Supplementary Material for: A Novel de novo Frameshift Mutation in the BCL11A Gene in a Patient with Intellectual Disability Syndrome and Epilepsy

Intellectual disability syndrome (IDS) associated with a hereditary persistence of fetal haemoglobin (HbF), also known as Dias-Logan syndrome, is commonly characterised by psychomotor developmental delay, intelectual disability, language delay, strabismus, thin upper lip, abnormalities of external ears, microcephaly, downslanting palpebral fissures. Sporadically, autism spectrum disorders and blue sclerae in infancy have been reported in IDS. Rarely, IDS-affected patients present with epilepsy and/or epileptic syndromes. It has been shown that a haploinsufficiency of the B cell leukaemia/lymphoma 11A gene (BCL11A) is responsible for IDS. Herein, we identified a novel de novo frameshift deletion (c.271delG; p.E91Afs*2) in the BCL11A gene in a boy affected with IDS. Interestingly, this heterozygous loss-of-function BCL11A mutation was also associated with a generalised idiopathic epilepsy and severe language delay observed in the patient. Moreover, our study showed that the combination of molecular genetic analyses with the monitoring of HbF was essential to make the final diagnosis of Dias-Logan syndrome. Because our patient suffered from well-controlled epilepsy, we propose to include the BCL11A gene in routinely used molecular genetic epilepsy-related gene panels. Additionally, many of the clinical features of IDS overlap with symptoms observed in patients with suspected alcohol spectrum disorders. Therefore, we also suggest monitoring HbF levels in patients with these syndromes to further facilitate clinical diagnosis.

与遗传性胎儿血红蛋白（HbF）持续存在相关的智力障碍综合征（Intellectual disability syndrome, IDS），又称Dias-Logan综合征，其典型临床表现为精神运动发育迟缓、智力障碍、语言发育迟缓、斜视、上唇菲薄、外耳畸形、小头畸形及睑裂下斜。该综合征偶可伴发自闭症谱系障碍与婴儿期蓝巩膜；极少数情况下，IDS患者可出现癫痫及（或）癫痫综合征。现有研究证实，B细胞白血病/淋巴瘤11A基因（BCL11A）的单倍体不足是IDS的致病原因。本研究在一名IDS患儿的BCL11A基因中，检出一例全新的新发移码缺失突变（c.271delG; p.E91Afs*2）。值得注意的是，该杂合型功能丧失性BCL11A突变同时与患者的全面性特发性癫痫及重度语言发育迟缓相关。此外，本研究表明，联合分子遗传学分析与HbF水平监测，是确诊Dias-Logan综合征的必要手段。鉴于本研究纳入的患者癫痫病情控制良好，我们建议将BCL11A基因纳入临床常规使用的癫痫相关分子遗传学检测基因组合。另外，IDS的诸多临床特征与疑似酒精谱系障碍患者的症状存在重叠，因此我们建议对此类综合征患者开展HbF水平监测，以进一步辅助临床诊断。