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

De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders.

Author information

1
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
2
Functional Cancer Genomics, Institute of Oncology Research, 6500 Bellinzona, Switzerland; Faculty of Biomedical Science, Università della Svizzera Italiana, 6900 Lugano, Switzerland; University of Lausanne, 1015 Lausanne, Switzerland.
3
Department of Genetics, Children's Hospital of Eastern Ontario and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON K1H 8L1, Canada.
4
Molecular Diagnostic Laboratory, Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
5
Department of Clinical Genetics, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK.
6
Department of Genetics, UMC Utrecht, 3584 CX Utrecht, the Netherlands.
7
Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
8
University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
9
Special Care Clinic, Children's Hospital Colorado, Aurora, CO 80011, USA; University of Colorado School of Medicine, Aurora, CO 80045, USA.
10
GeneDx, Gaithersburg, MD 20877, USA.
11
Center for Molecular and Biomolecular Informatics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
12
Department of Human Genetics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
13
Functional Cancer Genomics, Institute of Oncology Research, 6500 Bellinzona, Switzerland; Faculty of Biomedical Science, Università della Svizzera Italiana, 6900 Lugano, Switzerland. Electronic address: jean-philippe.theurillat@ior.usi.ch.
14
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands. Electronic address: bert.devries@radboudumc.nl.

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.

KEYWORDS:

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

PMID:
32109420
PMCID:
PMC7058825
[Available on 2020-09-05]
DOI:
10.1016/j.ajhg.2020.02.001

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