Abstract：
PIK3CA-related overgrowth spectrum (PROS) is an umbrella term to describe a diverse range of developmental disorders. Research to date has predominantly emerged from Europe and North America, resulting in a notable scarcity of studies focusing on East Asian populations. Currently, the prevalence and distribution of PIK3CA variants across various genetic loci and their correlation with distinct phenotypes in East Asian populations remain unclear. This study aims to elucidate the phenotype-genotype correlations of PROS in East Asian populations. We presented the phenotypes and genotypes of 82 Chinese patients. Among our cohort, 67 individuals carried PIK3CA variants, including missense, frameshift, and splice variants. Six patients presented with both PIK3CA and an additional variant. Seven PIK3CA-negative patients exhibited overlapping PROS manifestations with variants in GNAQ, AKT1, PTEN, MAP3K3, GNA11, or KRAS. An integrative review of the literature pertaining to East Asian populations revealed that specific variants are uniquely associated with certain PROS phenotypes. Some rare variants were exclusively identified in cases of megalencephaly and diffuse capillary malformation with overgrowth. Non-hotspot variants with undefined oncogenicity were more common in CNS phenotypes. Diseases with vascular malformation were more likely to have variants in the helical domain, whereas phenotypes involving adipose/muscle overgrowth without vascular abnormalities predominantly presented variants in the C2 domain. Our findings underscore the unique phenotype-genotype patterns within the East Asian PROS population, highlighting the necessity for an expanded cohort to further elucidate these correlations. Such endeavors would significantly facilitate the development of PI3Kα selective inhibitors tailored for the East Asian population in the future.
摘要：
PIK3CA相关的过度生长谱（PROS）是一个总称，用于描述各种发育障碍。迄今为止，研究主要来自欧洲和北美，导致针对东亚人群的研究明显缺乏。目前,在东亚人群中,PIK3CA变异在不同遗传基因座中的患病率和分布及其与不同表型的相关性尚不清楚.本研究旨在阐明东亚人群中PROS的表型-基因型相关性。我们介绍了82例中国患者的表型和基因型。在我们的队列中，67个人携带PIK3CA变体，包括错觉,移码,和剪接变体。六名患者同时出现PIK3CA和另一个变体。7名PIK3CA阴性患者表现出重叠的PROS表现与GNAQ变异，AKT1、PTEN、MAP3K3、GNA11或KRAS。对有关东亚人群的文献的综合综述显示，特定变体与某些PROS表型独特相关。在巨脑症和弥漫性毛细血管畸形过度生长的情况下，仅发现了一些罕见的变异。具有不确定致癌性的非热点变体在CNS表型中更常见。血管畸形的疾病更有可能在螺旋域有变异，而涉及脂肪/肌肉过度生长而无血管异常的表型主要在C2结构域呈现变异。我们的发现强调了东亚PROS人群中独特的表型-基因型模式，强调扩大队列以进一步阐明这些相关性的必要性。这些努力将大大促进未来针对东亚人群定制的PI3Kα选择性抑制剂的开发。
