：
Sayers EW