BACKGROUND In the last two decades, with the advent of whole-exome and whole-genome sequencing, supplemented with linkage analysis, more than 150 genes responsible for X-linked intellectual disability have been identified. Some genes like NEXMIF remain an enigmatic entity, as often the carrier females show wide phenotypic diversity ranging from completely asymptomatic to severe intellectual disability and drug-resistant epilepsy. METHODS We report three patients with pathogenic NEXMIF variants from an Indian family. All of them had language predominant developmental delay and later progressed to moderate intellectual disability with autistic features. We also reviewed the previously published reports of patients with pathogenic NEXMIF variants. RESULTS Together with the presented cases, 45 cases (24 symptomatic females) were identified from 15 relevant research items for analysis. Males have demonstrated a more severe intellectual disability and increasingly delayed walking age, autistic features, central hypotonia, and gastroesophageal reflux. In contrast, females have shown a predominant presentation with drug-resistant epilepsy and mild to moderate intellectual impairment. Notably, the affected females demonstrate a higher incidence of myoclonic, absence, and atonic seizures. The majority of the variants reported are nonsense or frameshift mutations, causing loss of function of the NEXMIF gene, while a considerable proportion possesses chromosomal translocations, microdeletions, and duplications. CONCLUSIONS NEXMIF gene mutations should be suspected in all cases of X-linked ID and autism cases in males or even in refractory epilepsy cases in females.

中文翻译：

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男性和女性 KIAA2022/NEXMIF 致病变异的临床谱：来自印度亲属的三名患者的报告以及对已发表患者的回顾

背景在过去的二十年中，随着全外显子组和全基因组测序的出现，并辅以连锁分析，已经确定了150多个与X连锁智力障碍有关的基因。一些基因如 NEXMIF 仍然是一个神秘的实体，因为携带者女性通常表现出广泛的表型多样性，从完全无症状到严重的智力障碍和耐药性癫痫。方法我们报告了来自印度家庭的三名具有致病性 NEXMIF 变异的患者。他们都以语言为主的发育迟缓，后来发展为具有自闭症特征的中度智力障碍。我们还审查了先前发表的有关具有致病性 NEXMIF 变异的患者的报告。结果 连同所呈现的案例，从15个相关研究项目中确定45例（24名有症状女性）进行分析。男性表现出更严重的智力障碍和越来越多的步行年龄延迟、自闭症特征、中枢性张力减退和胃食管反流。相比之下，女性以耐药性癫痫和轻度至中度智力障碍为主要表现。值得注意的是，受影响的女性表现出较高的肌阵挛、失神和张力性癫痫发作的发生率。报告的大多数变异是无义或移码突变，导致 NEXMIF 基因功能丧失，而相当一部分具有染色体易位、微缺失和重复。