Abstract：
POLE is a pleiotropic gene with phenotypic expression of pathogenic variants depending on the type of variant, impact on the protein, and mode of inheritance. Heterozygous missense variants located within the exonuclease domain have been shown to result in polymerase proofreading-associated polyposis (PPAP) which is characterized by an increased risk for colon polyps and colorectal cancer. Biallelic variants resulting in markedly reduced amounts of normal protein have been reported in two separate recessive pediatric syndromes: facial dysmorphism, immunodeficiency, livedo, and short stature as well as intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenital, and genital anomalies. Here we report two siblings identified to have POLE c.1686 + 32C > G in trans with POLE p.(Glu709*) via exome sequencing. A detailed review of the reported phenotypes in these two siblings and from available literature revealed that individuals with biallelic POLE pathogenic variants resulting in partial loss-of-function present with a similar phenotype: short stature and facial dysmorphism with or without immunodeficiency. These data suggest a phenotypic continuum between the previously reported POLE-related recessive disorders.
摘要：
POLE是一种多效性基因，其致病变异的表型表达取决于变异的类型，对蛋白质的影响，和继承模式。已显示位于外切核酸酶结构域内的杂合错义变体导致聚合酶校对相关息肉病(PPAP),其特征在于结肠息肉和结肠直肠癌的风险增加。在两个单独的隐性儿科综合征中，已经报道了导致正常蛋白质含量显着减少的双等位基因变异：面部畸形，免疫缺陷,Livedo,身材矮小以及宫内生长受限，干phy端发育不良,先天性肾上腺发育不全,和生殖器异常。在这里，我们报告了两个兄弟姐妹，通过外显子组测序鉴定为反式POLEc.1686+32C>G，POLEp。（Glu709*）。对这两个兄弟姐妹中报道的表型和现有文献的详细综述表明，具有双等位基因POLE致病变体的个体导致部分功能丧失，具有相似的表型：身材矮小和面部畸形，有或没有免疫缺陷。这些数据表明先前报道的POLE相关隐性疾病之间存在表型连续性。
