Introduction

Pathogenic variants in SURF1, a nuclear-encoded gene encoding a mitochondrial chaperone involved in COX assembly, are one of the most common causes of Leigh syndrome (LS).

Material-methods

Sixteen patients diagnosed to have SURF1-related LS between 2012 and 2020 were included in the study. Their clinical, biochemical and molecular findings were recorded. 10/16 patients were diagnosed using whole-exome sequencing (WES), 4/16 by Sanger sequencing of SURF1, 1/16 via targeted exome sequencing and 1/16 patient with whole-genome sequencing (WGS). The pathogenicity of SURF1 variants was evaluated by phylogenetic studies and modelling on the 3D structure of the SURF1 protein.

Results

We identified 16 patients from 14 unrelated families who were either homozygous or compound heterozygous for SURF1 pathogenic variants. Nine different SURF1 variants were detected The c.769G > A was the most common variant with an allelic frequency of 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] were the other detected variants. Two pathogenic variants, C.595_597delGGA and c.356C > T, were detected for the first time. The c.769 G > A variant detected in 6 patients from 5 families was evaluated in terms of phenotype-genotype correlation. There was no definite genotype – phenotype correlation.

Conclusions

To date, more than 120 patients of LS with SURF1 pathogenic variants have been reported. We shared the clinical, molecular data and natural course of 16 new SURF1 defect patients from our country. This study is the first comprehensive research from Turkey that provides information about disease-causing variants in the SURF1 gene. The identification of common variants and phenotype of the SURF1 gene is important for understanding SURF1 related LS.

Synopsis

SURF1 gene defects are one of the most important causes of LS; patients have a homogeneous clinical and biochemical phenotype.

中文翻译：

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SURF1 相关 Leigh 综合征：来自土耳其的 16 名患者的临床和分子发现

介绍

SURF1中的致病变异是一种核编码基因，编码参与 COX 组装的线粒体伴侣，是 Leigh 综合征 (LS) 的最常见原因之一。

材料方法

该研究包括16 名在 2012 年至 2020 年间被诊断患有SURF1相关 LS 的患者。记录了他们的临床、生化和分子发现。10/16 名患者使用全外显子组测序 (WES) 进行诊断，4/16 名患者通过SURF1的 Sanger 测序进行诊断，1/16 名患者通过靶向外显子组测序进行诊断，1/16 名患者使用全基因组测序 (WGS) 进行诊断。通过系统发育研究和对 SURF1 蛋白 3D 结构的建模来评估SURF1变体的致病性。

结果

我们确定了来自 14 个无关家庭的 16 名患者，这些家庭是纯合子或复合杂合子的SURF1致病变异。九种不同的SURF1检测到变体 c.769G > A 是最常见的变体，等位基因频率为 42.8% (12/28), c.870dupT [(p.Lys291*); (8/28 28.5%)], c.169delG [(p.Glu57Lysfs*15), (2/24; 7.1%)], c.532 T > A [(p.Tyr178Asn); (2/28, 7.1%)], c.653_654delCT [(p.Pro218Argfs*29); (4/28, 14.2%)] c.595_597delGGA [(p.Gly199del); (1/28, 3.5%)], c.751 + 1G > A (2/28, 4.1%), c.356C > T [(p.Pro119Leu); (2/28, 3.5%)] 是其他检测到的变体。首次检测到两个致病变异C.595_597delGGA和c.356C > T。在表型-基因型相关性方面评估了在来自 5 个家庭的 6 名患者中检测到的 c.769 G > A 变体。没有明确的基因型-表型相关性。

结论

迄今为止，已经报道了 120 多名具有SURF1致病变异的 LS 患者。我们分享了来自我国的 16 名新的 SURF1 缺陷患者的临床、分子数据和自然病程。这项研究是土耳其首次提供有关SURF1基因致病变异信息的综合研究。鉴定SURF1基因的常见变体和表型对于了解 SURF1 相关的 LS 很重要。

概要

SURF1基因缺陷是LS最重要的原因之一；患者具有同质的临床和生化表型。