Intragenic deletions of <i>IL1RAPL1</i>: Report of two cases and review of the literature

Behnecke, Anne; Hinderhofer, Katrin; Bartsch, Oliver; Nümann, Astrid; Ipach, Marie-Luise; Damatova, Natalja; Haaf, Thomas; Dufke, Andreas; Rieß, Olaf; Moog, Ute

doi:10.1002/ajmg.a.33656

Cited by 32 publications

(29 citation statements)

References 28 publications

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“…We propose that small 10 bp deletion may have created a sequence conformation favouring further instability and leading to the larger deletion observed in the second brother (see online supplementary figure S14). Indeed, a large proportion of IL1RAPL1 causative mutations are intragenic exon deletions or pericentric inversions,19 supporting that IL1RAPL1 region is highly susceptible to recombination events.…”

Section: Resultsmentioning

confidence: 95%

Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

et al. 2014

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BackgroundIntellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation.MethodsWe report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases.ResultsWe identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients’ clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders.ConclusionsWith a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism.

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Section: Resultsmentioning

confidence: 95%

Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

et al. 2014

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“…Accumulating evidence supports the importance of synaptic adhesion proteins in ID. For example, researchers have found multiple mutations in IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) in ID and ASD patients (Behnecke et al 2011 with postsynaptic partners PSD95 and Rho-GAP to cooperatively regulate glutamatergic synapse number, synaptic transmission, plasticity, and cognitive function (Pavlowsky et al 2010, Yasumura et al 2014. Neuroligins (NLGNs) are another class of postsynaptic cell adhesion molecules that regulate synapse maturation and stabilization in cooperation with their presynaptic partner neurexins (NRXNs).…”

Section: Intellectual Disabilitymentioning

confidence: 99%

Glutamate Synapses in Human Cognitive Disorders

Volk

Chiu

Sharma

et al. 2015

Annu. Rev. Neurosci.

218

179

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Accumulating data, including those from large genetic association studies, indicate that alterations in glutamatergic synapse structure and function represent a common underlying pathology in many symptomatically distinct cognitive disorders. In this review, we discuss evidence from human genetic studies and data from animal models supporting a role for aberrant glutamatergic synapse function in the etiology of intellectual disability (ID), autism spectrum disorder (ASD), and schizophrenia (SCZ), neurodevelopmental disorders that comprise a significant proportion of human cognitive disease and exact a substantial financial and social burden. The varied manifestations of impaired perceptual processing, executive function, social interaction, communication, and/or intellectual ability in ID, ASD, and SCZ appear to emerge from altered neural microstructure, function, and/or wiring rather than gross changes in neuron number or morphology. Here, we review evidence that these disorders may share a common underlying neuropathy: altered excitatory synapse function. We focus on the most promising candidate genes affecting glutamatergic synapse function, highlighting the likely disease-relevant functional consequences of each. We first present a brief overview of glutamatergic synapses and then explore the genetic and phenotypic evidence for altered glutamate signaling in ID, ASD, and SCZ.

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“…In addition to point mutations and indels [38,39], exome sequencing data can be used to discover larger events of potential relevance to disease [40,41]. Similarly, higher resolution and targeted array studies have identified numerous candidate CNVs well below 500 kbp [42][43][44][45][46]. Some recent prominent examples include a small duplication of VIPR2 in schizophrenia, and focal partial deletions of TMHLE in ASD [44,47,48].…”

Section: Size Spectrum Of Copy Number Variationmentioning

confidence: 99%

A genetic model for neurodevelopmental disease

Coe¹,

Girirajan²,

Eichler³

2012

Current Opinion in Neurobiology

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The genetic basis of neurodevelopmental and neuropsychiatric diseases has been advanced by the discovery of large and recurrent copy number variants significantly enriched in cases when compared to controls. The pattern of this variation strongly implies that rare variants contribute significantly to neurological disease; that different genes will be responsible for similar diseases in different families; and that the same "primary" genetic lesions can result in a different disease outcome depending potentially on the genetic background. Next-generation sequencing technologies are beginning to broaden the spectrum of disease-causing variation and provide specificity by pinpointing both genes and pathways for future diagnostics and therapeutics.

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Intragenic deletions of IL1RAPL1: Report of two cases and review of the literature

Cited by 32 publications

References 28 publications

Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing

Glutamate Synapses in Human Cognitive Disorders

A genetic model for neurodevelopmental disease

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