Supplementary Material for: A TMEM260 biallelic deletion underlies truncus arteriosus

Introduction: Truncus arteriosus (TA) is a life-threatening cardiovascular anomaly involving a ventricular septal defect and a common ventricular outflow tract. Recently, biallelic variants in TMEM260 have been identified as causative for Structural Heart Defects and Renal Anomalies syndrome (SHDRA, MIM 617478), which includes TA. Approximately 30 patients with SHDRA have been reported, but the genotype–phenotype correlation remains unclear. Founder variants have been identified in patients of East Asian and Ashkenazi Jewish ancestry. Case Presentation: The male infant, the third child of unrelated Japanese parents, was prenatally diagnosed with TA via detailed ultrasound examination. His older sister also had TA and died at 20 days of age. Despite intensive cardiorespiratory care, the patient passed away at 53 days due to heart failure. Genetic analysis identified a homozygous deletion of TMEM260 exons 6 and 7, resulting from a 7066 bp deletion with a 1 bp insertion, inherited from heterozygous parents. This deletion is included in the structural variation dataset with an allele frequency of 0.00173 (29/8380) in ToMMo 8.3K JPN-SV. Discussion: This is the first familial TA caused by a biallelic structural variation in TMEM260. The 7066-bp deletion shows a high allele frequency in the Japanese population. These findings support the idea that this TMEM260 deletion may be a significant cause of TA and should therefore be considered alongside the previously known c.1617del variant as a potential causative factor.

引言：永存动脉干（Truncus arteriosus, TA）是一种危及生命的心血管畸形，伴有室间隔缺损与共同心室流出道。近期研究证实，TMEM260基因的双等位基因变异可引发结构性心脏缺陷与肾脏异常综合征（Structural Heart Defects and Renal Anomalies syndrome, SHDRA, MIM 617478），TA即为该综合征的表型之一。目前全球已报道约30例SHDRA患者，但该疾病的基因型-表型关联仍未明确。在东亚及德系犹太裔人群的患者中已检出该综合征的奠基者变异。

病例报告：本次研究的男性患儿为非血缘日本籍夫妇的第三胎，经详细超声检查产前确诊为TA。其长姐同样罹患TA，并于出生后20天夭折。尽管接受了心肺重症监护治疗，该患儿仍因心力衰竭于出生后53天死亡。基因分析显示，患儿携带TMEM260基因第6、7号外显子的纯合缺失，该变异由一段7066bp的片段缺失伴1bp插入所导致，其父母均为该变异的杂合携带者。此缺失变异已被纳入结构变异数据集，在ToMMo 8.3K JPN-SV队列中的等位基因频率为0.00173（29/8380）。

讨论：本研究首次报道了由TMEM260基因双等位基因结构变异引发的家族性TA。该7066bp缺失变异在日本人群中具有较高的等位基因频率。上述研究结果支持该TMEM260缺失变异可能是TA的重要致病因素，应与此前已知的c.1617del变异一同作为TA的潜在致病因子纳入筛查范畴。