Zhu–Tokita–Takenouchi–Kim (ZTTK) syndrome, an intellectual disability syndrome first described in 2016, is caused by heterozygous loss-of-function variants in SON. Its encoded protein promotes pre-mRNA splicing of many genes essential for development. Whereas individual phenotypic traits have previously been linked to erroneous splicing of SON target genes, the phenotypic spectrum and the pathogenicity of missense variants have not been further evaluated. We present the phenotypic abnormalities in 52 individuals, including 17 individuals who have not been reported before. In total, loss-of-function variants were detected in 49 individuals (de novo in 47, inheritance unknown in 2), and in 3, a missense variant was observed (2 de novo, 1 inheritance unknown). Phenotypic abnormalities, systematically collected and analyzed in Human Phenotype Ontology, were found in all organ systems. Significant inter-individual phenotypic variability was observed, even in individuals with the same recurrent variant (n = 13). SON haploinsufficiency was previously shown to lead to downregulation of downstream genes, contributing to specific phenotypic features. Similar functional analysis for one missense variant, however, suggests a different mechanism than for heterozygous loss-of-function. Although small in numbers and while pathogenicity of these variants is not certain, these data allow for speculation whether de novo missense variants cause ZTTK syndrome via another mechanism, or a separate overlapping syndrome. In conclusion, heterozygous loss-of-function variants in SON define a recognizable syndrome, ZTTK, associated with a broad, severe phenotypic spectrum, characterized by a large inter-individual variability. These observations provide essential information for affected individuals, parents, and healthcare professionals to ensure appropriate clinical management.

Zhu-Tokita-Takenouchi-Kim (ZTTK) 综合征是一种智力障碍综合征，于 2016 年首次被描述，由SON中的杂合功能丧失变异引起。其编码的蛋白质促进许多对发育至关重要的基因的 pre-mRNA 剪接。鉴于个体表型特征先前已与SON的错误剪接相关联目标基因、表型谱和错义变异的致病性尚未得到进一步评估。我们展示了 52 个个体的表型异常，其中包括 17 个以前未被报道过的个体。总共在 49 个个体中检测到功能丧失变异（47 个从头发现，2 个遗传未知），在 3 个个体中观察到错义变异（2 个从头发现，1 个遗传未知）。在所有器官系统中都发现了人类表型本体中系统收集和分析的表型异常。观察到显着的个体间表型变异性，即使在具有相同复发变异的个体中也是如此 ( n  = 13)。儿子先前已证明单倍体不足会导致下游基因下调，从而导致特定的表型特征。然而，对一个错义变异的类似功能分析表明了一种与杂合子功能丧失不同的机制。尽管数量很少，而且这些变异的致病性尚不确定，但这些数据允许推测新的错义变异是否通过另一种机制或单独的重叠综合征引起 ZTTK 综合征。总之，SON中的杂合功能丧失变异体定义一个可识别的综合征，ZTTK，与广泛、严重的表型谱相关，其特征是个体间差异很大。这些观察结果为受影响的个人、父母和医疗保健专业人员提供了必要的信息，以确保进行适当的临床管理。