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人类原发性小头畸形的双基因遗传阐明了中心体和非中心体途径。

Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways.

机构信息

Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Université Libre de Bruxelles, Brussels, Belgium.

Interuniversity Institute of Bioinformatics in Brussels, Université Libre de Bruxelles-Vrije Universiteit Brussel, Brussels, Belgium.

出版信息

Hum Mutat. 2020 Feb;41(2):512-524. doi: 10.1002/humu.23948. Epub 2019 Nov 27.

DOI:10.1002/humu.23948
PMID:31696992
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7496698/
Abstract

Primary microcephaly (PM) is characterized by a small head since birth and is vastly heterogeneous both genetically and phenotypically. While most cases are monogenic, genetic interactions between Aspm and Wdr62 have recently been described in a mouse model of PM. Here, we used two complementary, holistic in vivo approaches: high throughput DNA sequencing of multiple PM genes in human patients with PM, and genome-edited zebrafish modeling for the digenic inheritance of PM. Exomes of patients with PM showed a significant burden of variants in 75 PM genes, that persisted after removing monogenic causes of PM (e.g., biallelic pathogenic variants in CEP152). This observation was replicated in an independent cohort of patients with PM, where a PM gene panel showed in addition that the burden was carried by six centrosomal genes. Allelic frequencies were consistent with digenic inheritance. In zebrafish, non-centrosomal gene casc5 -/- produced a severe PM phenotype, that was not modified by centrosomal genes aspm or wdr62 invalidation. A digenic, quadriallelic PM phenotype was produced by aspm and wdr62. Our observations provide strong evidence for digenic inheritance of human PM, involving centrosomal genes. Absence of genetic interaction between casc5 and aspm or wdr62 further delineates centrosomal and non-centrosomal pathways in PM.

摘要

原发性小头畸形 (PM) 的特征是出生时头围小，在遗传和表型上都有很大的异质性。虽然大多数病例是单基因的，但最近在 PM 的小鼠模型中描述了 Aspm 和 Wdr62 之间的遗传相互作用。在这里，我们使用了两种互补的、整体的体内方法：对 PM 患者的多个 PM 基因进行高通量 DNA 测序，以及用于 PM 双基因遗传的基因组编辑斑马鱼模型。PM 患者的外显子组显示出 75 个 PM 基因的变异负担显著增加，在去除 PM 的单基因原因（例如 CEP152 的双等位致病性变异）后仍然存在。这一观察结果在 PM 患者的另一独立队列中得到了复制，其中 PM 基因面板显示，负担还由六个中心体基因承担。等位基因频率与双基因遗传一致。在斑马鱼中，非中心体基因 casc5-/- 产生严重的 PM 表型，而中心体基因 aspm 或 wdr62 的无效并不改变该表型。aspm 和 wdr62 产生双基因、四等位 PM 表型。我们的观察结果为涉及中心体基因的人类 PM 的双基因遗传提供了有力证据。casc5 和 aspm 或 wdr62 之间缺乏遗传相互作用进一步描绘了 PM 中的中心体和非中心体途径。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/e2f8e54fc927/HUMU-41-512-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/0ab6ecf08df3/HUMU-41-512-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/85a8fc707173/HUMU-41-512-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/8b6e1336a550/HUMU-41-512-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/e2f8e54fc927/HUMU-41-512-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/0ab6ecf08df3/HUMU-41-512-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/85a8fc707173/HUMU-41-512-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/8b6e1336a550/HUMU-41-512-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/822d/7496698/e2f8e54fc927/HUMU-41-512-g004.jpg

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