Oligogenic rare variant contributions in schizophrenia and their convergence with genes harbouring de novo mutations in schizophrenia, autism and intellectual disability: Evidence from multiplex families

AbstractClinical and genetic heterogeneity has been documented extensively in schizophrenia, a common behavioural disorder with heritability estimates of about 80%. Common and rare de novo variant based studies have provided notable evidence for the likely involvement of a range of pathways including glutamatergic, synaptic signalling and neurodevelopment. To complement these studies, we sequenced exomes of 11 multimember affected schizophrenia families from India. Variant prioritisation performed based on their rarity (MAF <0.01), shared presence among the affected individuals in the respective families and predicted deleterious nature, yielded a total of 785 inherited rare protein sequence altering variants in 743 genes among the 11 families. These showed an enrichment of genes involved in the extracellular matrix and cytoskeleton components, synaptic and neuron related ontologies and neurodevelopmental pathways, consistent with major etiological hypotheses. We also noted an overrepresentation of genes from previously reported gene sets with de novo protein sequence altering variants in schizophrenia, autism, intellectual disability; FMRP target and loss of function intolerant genes. Furthermore, a minimum of five genes known to manifest behavioural/neurological and nervous system abnormalities in rodent models had deleterious variants in them shared among all affected individuals in each of the families. Majority of such variants segregated within and not across families providing strong suggestive evidence for the genetically heterogeneous nature of disease. More importantly, study findings unequivocally support the classical paradigm of cumulative contribution of multiple genes, notably with an apparent threshold effect for disease manifestation and offer a likely explanation for the unclear mode of inheritance in familial schizophrenia.

Download Full-text

A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES)

Genes ◽

10.3390/genes11030344 ◽

2020 ◽

Vol 11 (3) ◽

pp. 344 ◽

Cited By ~ 2

Author(s):

Emanuela Leonardi ◽

Mariagrazia Bellini ◽

Maria C. Aspromonte ◽

Roberta Polli ◽

Anna Mercante ◽

...

Keyword(s):

Intellectual Disability ◽

Status Epilepticus ◽

Behavioral Problems ◽

Rare Variants ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Somatic Mosaicism ◽

Coiled Coil ◽

Loss Of Function ◽

De Novo Mutations

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five WAC rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another WAC individual. This first report of a WAC somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with WAC pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.

Download Full-text

De Novo Mutations in the Genome Organizer CTCF Cause Intellectual Disability

The American Journal of Human Genetics ◽

10.1016/j.ajhg.2013.05.007 ◽

2013 ◽

Vol 93 (1) ◽

pp. 124-131 ◽

Cited By ~ 75

Author(s):

Anne Gregor ◽

Martin Oti ◽

Evelyn N. Kouwenhoven ◽

Juliane Hoyer ◽

Heinrich Sticht ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

De Novo Mutations

Download Full-text

De novo mutations in inhibitors of Wnt, BMP, and Ras/ERK signaling pathways in non-syndromic midline craniosynostosis

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1709255114 ◽

2017 ◽

Vol 114 (35) ◽

pp. E7341-E7347 ◽

Cited By ~ 29

Author(s):

Andrew T. Timberlake ◽

Charuta G. Furey ◽

Jungmin Choi ◽

Carol Nelson-Williams ◽

Erin Loring ◽

...

Keyword(s):

De Novo ◽

Erk Signaling ◽

Loss Of Function ◽

De Novo Mutations ◽

Neurodevelopmental Outcomes ◽

Locus Heterogeneity ◽

Syndromic Craniosynostosis ◽

New Genes ◽

Morphogenetic Protein ◽

Nuclear Targets

Non-syndromic craniosynostosis (NSC) is a frequent congenital malformation in which one or more cranial sutures fuse prematurely. Mutations causing rare syndromic craniosynostoses in humans and engineered mouse models commonly increase signaling of the Wnt, bone morphogenetic protein (BMP), or Ras/ERK pathways, converging on shared nuclear targets that promote bone formation. In contrast, the genetics of NSC is largely unexplored. More than 95% of NSC is sporadic, suggesting a role for de novo mutations. Exome sequencing of 291 parent–offspring trios with midline NSC revealed 15 probands with heterozygous damaging de novo mutations in 12 negative regulators of Wnt, BMP, and Ras/ERK signaling (10.9-fold enrichment, P = 2.4 × 10−11). SMAD6 had 4 de novo and 14 transmitted mutations; no other gene had more than 1. Four familial NSC kindreds had mutations in genes previously implicated in syndromic disease. Collectively, these mutations contribute to 10% of probands. Mutations are predominantly loss-of-function, implicating haploinsufficiency as a frequent mechanism. A common risk variant near BMP2 increased the penetrance of SMAD6 mutations and was overtransmitted to patients with de novo mutations in other genes in these pathways, supporting a frequent two-locus pathogenesis. These findings implicate new genes in NSC and demonstrate related pathophysiology of common non-syndromic and rare syndromic craniosynostoses. These findings have implications for diagnosis, risk of recurrence, and risk of adverse neurodevelopmental outcomes. Finally, the use of pathways identified in rare syndromic disease to find genes accounting for non-syndromic cases may prove broadly relevant to understanding other congenital disorders featuring high locus heterogeneity.

