DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes.
DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes.
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DOI：
10.1038/s41431-022-01083-0
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发表时间：
2022-06
影响因子：
5.2
通讯作者：
Weksberg, Rosanna
中科院分区：
文献类型：
--
作者：
Awamleh, Zain;Chater-Diehl, Eric;Choufani, Sanaa;Wei, Elizabeth;Kianmahd, Rebecca R.;Yu, Anna;Chad, Lauren;Costain, Gregory;Tan, Wen-Hann;Scherer, Stephen W.;Arboleda, Valerie A.;Russell, Bianca E.;Weksberg, Rosanna
由ASXL 1、ASXL 2和ASXL 3编码的额外性梳样（ASXL）基因家族对哺乳动物的发育至关重要。ASXL基因家族中的致病性变体与三种表型不同的神经发育综合征相关。我们以前的工作已经表明，由表观遗传调控基因中的致病性变体引起的综合征状况显示出全基因组DNA甲基化（DNAm）改变的一致模式，即，外周血中的DNA标记。鉴于ASXL 1在染色质修饰中的作用，我们假设Bohring-Opitz综合征（BOS）的致病性ASXL 1变体具有独特的DNAm特征。我们使用Illumina的Infinium EPIC阵列分析了17个ASXL 1变体和35个性别和年龄匹配的典型发育个体的全血DNAm。我们在BOS患者中鉴定了763个差异甲基化的CpG位点。差异甲基化位点重叠323个独特的基因，包括HOXA 5和HOXB 4，支持DNAm标签的功能相关性。我们使用基于BOS DNAm特征的机器学习分类模型来分类ASXL 1中不确定意义的变体，以及致病性ASXL 2和ASXL 3变体。一个ASXL 2变异个体的DNAm图谱为BOS样，而三个ASXL 3变异个体的DNAm图谱为对照样。我们还使用了Horvath的表观遗传时钟，该时钟显示具有致病性ASXL 1变异体的个体和具有致病性ASXL 2变异体的个体的DNAm年龄加速，但在具有ASXL 3变异体的个体中没有。这些研究增强了我们对ASXL基因家族相关综合征的表观遗传失调的理解。
The additional sex combs-like (ASXL) gene family—encoded by ASXL1, ASXL2, and ASXL3—is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina’s Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath’s epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.
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了解 ASXL 相关疾病的表型谱：十个病例和文献综述。
DOI：
10.1002/ajmg.a.62156
发表时间：
2021-06
期刊：
American journal of medical genetics. Part A
影响因子：
--
作者：
Cuddapah VA;Dubbs HA;Adang L;Kugler SL;McCormick EM;Zolkipli-Cunningham Z;Ortiz-González XR;McCormack S;Zackai E;Licht DJ;Falk MJ;Marsh ED
通讯作者：
Marsh ED
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
2.7
作者：
Jeannotte L;Gotti F;Landry-Truchon K
通讯作者：
Landry-Truchon K
影响因子：
9.8
作者：
Choufani, Sanaa;Gibson, William T.;Weksberg, Rosanna
通讯作者：
Weksberg, Rosanna
影响因子：
12.3
作者：
Bainbridge MN;Hu H;Muzny DM;Musante L;Lupski JR;Graham BH;Chen W;Gripp KW;Jenny K;Wienker TF;Yang Y;Sutton VR;Gibbs RA;Ropers HH
通讯作者：
Ropers HH