Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.
Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder.
复制标题
DOI：
10.1016/j.kint.2016.03.027
复制
发表时间：
2016-07
影响因子：
19.6
通讯作者：
Bingham C
中科院分区：
文献类型：
--
作者：
Clissold RL;Shaw-Smith C;Turnpenny P;Bunce B;Bockenhauer D;Kerecuk L;Waller S;Bowman P;Ford T;Ellard S;Hattersley AT;Bingham C
HNF1B基因杂合突变是已知的最常见的发育性肾脏疾病的单基因原因。一半的患者有染色体17q12的缺失(约1.3Mb)，包括HNF1B和14个额外的基因。这种17q12缺失与患神经发育障碍的风险增加有关，例如自闭症。在这里，我们比较了38例HNF1B相关性肾病患者的神经发育表型，其中18例是由于基因内突变，20例是由于17q12缺失，以确定HNF1B单倍体不足是否与神经发育表型有关。值得注意的是，在有缺失的儿童中进行简短的行为筛查显示，精神病理学及其影响水平很高。8名缺失个体(40%)有神经发育障碍的临床诊断，而没有基因内突变的个体。17q12缺失也与更多的自闭症特征有关。两位独立的临床遗传学家在评估面部畸形特征时，能够预测缺失的存在，敏感度为83%，特异度为79%。因此，17q12缺失而不是HNF1B基因内突变与神经发育障碍有关。因此，HNF1B基因与这些患者的神经发育表型无关。肾科医生需要意识到这种联系，以确保适当的转诊到精神科服务。
Heterozygous mutations of the HNF1B gene are the commonest known monogenic cause of developmental kidney disease. Half of patients have a deletion (approximately 1.3 Mb) of chromosome 17q12, encompassing HNF1B plus 14 additional genes. This 17q12 deletion has been linked with an increased risk of neurodevelopmental disorders, such as autism. Here we compared the neurodevelopmental phenotype of 38 patients with HNF1B-associated renal disease due to an intragenic mutation in 18 patients or due to 17q12 deletion in 20 patients to determine whether haploinsufficiency of HNF1B is responsible for the neurodevelopmental phenotype. Significantly, brief behavioral screening in children with the deletion showed high levels of psychopathology and its impact. Eight individuals (40%) with a deletion had a clinical diagnosis of a neurodevelopmental disorder compared to none with an intragenic mutation. The 17q12 deletions were also associated with more autistic traits. Two independent clinical geneticists were able to predict the presence of a deletion with a sensitivity of 83% and specificity of 79% when assessing facial dysmorphic features as a whole. Thus, the 17q12 deletions but not HNF1B intragenic mutations are associated with neurodevelopmental disorders. Hence, the HNF1B gene is not involved in the neurodevelopmental phenotype of these patients. Nephrologists need to be aware of this association to ensure appropriate referral to psychiatric services.