13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.

中文翻译：

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杂合 HMGB1 功能丧失变异与发育迟缓和小头畸形有关

13q12.3 微缺失综合征是综合征性智力障碍的罕见原因。13q12.3 微缺失综合征患者的鉴定和遗传特征继续扩大与其相关的表型谱。先前的研究确定了大约 300 Kb 最小关键区域内的四个基因，包括两个候选蛋白质编码基因：KATNAL1和HMGB1。迄今为止，尚未描述在HMGB1或KATNAL1中携带序列水平变异或单个基因缺失的患者。在这里，我们报告了 6 名患有HMGB1功能丧失变异的患者并且具有与先前描述的 13q12.3 微缺失综合征病例相似的表型特征。共同特征包括发育迟缓、语言迟缓、小头畸形、肥胖和畸形特征。计算机分析表明HMGB1可能对功能丧失不耐受，之前的体外数据与HMGB1在神经发育中的作用一致。这些结果强烈表明HMGB1基因的单倍体不足可能在 13q12.3 微缺失综合征的发病机制中起关键作用。