De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders

Am J Hum Genet. 2020 Mar 5;106(3):405-411. doi: 10.1016/j.ajhg.2020.02.001. Epub 2020 Feb 27.


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.

Keywords: BET protein; SPOP; craniofacial dysmorphisms; de novo mutation; germ line mutation; intellectual disabilty syndrome; macrocephaly; microcephaly; missense mutation; neurodevelopmental disorder.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Child
  • Child, Preschool
  • Facies
  • Female
  • Humans
  • Infant
  • Intellectual Disability / genetics
  • Male
  • Mutation, Missense*
  • Neurodevelopmental Disorders / genetics*
  • Nuclear Proteins / genetics*
  • Repressor Proteins / genetics*
  • Skull / abnormalities
  • Young Adult


  • Nuclear Proteins
  • Repressor Proteins
  • SPOP protein, human