Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Unit on Vascular Malformations, Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
Sci Adv. 2023 Mar 10;9(10):eade1463. doi: 10.1126/sciadv.ade1463.
Pathogenic variants in , a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest ( = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in -related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems.
基因中的致病性变异与全身性发育迟缓、大头畸形、自闭症和先天异常有关（OMIM 617788）。鉴于这种疾病是最近才发现的，因此尚未得到充分的描述。迄今为止对最大的（=43）患者队列进行的深度表型分析表明，张力减退和先天性心脏缺陷是以前与该综合征无关的突出特征。错义变异和推定的功能丧失变异都会导致患者来源的细胞系生长缓慢。KMT5B 纯合敲除小鼠的体型小于其野生型同窝仔，但大脑没有明显变小，表明相对的大头畸形，这也是一个突出的临床特征。对患者淋巴母细胞和杂合不足的小鼠大脑进行 RNA 测序，确定了与神经系统发育和功能相关的差异表达途径，包括轴突导向信号。总的来说，我们在与 KMT5B 相关的神经发育障碍中发现了额外的致病性变异和临床特征，并使用多种模型系统深入了解该疾病的分子机制。
