Despite the wide use of genomics to investigate the molecular basis of rare congenital malformations, a significant fraction of patients remains bereft of diagnosis. As part of our continuous effort to recruit and perform genomic and functional studies on such cohorts, we investigated the genetic and mechanistic cause of disease in two independent consanguineous families affected by overlapping craniofacial, cardiac, laterality, and neurodevelopmental anomalies. Using whole exome sequencing, we identified homozygous frameshift CCDC32 variants in three affected individuals. Functional analysis in a zebrafish model revealed that ccdc32 depletion recapitulates the human phenotypes. Because some of the patient phenotypes overlap defects common to ciliopathies, we asked if loss of CCDC32 might contribute to the dysfunction of this organelle. Consistent with this hypothesis, we show that ccdc32 is required for normal cilia formation in zebrafish embryos and mammalian cell culture, arguing that ciliary defects are at least partially involved in the pathomechanism of this disorder.

中文翻译：

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CCDC32 中的功能丧失突变导致以颅面、心脏和神经发育异常为特征的先天性综合征。

尽管基因组学被广泛用于研究罕见先天性畸形的分子基础，但仍有很大一部分患者没有得到诊断。作为我们不断努力招募和对此类队列进行基因组和功能研究的一部分，我们调查了受重叠颅面、心脏、偏侧和神经发育异常影响的两个独立近亲家族中疾病的遗传和机制原因。使用全外显子组测序，我们在三个受影响的个体中鉴定了纯合移码 CCDC32 变体。斑马鱼模型中的功能分析显示 ccdc32 耗竭概括了人类表型。由于某些患者表型与纤毛病常见的缺陷重叠，我们询问 CCDC32 的缺失是否可能导致该细胞器的功能障碍。