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持续存在症（hereditary persistence of fetal haemoglobin, HbF）相关的智力障碍综合征（intellectual disability syndrome, IDS），亦称迪亚斯-洛根综合征（Dias-Logan syndrome），其典型临床特征包括精神运动发育迟缓、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。散发病例中，曾有报道该综合征患者于婴儿期出现孤独症谱系障碍与蓝巩膜表现；罕见情况下，受累患者可伴发癫痫及癫痫综合征。研究证实，B细胞白血病/淋巴瘤11A基因（B cell leukaemia/lymphoma 11A gene, BCL11A）单倍体不足是该综合征的致病原因。本研究于1例确诊智力障碍综合征的男性患儿体内，检出BCL11A基因1个新发移码缺失突变（c.271delG; p.E91Afs*2）。值得注意的是，该杂合功能丧失型BCL11A突变同时与患儿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，是确诊迪亚斯-洛根综合征的必要手段。鉴于该患儿的癫痫可得到良好控制，我们建议将BCL11A基因纳入常规分子遗传学癫痫相关基因检测组（panel）。同时，智力障碍综合征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，因此我们亦建议对这类患者检测HbF水平，以进一步辅助临床诊断。