De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders
Nabais Sá, Maria J.; El Tekle, Geniver; de Brouwer, Arjan P.M.; Sawyer, Sarah L.; del Gaudio, Daniela; Parker, Michael J.; Kanani, Farah; van den Boogaard, Marie José H.; van Gassen, Koen; Van Allen, Margot I.; Wierenga, Klaas; Purcarin, Gabriela; Elias, Ellen Roy; Begtrup, Amber; Keller-Ramey, Jennifer; Bernasocchi, Tiziano; van de Wiel, Laurens; Gilissen, Christian; Venselaar, Hanka; Pfundt, Rolph; Vissers, Lisenka E.L.M.; Theurillat, Jean Philippe P.; de Vries, Bert B.A.
(2020) American Journal of Human Genetics, volume 106, issue 3, pp. 405 - 411
(Article)
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
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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.
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Keywords: BET protein, craniofacial dysmorphisms, de novo mutation, germ line mutation, intellectual disabilty syndrome, macrocephaly, microcephaly, missense mutation, neurodevelopmental disorder, SPOP, Humans, Child, Preschool, Infant, Male, Mutation, Missense, Young Adult, Facies, Female, Nuclear Proteins/genetics, Child, Repressor Proteins/genetics, Intellectual Disability/genetics, Adolescent, Skull/abnormalities, Neurodevelopmental Disorders/genetics, Genetics(clinical), Genetics, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0002-9297
Publisher: Cell Press
Note: Funding Information: We are grateful to all the families for participating in this study. We thank the Care 4 Rare Canadian Consortium for logistical help and scientific expertise for individual 1. We are thankful to Erin Torti (GeneDx, Inc) for bringing us in contact with the clinicians of families 3, 4, and 5. We would like to acknowledge the work of Julian A. Martinez-Agosto and Rebecca H. Signer, who evaluated individual 4 within the Undiagnosed Diseases Network research study at UCLA (Los Angeles, CA, USA). We also thank S.D. van der Velde-Visser for the technical assistance with cell culturing at the Cell Culturing Facility of Genome Research Nijmegen (Nijmegen, the Netherlands). This work was financially supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917–86–319 and 912–12–109 to B.B.A.d.V.), the Krebsliga Schweiz ( KLS-4248-08-2017 to J.P.T), the Swiss National Science Foundation ( PP00P3_179072 to J.P.T), and the Fidinam Foundation . Funding Information: We are grateful to all the families for participating in this study. We thank the Care 4 Rare Canadian Consortium for logistical help and scientific expertise for individual 1. We are thankful to Erin Torti (GeneDx, Inc) for bringing us in contact with the clinicians of families 3, 4, and 5. We would like to acknowledge the work of Julian A. Martinez-Agosto and Rebecca H. Signer, who evaluated individual 4 within the Undiagnosed Diseases Network research study at UCLA (Los Angeles, CA, USA). We also thank S.D. van der Velde-Visser for the technical assistance with cell culturing at the Cell Culturing Facility of Genome Research Nijmegen (Nijmegen, the Netherlands). This work was financially supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917?86?319 and 912?12?109 to B.B.A.d.V.), the Krebsliga Schweiz (KLS-4248-08-2017 to J.P.T), the Swiss National Science Foundation (PP00P3_179072 to J.P.T), and the Fidinam Foundation. Publisher Copyright: © 2020 American Society of Human Genetics
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