Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Geisheker, Madeleine R.; Heymann, Gabriel; Wang, Tianyun; Coe, Bradley P.; Turner, Tychele N.; Stessman, Holly A.F.; Hoekzema, Kendra; Kvarnung, Malin; Shaw, Marie; Friend, Kathryn; Liebelt, Jan; Barnett, Christopher; Thompson, Elizabeth; Haan, Eric; Guo, Hui; Anderlid, Britt Marie; Nordgren, Ann; Wedell, Anna; Vandeweyer, Geert; Alberti, Antonino; Avola, Emanuela; Vinci, Mirella; Giusto, Stefania; Pramparo, Tiziano; Pierce, Karen; Nalabolu, Srinivasa; Michaelson, Jacob J.; Sedláček, Zdeněk; Santen, Gijs W.E.; Peeters, Hilde; Hákonarson, Hákon; Courchesne, Eric; Romano, Corrado; Kooy, R. Frank; Bernier, Raphael; Nordenskjöld, Magnus; Gécz, Jozef; Xia, Kun; Zweifel, Larry S.; Eichler, Evan E.

doi:10.1038/nn.4589

Cited by 154 publications

(184 citation statements)

References 81 publications

(105 reference statements)

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“…Moreover, until now, novel gene discovery in epilepsy has largely focused on truncating variants, partly because these variants are easier to interpret in the context of a haploinsufficient model. However, in accordance with a recent study that included molecular data from patients 6 and 9, the present study emphasizes the importance of recurrent missense variation in neurodevelopmental disorders, including intellectual disability and epilepsy 26 . This observation has also been illustrated in the epilepsies in a recent study that identified a recurrent missense mutation in a more common epilepsy gene, SCN1A , that produced a profound phenotype, far more severe than the well-established Dravet syndrome presentation of this gene 7 .…”

Section: Discussionsupporting

confidence: 89%

“…However, in accord with a recent study that included molecular data from patients 6 and 9, the present study emphasizes the importance of recurrent missense variation in neurodevelopmental disorders, including intellectual disability and epilepsy. 26 This observation has also been illustrated in the epilepsies in a recent study that identified a recurrent missense mutation in a more common epilepsy gene, SCN1A, that produced a profound phenotype, far more severe than the well-established Dravet syndrome presentation of this gene. 7 In addition, the role of missense mutations in DEE, and especially recurrent ones, has been emphasized in another recent article.…”

Section: Discussionmentioning

confidence: 84%

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The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Chatron

Møller

Champaigne

et al. 2018

Annals of Neurology

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 84%

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

Chatron

Møller

Champaigne

et al. 2018

Annals of Neurology

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“…Loss of function of ITPR1 has been found by multiple groups to be a rare single gene cause of autism 106,[153][154][155][156] . This prompted Gargus and colleagues to look at functional deficits in IP3-mediated calcium signaling in primary skin fibroblasts from Fragile X patients as they represent a common syndromic cause of autism 157 .…”

Section: Loss Of Function Of Fmrp Causes Altered Behavior and Cognitimentioning

confidence: 99%

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Driesche

Sawicka

Zhang

et al. 2019

Preprint

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Highlights 1. We have created a mouse model in which endogenous FMRP can be conditionally tagged.2. Using tag-specific CLIP we describe ranked and specific sets of in vivo FMRP mRNA targets in two types of neurons.3. This ranking was used to reveal that FMRP regulates mRNAs with long coding sequences.4. FMRP mRNA targets in Purkinje cells, including the top-ranked IP3 receptor, are related to cell-autonomous Fragile X phenotypes. 5.We have updated our previous list of whole mouse brain FMRP mRNA targets with more replicates, deeper sequencing and improved analysis 6. The use of tagged FMRP in less abundant cell populations allowed identification of novel mRNA targets missed in a whole brain analysis

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“…[3][4][5][6] Similarly, largescale WES studies of individuals affected by ID/DD have recently leveraged this phenomenon as supporting evidence of the involvement of a gene in disease. 7,8 This spatial clustering of de novo mutations (DNMs) is typical for missense mutations in genes without clear, or limited numbers of, truncating mutations subsequently degraded by nonsense-mediated mRNA decay, suggesting that these clustered mutations act through a different mechanism than haploinsufficiency (HI).…”

mentioning

confidence: 90%

“…32,33 GABBR2 was very recently also reported by others to show significant de novo mutation clustering in a neurodevelopmental cohort. 6 Our method might potentially identify clustering based on identical mutations in multiple individuals only as a result of issues in the underlying cohort. It could for instance be that the same individual was included in multiple studies and therefore occurs twice in the cohort.…”

mentioning

confidence: 99%

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

Lelieveld

Wiel

Venselaar

et al. 2017

The American Journal of Human Genetics

101

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SummaryHaploinsufficiency (HI) is the best characterized mechanism through which dominant mutations exert their effect and cause disease. Non-haploinsufficiency (NHI) mechanisms, such as gain-of-function and dominant-negative mechanisms, are often characterized by the spatial clustering of mutations, thereby affecting only particular regions or base pairs of a gene. Variants leading to haploinsufficency might occasionally cluster as well, for example in critical domains, but such clustering is on the whole less pronounced with mutations often spread throughout the gene. Here we exploit this property and develop a method to specifically identify genes with significant spatial clustering patterns of de novo mutations in large cohorts. We apply our method to a dataset of 4,061 de novo missense mutations from published exome studies of trios with intellectual disability and developmental disorders (ID/DD) and successfully identify 15 genes with clustering mutations, including 12 genes for which mutations are known to cause neurodevelopmental disorders. For 11 out of these 12, NHI mutation mechanisms have been reported. Additionally, we identify three candidate ID/DD-associated genes of which two have an established role in neuronal processes. We further observe a higher intolerance to normal genetic variation of the identified genes compared to known genes for which mutations lead to HI. Finally, 3D modeling of these mutations on their protein structures shows that 81% of the observed mutations are unlikely to affect the overall structural integrity and that they therefore most likely act through a mechanism other than HI.De novo mutations affecting protein-coding genes are a major cause of intellectual disability (ID) and other developmental disorders (DDs). We downloaded all DNMs occurring in individuals with ID/DD from de novo-db version 1.3 14 identified through WES and whole genome sequencing which were then reannotated with our in-house variant annotation pipeline. The de novo mutations included in the analysis were previously validated by a second independent method or showed a high validation rate for a subset of de novo mutations. In addition, we added 1,183 de novo variants identified in the exomes of an in-house ID cohort that was previously published. 8 To further reduce the risk of including sequencing artifacts and/or genotyping errors, we excluded all de novo variants that were present more than once in the ExAC dataset (Table S1). 15 These efforts resulted in 6,495 protein coding DNMs, including 4,061 missense mutations, in 5,302 individuals with ID/DD (Table S2). We set out to determine for any gene whether the observed de novo missense mutations cluster more than expected compared to random permutations. Hereto, we selected for each the longest representative transcript (i.e., part of the GENCODE basic set) 16 and calculated the geometric mean distance d g over all missense DNMs on

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Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Cited by 154 publications

References 81 publications

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant

FMRP binding to a ranked subset of long genes is revealed by coupled CLIP and TRAP in specific neuronal cell types

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

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