Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

Silfhout, Anneke T. Vulto-van; Rajamanickam, Subapriya; Jensik, Philip J.; Vergult, Sarah; Rocker, Nina De; Newhall, Kathryn J.; Raghavan, Ramya; Reardon, Sara; Jarrett, Kelsey E; McIntyre, Tara; Bulinski, Joseph; Ownby, Stacy L.; Huggenvik, Jodi I.; McKnight, G. Stanley; Rose, Gregory M.; Cai, Xiang; Willaert, Andy; Zweier, Christiane; Endele, Sabine; Ligt, Joep de; Bon, Bregje W.M. van; Lugtenberg, Dorien; Vries, Petra F. de; Veltman, Joris A.; Bokhoven, Hans van; Brunner, Han G.; Rauch, Anita; Brouwer, Arjan P.M. de; Carvill, Gemma L.; Hoischen, Alexander; Mefford, Heather C; Eichler, Evan E.; Vissers, Lisenka E.L.M.; Menten, Björn; Collard, Michael W.; Vries, Bert B.A. de

doi:10.1016/j.ajhg.2014.03.013

Cited by 60 publications

(59 citation statements)

References 37 publications

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“…Furthermore, two damaging de novo missense mutations (p.Q264P and p.I228S) in DEAF1 (DEAF1 transcription factor) were described in two independent ID studies. DEAF1 is expressed in the neurons and is associated with anxiety and depression phenotypes and behavioral problems 58, 59 . In fact, numerous candidate genes harboring only one extreme DNM were identified with significant P -values.…”

Section: Discussionmentioning

confidence: 99%

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database

et al. 2015

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Currently, many studies on neuropsychiatric disorders have utilized massive trio-based whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify numerous de novo mutations (DNMs). Here, we retrieved 17,104 DNMs from 3,555 trios across four neuropsychiatric disorders: autism spectrum disorder (ASD), epileptic encephalopathy (EE), intellectual disability (ID), schizophrenia (SCZ), in addition to unaffected siblings (Control), from 36 studies by WES/WGS. After eliminating non-exonic variants, we focused on 3,334 exonic DNMs for evaluation their association with these diseases. Our results revealed a higher prevalence of DNMs in the probands of all four disorders than the one in the controls (P < 1.3 × 10-7). The elevated DNM frequency is dominated by loss-of-function/deleterious single nucleotide variants and frameshift indels (i.e., extreme mutations, P < 4.5 × 10-5). With extensive annotation of these “extreme” mutations, we prioritized 764 candidate genes in these four disorders. A combined analysis of Gene Ontology, microRNA targets, and transcription factor targets revealed shared biological process and non-coding regulatory elements of candidate genes in the pathology of neuropsychiatric disorders. In addition, weighted gene co-expression network analysis (WGCNA) of human laminar-specific neocortical expression data showed that candidate genes are convergent on eight shared modules with specific layer-enrichment and biological process features. Furthermore, we identified that 53 candidate genes are associated with more than one disorder (P < 0.000001), suggesting a possibly shared genetic etiology underlying these disorders. Particularly, DNMs of the SCN2A gene are frequently occurred across all four disorders. Finally, we constructed a freely available NPdenovo database, which provides a comprehensive catalog of the DNMs identified in neuropsychiatric disorders.

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Section: Discussionmentioning

confidence: 99%

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database

et al. 2015

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“…This resulted in the most significant enrichment of ID genes and genes associated with CNS disorders when applying neuron-specific H3K4me3 as a feature. A large proportion of the known and candidate ID genes (581/1134) fulfilled this criterion, including several of our recently reported candidate ID genes such as MYT1L, DEAF1, CACNA2D1 and POU3F3 3839404142. For those that do not present with neuron-specific trimethylation of H3K4, an explanation can be found in the function of these genes, as several of them (e.g.…”

Section: Discussionmentioning

confidence: 89%

Identification of long non-coding RNAs involved in neuronal development and intellectual disability

D’haene

Jacobs

Volders

et al. 2016

Sci Rep

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Recently, exome sequencing led to the identification of causal mutations in 16–31% of patients with intellectual disability (ID), leaving the underlying cause for many patients unidentified. In this context, the noncoding part of the human genome remains largely unexplored. For many long non-coding RNAs (lncRNAs) a crucial role in neurodevelopment and hence the human brain is anticipated. Here we aimed at identifying lncRNAs associated with neuronal development and ID. Therefore, we applied an integrated genomics approach, harnessing several public epigenetic datasets. We found that the presence of neuron-specific H3K4me3 confers the highest specificity for genes involved in neurodevelopment and ID. Based on the presence of this feature and GWAS hits for CNS disorders, we identified 53 candidate lncRNA genes. Extensive expression profiling on human brain samples and other tissues, followed by Gene Set Enrichment Analysis indicates that at least 24 of these lncRNAs are indeed implicated in processes such as synaptic transmission, nervous system development and neurogenesis. The bidirectional or antisense overlapping orientation relative to multiple coding genes involved in neuronal processes supports these results. In conclusion, we identified several lncRNA genes putatively involved in neurodevelopment and CNS disorders, providing a resource for functional studies.

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“…We focused on two genes, DEAF1 and CNTNAP2. DEAF1 exhibits putative DAEEs in the macaque DRN (Figure 7B) and is linked to autism, language impairment, and intellectual disability in humans (Rajab et al, 2015; Vulto-van Silfhout et al, 2014). CNTNAP2 exhibits a trend toward allele CoEEs in the macaque DRN (Figure 7B), exhibits high-confidence allele CoEEs in the mouse DRN (Figure 2G), and is also linked to autism, language impairment, and intellectual disability in humans (Alarcón et al, 2008; Arking et al, 2008).…”

Section: Resultsmentioning

confidence: 99%

Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain

Huang

Ferris

Cheng

et al. 2017

Neuron

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SUMMARY Interactions between genetic and epigenetic effects shape brain function, behavior, and the risk for mental illness. Random X inactivation and genomic imprinting are epigenetic allelic effects that are well known to influence genetic architecture and disease risk. Less is known about the nature, prevalence, and conservation of other potential epigenetic allelic effects in vivo in the mouse and primate brain. Here we devise genomics, in situ hybridization, and mouse genetics strategies to uncover diverse allelic effects in the brain that are not caused by imprinting or genetic variation. We found allelic effects that are developmental stage and cell type specific, that are prevalent in the neonatal brain, and that cause mosaics of monoallelic brain cells that differentially express wild-type and mutant alleles for heterozygous mutations. Finally, we show that diverse non-genetic allelic effects that impact mental illness risk genes exist in the macaque and human brain. Our findings have potential implications for mammalian brain genetics.

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Mutations Affecting the SAND Domain of DEAF1 Cause Intellectual Disability with Severe Speech Impairment and Behavioral Problems

Cited by 60 publications

References 37 publications

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database

Genes with de novo mutations are shared by four neuropsychiatric disorders discovered from NPdenovo database

Identification of long non-coding RNAs involved in neuronal development and intellectual disability

Diverse Non-genetic, Allele-Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain

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