Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies
Mutations in NCAPG2 Cause a Severe Neurodevelopmental Syndrome that Expands the Phenotypic Spectrum of Condensinopathies
复制标题
DOI：
10.1016/j.ajhg.2018.11.017
复制
发表时间：
2019-01-03
影响因子：
9.8
通讯作者：
Katsanis, Nicholas
中科院分区：
文献类型：
--
作者：
Khan, Tahir N.;Khan, Kamal;Katsanis, Nicholas
全外显子组和全基因组测序的使用已经成为基因优先的诊断方法的催化剂。在这一模式下，我们对疑似遗传性疾病的新生儿和幼儿进行了系统的测序。在这里，我们报告了两个NCAPG2隐性突变和重叠的临床表型，包括严重的神经发育缺陷，发育不良，眼睛异常，以及泌尿生殖和肢体形态发育缺陷。NCAPG2编码凝聚素II复合体的一个成员，这是细胞分裂前染色体凝聚所必需的。与NCAPG2的因果作用一致，我们在先证者和皮肤成纤维细胞的子代细胞中发现了异常的染色体凝集、后期染色质桥形成和微核。为了测试发现的变体的功能相关性，我们生成了一个ncapg2斑马鱼模型。形态表现为临床相关的表型，如肾脏异常、小头畸形、伴随的细胞凋亡增加和有丝分裂进程改变。这些基因可被野生型但不能被突变型人NCAPG2mRNA拯救，并在CRISPR-Cas9F0突变体中重现。最后，我们注意到，患有复杂泌尿生殖系统缺陷的个体也存在杂合性NPHP1缺失，这是导致肾炎的常见因素。为了测试NPHP1基因的敏化是否可能导致更严重的肾脏表型，我们共同抑制了nphp1和ncapg2，这导致斑马鱼幼体肾小管发育不良的显著增加。综上所述，我们的数据表明NCAPG2的功能受损会导致严重的凝集性病变，这些数据突显了在原发疾病部位以外检查候选致病病变的潜在效用。
The use of whole-exome and whole-genome sequencing has been a catalyst for a genotype-first approach to diagnostics. Under this paradigm, we have implemented systematic sequencing of neonates and young children with a suspected genetic disorder. Here, we report on two families with recessive mutations in NCAPG2 and overlapping clinical phenotypes that include severe neurodevelopmental defects, failure to thrive, ocular abnormalities, and defects in urogenital and limb morphogenesis. NCAPG2 encodes a member of the condensin II complex, necessary for the condensation of chromosomes prior to cell division. Consistent with a causal role for NCAPG2, we found abnormal chromosome condensation, augmented anaphase chromatin-bridge formation, and micronuclei in daughter cells of proband skin fibroblasts. To test the functional relevance of the discovered variants, we generated an ncapg2 zebrafish model. Morphants displayed clinically relevant phenotypes, such as renal anomalies, microcephaly, and concomitant increases in apoptosis and altered mitotic progression. These could be rescued by wild-type but not mutant human NCAPG2 mRNA and were recapitulated in CRISPR-Cas9 F0 mutants. Finally, we noted that the individual with a complex urogenital defect also harbored a heterozygous NPHP1 deletion, a common contributor to nephronophthisis. To test whether sensitization at the NPHP1 locus might contribute to a more severe renal phenotype, we co-suppressed nphp1 and ncapg2, which resulted in significantly more dysplastic renal tubules in zebrafish larvae. Together, our data suggest that impaired function of NCAPG2 results in a severe condensinopathy, and they highlight the potential utility of examining candidate pathogenic lesions beyond the primary disease locus.