Supplementary Material for: Clinical and Molecular Heterogeneity in Brazilian Patients with Sotos Syndrome

Sotos syndrome (SoS) is a multiple anomaly, congenital disorder characterized by overgrowth, macrocephaly, distinctive facial features and variable degree of intellectual disability. Haploinsufficiency of the <i>NSD1</i> gene at 5q35.3, arising from 5q35 microdeletions, point mutations, and partial gene deletions, accounts for a majority of patients with SoS. Recently, mutations and possible pathogenetic rare CNVs, both affecting a few candidate genes for overgrowth, have been reported in patients with Sotos-like overgrowth features. To estimate the frequency of <i>NSD1</i> defects in the Brazilian SoS population and possibly reveal other genes implicated in the etiopathogenesis of this syndrome, we collected a cohort of 21 Brazilian patients, who fulfilled the diagnostic criteria for SoS, and analyzed the <i>NSD1</i> and <i>PTEN</i> genes by means of multiplex ligation-dependent probe amplification and mutational screening analyses. We identified a classical <i>NSD1</i> microdeletion, a novel missense mutation (p.C1593W), and 2 previously reported truncating mutations: p.R1984X and p.V1760Gfs*2. In addition, we identified a novel de novo <i>PTEN</i> gene mutation (p.D312Rfs*2) in a patient with a less severe presentation of SoS phenotype, which did not include pre- and postnatal overgrowth. For the first time, our study implies <i>PTEN</i> in the pathogenesis of SoS and further emphasizes the existence of ethno-geographical differences in <i>NSD1</i> molecular alterations between patients with SoS from Europe/North America (70-93%) and those from South America (10-19%).

索托斯综合征（Sotos syndrome，SoS）是一类以过度生长、巨头畸形、特征性面部体征以及程度不等的智力障碍为特征的多发畸形性先天性疾病。位于5q35.3区域的NSD1基因发生单倍体剂量不足，该情况由5q35微缺失、点突变及部分基因缺失引发，是多数SoS患者的致病分子机制。近期，有研究在表现出类索托斯过度生长表型的患者中，报道了两类致病相关变异：一类可影响数个过度生长相关候选基因的突变，另一类为可能具有致病性的罕见拷贝数变异（Copy Number Variants，CNVs）。为评估巴西索托斯综合征人群中NSD1基因缺陷的发生频率，并潜在揭示该综合征发病机制中涉及的其他致病基因，本研究纳入21名符合索托斯综合征诊断标准的巴西患者队列，通过多重连接依赖性探针扩增（multiplex ligation-dependent probe amplification，MLPA）与突变筛查分析，对NSD1及PTEN基因开展了检测。本研究检出1例经典的NSD1微缺失、1例新发错义突变（p.C1593W），以及2例既往已报道的截短突变：p.R1984X与p.V1760Gfs*2。此外，我们在1例表型较轻的索托斯综合征患者中检出1例新发的PTEN基因从头突变（p.D312Rfs*2），该患者无产前及产后过度生长表现。本研究首次将PTEN基因关联至索托斯综合征的发病机制，并进一步证实了欧洲/北美索托斯综合征患者（NSD1分子改变发生率为70%~93%）与南美索托斯综合征患者（10%~19%）之间存在的族裔地理分子差异。