Abstract：
Due to the majority of currently available genome data deriving from individuals of European ancestry, the clinical interpretation of genomic variants in individuals from diverse ethnic backgrounds remains a major diagnostic challenge. Here, we investigated the genetic cause of a complex neurodevelopmental phenotype in two Palestinian siblings. Whole exome sequencing identified a homozygous missense TECPR2 variant (Chr14(GRCh38):g.102425085G>A; NM_014844.5:c.745G>A, p.(Gly249Arg)) absent in gnomAD, segregating appropriately with the inheritance pattern in the family. Variant assessment with in silico pathogenicity prediction and protein modeling tools alongside population database frequencies led to classification as a variant of uncertain significance. As pathogenic TECPR2 variants are associated with hereditary sensory and autonomic neuropathy with intellectual disability, we reviewed previously published candidate TECPR2 missense variants to clarify clinical outcomes and variant classification using current approved guidelines, classifying a number of published variants as of uncertain significance. This work highlights genomic healthcare inequalities and the challenges in interpreting rare genetic variants in populations underrepresented in genomic databases. It also improves understanding of the clinical and genetic spectrum of TECPR2-related neuropathy and contributes to addressing genomic data disparity and inequalities of the genomic architecture in Palestinian populations.
摘要：
由于目前大多数可用的基因组数据来自欧洲血统的个体，来自不同种族背景的个体的基因组变异的临床解释仍然是一个主要的诊断挑战.这里,我们调查了两个巴勒斯坦兄弟姐妹中复杂神经发育表型的遗传原因。全外显子组测序确定了纯合错义TECPR2变体（Chr14（GRCh38）：g.102425085G>A；NM_014844.5：c.745G>A，p。（Gly249Arg））在gnomAD中缺失，与家庭中的继承模式适当地分离。使用计算机致病性预测和蛋白质建模工具以及种群数据库频率的变体评估导致分类为不确定意义的变体。由于致病性TECPR2变体与智力障碍的遗传性感觉和自主神经病变有关，我们回顾了先前发表的候选TECPR2错义变异,以使用当前批准的指南阐明临床结果和变异分类,将许多已发表的变体分类为不确定的意义。这项工作强调了基因组医疗保健的不平等以及在基因组数据库中代表性不足的人群中解释罕见遗传变异的挑战。它还提高了对TECPR2相关神经病的临床和遗传谱的理解，并有助于解决巴勒斯坦人群基因组数据差异和基因组结构不平等。
