线粒体蛋白质合成需要三种延伸因子,包括EF-Tu(TUFM;OMIM602389),EF-Ts(TSFM;OMIM604723),和EF-G1(GFM1;OMIM606639)。这三个成员中的任一个中的致病变体导致线粒体翻译缺陷,其可赋予氧化磷酸化(OXPHOS)缺陷。在这项研究中,我们调查了一个有血缘关系的巴基斯坦Pakhtun家庭.在这项研究时,有四个受影响的兄弟姐妹,一个受影响的女孩在婴儿期死亡。该指标患者有严重的智力障碍,全球发育迟缓,肌张力障碍,没有言语发展,喂养困难,和眼球震颤.MRI脑部显示call体变薄和多微回旋。全外显子组测序揭示了位于染色体3q25.32上的GFM1中的新型复合杂合变体。Sanger测序证实了所有四个受影响的兄弟姐妹中母体(NM_001308164.1:c.409G>A;p.Val137Met)和父系(NM_001308164.1:c.1880G>A;p.Arg627Gln)变体的隐性分离。根据ACMG/AMP指南的建议,这些变异被归类为“可能致病”。GFM1改变主要导致严重的表型,患者可能在新生儿早期死亡;然而,四个受影响的兄弟姐妹一直存活到10-17岁,没有发展任何危及生命的条件。大多数情况下,在堂兄婚姻中,致病变异是相同的血统,这些父母所生的受影响的兄弟姐妹是纯合子。在WES数据分析中入围了三个纯合变体,但是Sanger测序没有证实它们与疾病表型的分离。这是巴基斯坦首例扩大致病性GFM1基因的报导。
Mitochondrial protein synthesis requires three elongation factors including EF-Tu (TUFM; OMIM 602389), EF-Ts (TSFM; OMIM 604723), and EF-G1 (GFM1; OMIM 606639). Pathogenic variants in any of these three members result in defective mitochondrial translation which can impart an oxidative phosphorylation (OXPHOS) deficiency. In this study, we investigated a consanguineous Pakhtun Pakistani family. There were four affected siblings at the time of this study and one affected girl had died in infancy. The index patient had severe intellectual disability, global developmental delay, dystonia, no speech development, feeding difficulties, and nystagmus. MRI brain presented thinning of corpus callosum and polymicrogyria. Whole exome sequencing revealed a novel compound heterozygous variant in GFM1 located on chromosome 3q25.32. Sanger sequencing confirmed recessive segregation of the maternal (NM_001308164.1:c.409G > A; p.Val137Met) and paternal (NM_001308164.1:c.1880G > A; p.Arg627Gln) variants in all the four affected siblings. These variants are classified as \"likely-pathogenic\" according to the recommendation of ACMG/AMP guideline. GFM1 alterations mostly lead to severe phenotypes and the patients may die in early neonatal life; however, four of the affected siblings had survived till the ages of 10-17 years, without developing any life-threatening conditions. Mostly, in cousin marriages, the pathogenic variants are identical-by-descent, and affected siblings born to such parents are homozygous. Three homozygous variants were shortlisted in the analysis of the WES data, but Sanger sequencing did not confirm their segregation with the disease phenotype. This is the first report from Pakistan expanding pathogenicity of GFM1 gene.