Download Full-text

A de novo variant in CASK gene causing intellectual disability and brain hypoplasia: A Case Report and Literature Review

10.21203/rs.3.rs-317232/v1 ◽

2021 ◽

Author(s):

Ying Zhang ◽

Yanyan Nie ◽

Yu Mu ◽

Jie Zheng ◽

Xiaowei Xu ◽

...

Keyword(s):

Intellectual Disability ◽

Mental Disorders ◽

De Novo ◽

Clinical Symptoms ◽

Clinical Manifestations ◽

De Novo Mutation ◽

Loss Of Function ◽

Bioinformatics Analyses ◽

Whole Exome ◽

De Novo Variant

Abstract Background：The pathogenic variation of CASK gene can cause CASK related mental disorders. The main clinical manifestations are microcephaly with pontine and cerebellar hypoplasia, X-linked mental disorders with or without nystagmus and FG syndrome. The main pathogenic mechanism is the loss of function of related protein caused by mutation. We reported a Chinese male newborn with a de novo variant in CASK gene. Case presentation：We present an 18-day-old baby with intellectual disability and brain hypoplasia. Whole-exome sequencing was performed, which detected a hemizygous missense mutation c.764G>A of CASK gene. The mutation changed the 255th amino acid from Arg to His. Software based bioinformatics analyses were conducted to infer its functional effect.Conclusions：In this paper, a de novo mutation of CASK gene was reported. Moreover, a detailed description of all the cases described in the literature is reported.CASK mutations cause a variety of clinical phenotypes. Its diagnosis is difficult due to the lack of typical clinical symptoms. Genetic testing should be performed as early as possible if this disease is suspected. This case provides an important reference for the diagnosis and treatment of future cases.

Download Full-text

Three intellectual disability-associated de novo mutations in MECP2 identified by trio-WES analysis

BMC Medical Genetics ◽

10.1186/s12881-020-01042-w ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Yi Gu ◽

Bingwu Xiang ◽

Lina Zhu ◽

Xiuwei Ma ◽

Xiang Chen ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

De Novo Mutations

Download Full-text

De novo mutations in the SET nuclear proto-oncogene, encoding a component of the inhibitor of histone acetyltransferases (INHAT) complex in patients with nonsyndromic intellectual disability

Human Mutation ◽

10.1002/humu.23541 ◽

2018 ◽

Vol 39 (7) ◽

pp. 1014-1023 ◽

Cited By ~ 5

Author(s):

Servi J.C. Stevens ◽

Vyne van der Schoot ◽

Magalie S. Leduc ◽

Tuula Rinne ◽

Seema R. Lalani ◽

...

Keyword(s):

Intellectual Disability ◽

De Novo ◽

Histone Acetyltransferases ◽

De Novo Mutations

Download Full-text

Molecular Dissection of Neurodevelopmental Disorder-Causing Mutations in CYFIP2

Cells ◽

10.3390/cells9061355 ◽

2020 ◽

Vol 9 (6) ◽

pp. 1355

Author(s):

Matthias Schaks ◽

Michael Reinke ◽

Walter Witke ◽

Klemens Rottner

Keyword(s):

De Novo ◽

Neurodevelopmental Disorder ◽

Small Gtpases ◽

Normal Brain ◽

Loss Of Function ◽

De Novo Mutations ◽

Neuronal Morphogenesis ◽

Variable Extent ◽

Regulatory Complex ◽

Almost All

Actin remodeling is frequently regulated by antagonistic activities driving protrusion and contraction downstream of Rac and Rho small GTPases, respectively. WAVE regulatory complex (WRC), which primarily operates downstream of Rac, plays pivotal roles in neuronal morphogenesis. Recently, two independent studies described de novo mutations in the CYFIP2 subunit of WRC, which caused intellectual disability (ID) in humans. Although mutations had been proposed to effect WRC activation, no experimental evidence for this was provided. Here, we made use of CRISPR/Cas9-engineered B16-F1 cell lines that were reconstituted with ID-causing CYFIP variants in different experimental contexts. Almost all CYFIP2-derived mutations (7 out of 8) promoted WRC activation, but to variable extent and with at least two independent mechanisms. The majority of mutations occurs in a conserved WAVE-binding region, required for WRC transinhibition. One mutation is positioned closely adjacent to the Rac-binding A site and appears to ease Rac-mediated WRC activation. As opposed to these gain-of-function mutations, a truncating mutant represented a loss-of-function variant and failed to interact with WRC components. Collectively, our data show that explored CYFIP2 mutations frequently, but not always, coincide with WRC activation and suggest that normal brain development requires a delicate and precisely tuned balance of neuronal WRC activity.

Download Full-text