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De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders
Maria J Nabais Sá1, Geniver El Tekle2, Arjan P M de Brouwer1
1Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
Abstract:
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.
Insights
New SPOP gene variants cause distinct forms of intellectual disability. These SPOP variants lead to either gain-of-function or dominant-negative effects, resulting in different craniofacial features and developmental issues.
Area of Science:
- Genetics
- Developmental Biology
- Human Pathology
Background:
- SPOP (Speckle-type POZ protein) variants are known drivers of specific cancers, including endometrial and prostate cancers.
- These cancer-associated SPOP variants exert their effects through gain-of-function or dominant-negative mechanisms on BET proteins.
Purpose of the Study:
- To investigate the role of de novo SPOP variants in individuals presenting with developmental delay, intellectual disability, and congenital anomalies.
- To characterize the functional impact of identified SPOP variants on BET proteins and correlate these effects with distinct clinical phenotypes.
Main Methods:
- Clinical exome sequencing was employed to identify de novo pathogenic missense variants in the SPOP gene.
- Functional assays were performed using human endometrial cancer cells and patient-derived cell lines to measure the effect of SPOP variants on BET protein levels.
- Clinical data, including craniofacial dysmorphisms, were analyzed to identify distinct syndromic forms.
Main Results:
- Six de novo pathogenic missense SPOP variants were identified in seven individuals with developmental delay/intellectual disability and congenital anomalies.
- Two distinct groups of individuals were observed based on craniofacial features: microcephaly versus macrocephaly with hypertelorism.
- Specific SPOP variants (p.Arg121Gln, p.Asp144Asn) demonstrated gain-of-function effects, while others (p.Thr25Ala, p.Tyr83Cys, p.Gly132Val, p.Arg138Cys) exhibited dominant-negative effects on BET proteins.
Conclusions:
- De novo SPOP variants can cause syndromic forms of intellectual disability with distinct clinical presentations.
- The contrasting craniofacial dysmorphisms are associated with opposite functional effects (gain-of-function vs. dominant-negative) of SPOP variants on BET proteins.
- These findings highlight the diverse roles of SPOP in human development and disease beyond cancer.
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