MORC2 encodes an ATPase that plays a role in chromatin remodeling, DNA repair, and transcriptional regulation. Heterozygous variants in MORC2 have been reported in individuals with autosomal-dominant Charcot-Marie-Tooth disease type 2Z and spinal muscular atrophy, and the onset of symptoms ranges from infancy to the second decade of life. Here, we present a cohort of 20 individuals referred for exome sequencing who harbor pathogenic variants in the ATPase module of MORC2. Individuals presented with a similar phenotype consisting of developmental delay, intellectual disability, growth retardation, microcephaly, and variable craniofacial dysmorphism. Weakness, hyporeflexia, and electrophysiologic abnormalities suggestive of neuropathy were frequently observed but were not the predominant feature. Five of 18 individuals for whom brain imaging was available had lesions reminiscent of those observed in Leigh syndrome, and five of six individuals who had dilated eye exams had retinal pigmentary abnormalities. Functional assays revealed that these MORC2 variants result in hyperactivation of epigenetic silencing by the HUSH complex, supporting their pathogenicity. The described set of morphological, growth, developmental, and neurological findings and medical concerns expands the spectrum of genetic disorders resulting from pathogenic variants in MORC2.

MORC2编码一种 ATP 酶，在染色质重塑、DNA 修复和转录调控中发挥作用。在常染色体显性 Charcot-Marie-Tooth 病 2Z 型和脊髓性肌萎缩的个体中报告了MORC2 中的杂合变异，症状的发作范围从婴儿期到生命的第二个十年。在这里，我们展示了一个由 20 个人组成的队列，这些人在MORC2的 ATPase 模块中具有致病性变异。. 个体表现出类似的表型，包括发育迟缓、智力障碍、生长迟缓、小头畸形和可变颅面畸形。经常观察到提示神经病变的虚弱、反射减弱和电生理异常，但不是主要特征。18 名可进行脑成像的人中有 5 人的病变让人联想到 Leigh 综合征中观察到的病变，6 名散瞳检查的人中有 5 人有视网膜色素异常。功能分析表明，这些MORC2变异导致 HUSH 复合体表观遗传沉默的过度激活，支持其致病性。所描述的一组形态学、生长、发育和神经学发现以及医学问题扩大了由MORC2 中的致病变异引起的遗传疾病的范围。