McNeill Nathan, Nasca Alessia, Reyes Aurelio, Lemoine Benjamin, Cantarel Brandi, Vanderver Adeline, Schiffmann Raphael, Ghezzi Daniele
Baylor Research Institute (N.M., B.L., R.S.), Baylor Scott and White Health, Dallas, TX; Unit of Molecular Neurogenetics (A.N., D.G.), Foundation IRCCS Institute of Neurology "Besta," Milan, Italy; Mitochondrial Biology Unit (A.R.), Medical Research Council, Cambridge, United Kingdom; Department of Bioinformatics (B.C.), University of Texas Southwestern Medical Center, Dallas; and Department of Neurology (A.V.), George Washington University School of Medicine, Children's National Health, DC.
Neurol Genet. 2017 Jul 14;3(4):e162. doi: 10.1212/NXG.0000000000000162. eCollection 2017 Aug.
To investigate the genetic etiology of a patient diagnosed with leukoencephalopathy, brain calcifications, and cysts (LCC).
Whole-exome sequencing was performed on a patient with LCC and his unaffected family members. The variants were subject to in silico and in vitro functional testing to determine pathogenicity.
Whole-exome sequencing uncovered compound heterozygous mutations in , c.328G>A (p.G110S), and c.1045G>A (p.E349K). This gene has previously been implicated in the autosomal recessive leukoencephalopathy with thalamus and brainstem involvement and high lactate (LTBL). The p.G110S mutation has been found in multiple patients with LTBL. In silico analysis supported pathogenicity in the second variant. In vitro functional testing showed a significant mitochondrial dysfunction demonstrated by an ∼11% decrease in the oxygen consumption rate and ∼43% decrease in the maximum respiratory rate in the patient's skin fibroblasts compared with the control. EARS2 protein levels were reduced to 30% of normal controls in the patient's fibroblasts. These deficiencies were corrected by the expression of the wild-type EARS2 protein. However, a further unrelated genetic investigation of our patient revealed the presence of biallelic variants in a small nucleolar RNA () responsible for LCC.
Here, we report seemingly pathogenic mutations in a single patient with LCC with no biochemical or neuroimaging presentations of LTBL. This patient illustrates that variants with demonstrated impact on protein function should not necessarily be considered clinically relevant.
NCT00001671.
研究一名被诊断为白质脑病、脑钙化和囊肿（LCC）患者的遗传病因。
对一名LCC患者及其未受影响的家庭成员进行全外显子组测序。对这些变异进行计算机模拟和体外功能测试以确定其致病性。
全外显子组测序发现 基因存在复合杂合突变，即c.328G>A（p.G110S）和c.1045G>A（p.E349K）。该基因先前已被认为与伴有丘脑和脑干受累及高乳酸血症（LTBL）的常染色体隐性白质脑病有关。在多名LTBL患者中发现了p.G110S突变。计算机模拟分析支持第二个变异具有致病性。体外功能测试显示，与对照组相比，患者皮肤成纤维细胞的氧消耗率下降约11%，最大呼吸率下降约43%，表明存在明显的线粒体功能障碍。患者成纤维细胞中EARS2蛋白水平降至正常对照的30%。野生型EARS2蛋白的表达纠正了这些缺陷。然而，对我们患者进行的进一步无关基因研究发现，在一个负责LCC的小核仁RNA（ ）中存在双等位基因变异。
在此，我们报告了一名LCC患者中看似致病性的 突变，该患者无LTBL的生化或神经影像学表现。这名患者表明，对蛋白质功能有明确影响的变异不一定具有临床相关性。
NCT00001671。
