Novel KMT2B mutation causes cerebellar ataxia: Expanding the clinical phenotype,Clinical Genetics

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Novel KMT2B mutation causes cerebellar ataxia: Expanding the clinical phenotype
Clinical Genetics ( IF 2.9 ) Pub Date : 2021-09-03 , DOI: 10.1111/cge.14055
Joana Damásio _{1,

2,

3} , Mariana Santos ₂ , Raquel Samões ₁ , Maria Araújo ₄ , Mafalda Macedo ₄ , Ana Sardoeira ₁ , Sara Cavaco ₅ , Joel Freitas ₆ , José Barros _{1,

7} , Jorge Oliveira _{2,

3} , Jorge Sequeiros _{2,

3,

7}

Affiliation

Hereditary cerebellar ataxias comprise a heterogeneous group of neurodegenerative disorders affecting the cerebellum and/or cerebellar pathways. Next-generation sequencing techniques have contributed substantially to the expansion of ataxia-causing genes, including genes classically described in alternative phenotypes. Herein, we describe a patient with adult-onset cerebellar ataxia, minor dystonia, neuropathy, seizure and ophthalmological pathology, who bears a novel variant in KMT2B (NM_014727.2:c.3334 + 1G > A). Bioinformatic analysis suggested this variant completely abolished the splice-site at exon 8/intron 8, which was confirmed through analysis of mRNA extracted from fibroblasts. Exon 8 skipping would ultimately translate as an in-frame deletion at the protein level, corresponding to the loss of 91 aminoacids [p.(Gly1020_Asn1111del)]. So far, KMT2B disease causing variants have been described in patients with dystonia or neurodevelopmental delay, with no reports of a cerebellar predominant phenotype. Our findings highlight the possible role of KMT2B as a gene involved in hereditary cerebellar ataxias.

中文翻译：

新型 KMT2B 突变导致小脑共济失调：扩大临床表型

遗传性小脑共济失调包括影响小脑和/或小脑通路的一组异质性神经退行性疾病。下一代测序技术极大地促进了导致共济失调的基因的扩展，包括在替代表型中经典描述的基因。在此，我们描述了一名患有成人发作性小脑共济失调、轻微肌张力障碍、神经病变、癫痫发作和眼科病理学的患者，该患者携带KMT2B的新变体(NM_014727.2:c.3334 + 1G > A)。生物信息学分析表明，这种变体完全消除了外显子 8/内含子 8 的剪接位点，这通过分析从成纤维细胞中提取的 mRNA 得到了证实。外显子 8 跳跃最终会转化为蛋白质水平的框内缺失，对应于 91 个氨基酸的丢失 [p.(Gly1020_Asn1111del)]。到目前为止，已经在肌张力障碍或神经发育迟缓的患者中描述了导致KMT2B疾病的变异，没有关于小脑主要表型的报道。我们的研究结果强调了KMT2B作为参与遗传性小脑共济失调的基因的可能作用。

更新日期：2021-11-03

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