Interpreting rare variants remains a challenge in personal genomics, especially for disorders with several causal genes and for genes that cause multiple disorders. ZNF423 encodes a transcriptional regulatory protein that intersects several developmental pathways. ZNF423 has been implicated in rare neurodevelopmental disorders, consistent with midline brain defects in Zfp423-mutant mice, but pathogenic potential of most patient variants remains uncertain. We engineered ~50 patient-derived and small deletion variants into the highly-conserved mouse ortholog and examined neuroanatomical measures for 791 littermate pairs. Three substitutions previously asserted pathogenic appeared benign, while a fourth was effectively null. Heterozygous premature termination codon (PTC) variants showed mild haploabnormality, consistent with loss-of-function intolerance inferred from human population data. In-frame deletions of specific zinc fingers showed mild to moderate abnormalities, as did low-expression variants. These results affirm the need for functional validation of rare variants in biological context and demonstrate cost-effective modeling of neuroanatomical abnormalities in mice.

解释罕见变异仍然是个人基因组学中的一个挑战，特别是对于具有多个致病基因的疾病和导致多种疾病的基因。 ZNF423编码一种与多个发育途径相交叉的转录调节蛋白。 ZNF423与罕见的神经发育障碍有关，与Zfp423突变小鼠的中线脑缺陷一致，但大多数患者变异的致病潜力仍不确定。我们将约 50 个源自患者的小缺失变体设计到高度保守的小鼠直向同源物中，并检查了 791 对同窝小鼠的神经解剖学测量。先前断言致病的三个替代似乎是良性的，而第四个实际上是无效的。杂合的提前终止密码子（PTC）变异表现出轻度的单倍体异常，与从人群数据推断的功能丧失不耐受一致。特定锌指的框内缺失显示出轻度至中度异常，低表达变体也是如此。这些结果证实了在生物学背景下对罕见变异进行功能验证的必要性，并证明了小鼠神经解剖异常的经济有效的建模。