Recurrent somatic variants in SPOP are cancer specific; endometrial and prostate cancers result from gain-of-function and dominant-negative effects toward BET proteins, respectively. By using clinical exome sequencing, we identified six de novo pathogenic missense variants in SPOP in seven individuals with developmental delay and/or intellectual disability, facial dysmorphisms, and congenital anomalies. Two individuals shared craniofacial dysmorphisms, including congenital microcephaly, that were strikingly different from those of the other five individuals, who had (relative) macrocephaly and hypertelorism. We measured the effect of SPOP variants on BET protein amounts in human Ishikawa endometrial cancer cells and patient-derived cell lines because we hypothesized that variants would lead to functional divergent effects on BET proteins. The de novo variants c.362G>A (p.Arg121Gln) and c. 430G>A (p.Asp144Asn), identified in the first two individuals, resulted in a gain of function, and conversely, the c.73A>G (p.Thr25Ala), c.248A>G (p.Tyr83Cys), c.395G>T (p.Gly132Val), and c.412C>T (p.Arg138Cys) variants resulted in a dominant-negative effect. Our findings suggest that these opposite functional effects caused by the variants in SPOP result in two distinct and clinically recognizable syndromic forms of intellectual disability with contrasting craniofacial dysmorphisms.

中文翻译：

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SPOP的从头变异会导致两种临床上不同的神经发育障碍。

SPOP中的复发性体细胞变异具有癌症特异性。子宫内膜癌和前列腺癌分别来自对BET蛋白的功能获得和显性负效应。通过使用临床外显子组测序，我们在7名发育迟缓和/或智力残疾，面部畸形和先天性异常的个体中发现了SPOP中的6个新生病原体错义变体。两个人都有颅面畸形，包括先天性小头畸形，这与其他五个（相对）大头畸形和高位畸形的个体明显不同。我们测量了SPOP变体对人类Ishikawa子宫内膜癌细胞和患者源性细胞系中BET蛋白量的影响，因为我们假设这些变体会导致对BET蛋白的功能分歧。从头变异c.362G> A（p.Arg121Gln）和c。在前两个个体中发现430G> A（p.Asp144Asn），导致功能增强，相反，c.73A> G（p.Thr25Ala），c.248A> G（p.Tyr83Cys），c .395G> T（p.Gly132Val）和c.412C> T（p.Arg138Cys）变异导致显性负效应。我们的研究结果表明，由SPOP变异引起的这些相反的功能作用导致两种不同的，临床上可识别的智力障碍综合征形式，而颅面畸形则与此形成对比。Arg138Cys）变体产生显性负效应。我们的发现表明，由SPOP变体引起的这些相反的功能作用导致两种不同的，临床上可识别的智力障碍综合征形式，而颅面畸形则与此形成对比。Arg138Cys）变体产生显性负效应。我们的研究结果表明，由SPOP变异引起的这些相反的功能作用导致两种不同的，临床上可识别的智力障碍综合征形式，而颅面畸形则与此形成对比。