Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly
Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly
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DOI：
10.1038/s41436-019-0464-7
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发表时间：
2019-09-01
影响因子：
8.8
通讯作者：
Rauch, Anita
中科院分区：
文献类型：
--
作者：
Boonsawat, Paranchai;Joset, Pascal;Rauch, Anita
目的：小头畸形是许多遗传条件的标志，但很少有系统的评估。因此，我们全面研究了一个未选择的小头症患者队列的临床和遗传景观。方法：我们对62例患者（58%为原发性小头畸形[PM]， 27%为继发性小头畸形[SM]， 15%为未知发病）进行了临床评估、高分辨率染色体微阵列分析、外显子组测序和功能研究。结果：我们发现发育迟缓/智力残疾的严重程度与PM小头畸形的严重程度相关，而与SM无关。我们在48.4%的患者中检测到致病变异，并发现PM（主要是隐性和可能的基因破坏[LGD]）与SM（所有显性新生和均匀LGD或错义）的遗传和变异模式不同。虽然中心体相关途径仅在PM中被发现，但转录调控是SM和PM中最常受影响的途径。出乎意料的是，我们发现不同线粒体相关基因的致病变异约占患者的5%，这强调了它们在综合征性PM中的作用。此外，我们描绘了新的候选基因参与中心体相关途径（SPAG5, TEDC1）， Wnt信号（VPS26A, ZNRF3）和RNA运输（DDXI）。结论：我们的研究结果有助于改善PM和SM患者的评估和遗传咨询，并进一步阐明小头畸形的途径。
Purpose: Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly.Methods: We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset).Results: We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for similar to 5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDXI).Conclusion: Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.