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Chiari 1 malformation and exome sequencing in 51 trios: the emerging role of rare missense variants in chromatin-remodeling genes
Human Genetics ( IF 5.3 ) Pub Date : 2020-12-18 , DOI: 10.1007/s00439-020-02231-6
Aldesia Provenzano , Andrea La Barbera , Mirko Scagnet , Angelica Pagliazzi , Giovanna Traficante , Marilena Pantaleo , Lucia Tiberi , Debora Vergani , Nehir Edibe Kurtas , Silvia Guarducci , Sara Bargiacchi , Giulia Forzano , Rosangela Artuso , Viviana Palazzo , Ada Kura , Flavio Giordano , Daniele di Feo , Marzia Mortilla , Claudio De Filippi , Gianluca Mattei , Livia Garavelli , Betti Giusti , Lorenzo Genitori , Orsetta Zuffardi , Sabrina Giglio

Type 1 Chiari malformation (C1M) is characterized by cerebellar tonsillar herniation of 3–5 mm or more, the frequency of which is presumably much higher than one in 1000 births, as previously believed. Its etiology remains undefined, although a genetic basis is strongly supported by C1M presence in numerous genetic syndromes associated with different genes. Whole-exome sequencing (WES) in 51 between isolated and syndromic pediatric cases and their relatives was performed after confirmation of the defect by brain magnetic resonance image (MRI). Moreover, in all the cases showing an inherited candidate variant, brain MRI was performed in both parents and not only in the carrier one to investigate whether the defect segregated with the variant. More than half of the variants were Missense and belonged to the same chromatin-remodeling genes whose protein truncation variants are associated with severe neurodevelopmental syndromes. In the remaining cases, variants have been detected in genes with a role in cranial bone sutures, microcephaly, neural tube defects, and RASopathy. This study shows that the frequency of C1M is widely underestimated, in fact many of the variants, in particular those in the chromatin-remodeling genes, were inherited from a parent with C1M, either asymptomatic or with mild symptoms. In addition, C1M is a Mendelian trait, in most cases inherited as dominant. Finally, we demonstrate that modifications of the genes that regulate chromatin architecture can cause localized anatomical alterations, with symptoms of varying degrees.



中文翻译:

Chiari 1畸形和51个三重奏的外显子组测序:罕见的错义变体在染色质重塑基因中的新兴作用

1型Chiari畸形(C1M)的特征是小脑扁桃体突出3至5毫米或更多,其频率据认为比每千名出生的婴儿高出一倍。尽管有许多与不同基因相关的遗传综合症中C1M的存在为遗传基础提供了强有力的支持,但其病因仍未确定。在通过脑磁共振图像(MRI)确认缺陷后,对51例分离的和有症状的小儿病例及其亲属之间的全外显子测序(WES)进行了分析。此外,在所有显示出遗传候选变异的情况下,不仅在携带者中,而且在父母双方中都进行了脑部MRI检查,以研究缺陷是否与变异分离。超过一半的变体是Missense,属于相同的染色质重塑基因,其蛋白截短变体与严重的神经发育综合征相关。在其余情况下,已检测到与颅骨缝线,小头畸形,神经管缺损和RAS病有关的基因变异。这项研究表明,C1M的频率被低估了,实际上,许多变体,尤其是染色质重塑基因中的变体,都是从无症状或症状轻微的C1M父母那里遗传而来的。此外,C1M是孟德尔性状,在大多数情况下是遗传的。最后,我们证明调节染色质结构的基因的修饰可引起局部解剖改变,症状程度不同。

更新日期:2020-12-18
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