Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.
Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.
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DOI：
10.1186/s13073-021-00870-6
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发表时间：
2021-04-19
期刊：
影响因子：
12.3
通讯作者：
Eichler EE
中科院分区：
文献类型：
--
作者：
Gillentine MA;Wang T;Hoekzema K;Rosenfeld J;Liu P;Guo H;Kim CN;De Vries BBA;Vissers LELM;Nordenskjold M;Kvarnung M;Lindstrand A;Nordgren A;Gecz J;Iascone M;Cereda A;Scatigno A;Maitz S;Zanni G;Bertini E;Zweier C;Schuhmann S;Wiesener A;Pepper M;Panjwani H;Torti E;Abid F;Anselm I;Srivastava S;Atwal P;Bacino CA;Bhat G;Cobian K;Bird LM;Friedman J;Wright MS;Callewaert B;Petit F;Mathieu S;Afenjar A;Christensen CK;White KM;Elpeleg O;Berger I;Espineli EJ;Fagerberg C;Brasch-Andersen C;Hansen LK;Feyma T;Hughes S;Thiffault I;Sullivan B;Yan S;Keller K;Keren B;Mignot C;Kooy F;Meuwissen M;Basinger A;Kukolich M;Philips M;Ortega L;Drummond-Borg M;Lauridsen M;Sorensen K;Lehman A;CAUSES Study;Lopez-Rangel E;Levy P;Lessel D;Lotze T;Madan-Khetarpal S;Sebastian J;Vento J;Vats D;Benman LM;Mckee S;Mirzaa GM;Muss C;Pappas J;Peeters H;Romano C;Elia M;Galesi O;Simon MEH;van Gassen KLI;Simpson K;Stratton R;Syed S;Thevenon J;Palafoll IV;Vitobello A;Bournez M;Faivre L;Xia K;SPARK Consortium;Earl RK;Nowakowski T;Bernier RA;Eichler EE
随着基因组测序研究的不断增加，数百个基因与神经发育障碍（NDD）有关。基因发现的速度远远超过了我们对基因型-表型相关性的理解，临床特征仍然是理解 NDD 的瓶颈。大多数与疾病相关的孟德尔基因都是基因家族的成员，我们假设那些具有相关分子功能的基因具有共同的临床表现。我们通过考虑具有多个成员的基因家族来测试我们的假设，这些成员在 NDD 中富集从头变异，正如之前的荟萃分析所确定的。这些基因家族之一是异质核核糖核蛋白（hnRNP），它有 33 个成员，其中 5 个最近被鉴定为 NDD 基因（HNRNPK、HNRNPU、HNRNPH1、HNRNPH2 和 HNRNPR），其中两个在我们之前对 NDD 先证者的荟萃分析中显着富集（HNRNPU 和 SYNCRIP）。利用蛋白质同源性、突变分析、基因表达分析和表型表征，我们为 12 个 HNRNP 基因作为 NDD 候选基因的变异提供了证据。七个基因可能是新颖的，而该家族中的其余基因可能不会对 NDD 风险产生显着影响。我们通过测序和国际合作并结合已发表的临床病例报告报告了 119 个新的 NDD 病例（64 个新发变异）。我们考虑了 235 例具有基因破坏性单核苷酸变异或插入缺失的病例，以及 15 例具有小拷贝数变异的病例。三个 hnRNP 编码基因在从头变异富集方面达到名义或外显子组范围的显着性，而九个是致病突变的候选基因。 HNRNP 基因表达的比较显示出与大脑皮层发育中的作用一致的模式，并且在放射状胶质祖细胞中表达丰富。先证者 (n = 188–221) 的临床评估扩大了与 HNRNP 罕见变异相关的表型，与 HNRNP 基因变异相关的表型将其区分为 NDD 的一个亚组。总体而言，我们利用NDD中基因家族的新方法识别了新的HNRNP相关疾病，扩展了已知HNRNP相关疾病的表型，强烈暗示了NDD中hnRNP作为一个整体的破坏，并支持NDD亚型可能具有共同的分子发病机制。迄今为止，这是第一项根据相关基因中存在的疾病来识别新型遗传疾病的研究。我们还进行了首次针对相关基因的表型分析。最后，我们表明这些基因的放射状胶质细胞表达可能在神经发育过程中至关重要。这对于诊断以及制定最佳研究这些基因以开发治疗方法的策略非常重要。
With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype–phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations. We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk. We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188–221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs. Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
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影响因子：
2
作者：
de Kovel, Carolien G. F.;Brilstra, Eva H.;van Kempen, Marjan J. A.;van't Slot, Ruben;Nijman, Isaac J.;Afawi, Zaid;De Jonghe, Peter;Djemie, Tania;Guerrini, Renzo;Hardies, Katia;Helbig, Ingo;Hendrickx, Rik;Kanaan, Moine;Kramer, Uri;Lehesjoki, Anna-Elina E.;Lemke, Johannes R.;Marini, Carla;Mei, Davide;Moller, Rikke S.;Pendziwiat, Manuela;Stamberger, Hannah;Suls, Arvid;Weckhuysen, Sarah;Koeleman, Bobby P. C.
通讯作者：
Koeleman, Bobby P. C.
影响因子：
9.8
作者：
Coban-Akdemir, Zeynep;White, Janson J.;Carvalho, Claudia M. B.
通讯作者：
Carvalho, Claudia M. B.
影响因子：
12.7
作者：
Cooper-Knock J;Higginbottom A;Stopford MJ;Highley JR;Ince PG;Wharton SB;Pickering-Brown S;Kirby J;Hautbergue GM;Shaw PJ
通讯作者：
Shaw PJ
影响因子：
30.8
作者：
Coe, Bradley P.;Stessman, Holly A. F.;Eichler, Evan E.
通讯作者：
Eichler, Evan E.
影响因子：
1.9
作者：
Caliebe, Almuth;Kroes, Hester Y.;Poot, Martin
通讯作者：
Poot, Martin