Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability.

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID.

Direct measure of the de novo mutation rate in autism and schizophrenia cohorts.

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing.

Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors.

De novo mutations in the gene encoding the synaptic scaffolding protein SHANK3 in patients ascertained for schizophrenia.

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism.

De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy.

We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.

Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.

Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients.

Mutations in the calcium-related gene IL1RAPL1 are associated with autism.

In a systematic sequencing screen of synaptic genes on the X chromosome, we have identified an autistic female without mental retardation (MR) who carries a de novo frameshift Ile367SerfsX6 mutation in Interleukin-1 Receptor Accessory Protein-Like 1 (IL1RAPL1), a gene implicated in calcium-regulated vesicle release and dendrite differentiation. We showed that the function of the resulting truncated IL1RAPL1 protein is severely altered in hippocampal neurons, by measuring its effect on neurite outgrowth activity. We also sequenced the coding region of the close related member IL1RAPL2 and of NCS-1/FREQ, which physically interacts with IL1RAPL1, in a cohort of subjects with autism.

Novel de novo SHANK3 mutation in autistic patients.

A number of studies have confirmed that genetic factors play an important role in autism spectrum disorder (ASD). More recently de novo mutations in the SHANK3 gene, a synaptic scaffolding protein, have been associated with the ASD phenotype. As part of our gene discovery strategy, we sequenced the SHANK3 gene in a cohort of 427 ASD subjects and 190 controls.

Mapping susceptibility genes for bipolar disorder: a pharmacogenetic approach based on excellent response to lithium.

Genetic mapping studies in bipolar disorder (BD) have been hampered by the unclear boundaries of the phenotypic spectrum, and possibly, by the complexity of the underlying genetic mechanisms, and heterogeneity. Among the suggested approaches to circumvent these problems, a pharmacogenetic strategy has been increasingly proposed. Several studies have indicated that patients with BD who respond well to lithium prophylaxis constitute a biologically distinct subgroup.

Varicella-zoster virus DNA in CSF and arteries in delayed contralateral hemiplegia: evidence for viral invasion of cerebral arteries.

A 78-year-old woman presented with a right basal ganglia infarct 6 weeks after a left herpes zoster ophthalmicus. MR angiography showed focal segmental stenosis of the proximal segments of the anterior, middle, and posterior cerebral arteries. Varicella DNA was detected in the CSF by polymerase chain reaction (PCR).

The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q.

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN) is a devastating neurodegenerative disorder that is transmitted as an autosomal recessive trait. Genealogical studies in a large number of affected French Canadian individuals suggest that ACCPN results from a single founder mutation. A genomewide search using 120 microsatellite DNA markers in 14 French Canadian families allowed the mapping of the ACCPN gene to a 5-cM region on chromosome 15q13-q15 that is flanked by markers D15S1040 and D15S118.

Schwannomin: new insights into this member of the band 4.1 superfamily.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease characterized by the development of central nervous system tumours. The NF2 gene was recently cloned and found to encode a protein, schwannomin (or merlin), with homology to the band 4.1 superfamily.

The mouse homologue of the neurofibromatosis type 2 gene is highly conserved.

Neurofibromatosis type 2 (NF2) is a complex nervous system disorder characterized by the development of schwannomas (especially vestibular), meningiomas, ependymomas and juvenile lens opacities. Mutation in the NF2 gene, which encodes for the schwannomin protein (SCH), a member of the band 4.1 superfamily of genes, predisposes carriers to these central nervous system tumors.

Familial meningioma is not allelic to neurofibromatosis 2.

Meningiomas frequently lose parts of chromosome 22 (CHR 22), suggesting that a meningioma tumor-suppressor gene is located on CHR 22. Since meningiomas are common in neurofibromatosis 2 (NF2) and the NF2 gene is mapped to CHR 22, the NF2 gene is a candidate for the meningioma gene. To determine whether NF2 and familial meningioma are allelic mutations, we studied a family with multiple meningiomas and ependymomas in two generations using genetic linkage analysis with DNA markers known to flank the NF2 locus.

Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus.

Neurofibromatosis type 2 (NF2) is an autosomal dominant disease which predisposes to the development of schwannomas, meningiomas, ependymomas, and juvenile cataracts. The NF2 gene (NF2) has recently been isolated and maps to chromosome 22q12 between the loci D22S212 and D22S32. Deletion studies in sporadic and NF2 associated schwannomas and meningiomas, and the presence of inactivating mutations in NF2 in patients suggest that it acts as a tumor suppressor gene.

Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a monogenic dominantly inherited disease predisposing carriers to develop nervous system tumours. To identify the genetic defect, the region between two flanking polymorphic markers on chromosome 22 was cloned and several genes identified. One is the site of germ-line mutations in NF2 patients and of somatic mutations in NF2-related tumours.

Cloning of six new genes with zinc finger motifs mapping to short and long arms of human acrocentric chromosome 22 (p and q11.2).

Zinc finger genes encode proteins containing tandemly repeated zinc-mediated folded structures that are found in several transcriptional regulatory proteins. To identify new zinc finger genes, we have screened at low stringency human cosmid libraries enriched in chromosome 22 sequences with a probe derived from the finger region of the mouse Kruppel-like gene, mKr2. We identified 23 nonoverlapping human cosmids cross-hybridizing with the probe.

Occurrence of a copia-like transposable element in one of the introns of the potato starch phosphorylase gene.

The gene coding for starch phosphorylase (EC 2.4.1.