Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes.
Evidence That Non-Syndromic Familial Tall Stature Has an Oligogenic Origin Including Ciliary Genes.
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DOI：
10.3389/fendo.2021.660731
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发表时间：
2021
影响因子：
5.2
通讯作者：
Rappold GA
中科院分区：
文献类型：
--
作者：
Weiss B;Eberle B;Roeth R;de Bruin C;Lui JC;Paramasivam N;Hinderhofer K;van Duyvenvoorde HA;Baron J;Wit JM;Rappold GA
人类的成长是一个复杂的特征。相当多的基因缺陷已被证明会导致身材矮小，但只有少数的例子，遗传原因的非综合征高个子。除了影响大的罕见变异和影响小的常见风险等位基因外，寡基因效应也可能导致这种表型。对身高3.5 SDS的男性及其父母进行外显子组测序。通过Sanger测序在三人组和其他三个受影响的家庭成员和一个未受影响的家庭成员中验证了过滤后的具有高CADD分数的破坏性变异。通过网络分析评估候选基因之间的联系，并通过微阵列和RNA Seq分析小鼠生长板的转录组。预测具有破坏性的CEP104、CROCC、NEK1、TOM1L2和TSTD2的杂合基因变异在4个高个子家庭成员中被发现是共享的。这5个基因中的3个（CEP104、CROCC和NEK1）属于纤毛基因家族。所有基因均在小鼠生长板中表达。通路和网络分析显示了密切的功能联系。总之，这些数据扩展了与线性生长和高个子表型有关的基因谱。
Human growth is a complex trait. A considerable number of gene defects have been shown to cause short stature, but there are only few examples of genetic causes of non-syndromic tall stature. Besides rare variants with large effects and common risk alleles with small effect size, oligogenic effects may contribute to this phenotype. Exome sequencing was carried out in a tall male (height 3.5 SDS) and his parents. Filtered damaging variants with high CADD scores were validated by Sanger sequencing in the trio and three other affected and one unaffected family members. Network analysis was carried out to assess links between the candidate genes, and the transcriptome of murine growth plate was analyzed by microarray as well as RNA Seq. Heterozygous gene variants in CEP104, CROCC, NEK1, TOM1L2, and TSTD2 predicted as damaging were found to be shared between the four tall family members. Three of the five genes (CEP104, CROCC, and NEK1) belong to the ciliary gene family. All genes are expressed in mouse growth plate. Pathway and network analyses indicated close functional connections. Together, these data expand the spectrum of genes with a role in linear growth and tall stature phenotypes.
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