No abstract

Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.

Structural genetic changes, especially copy number variants (CNVs), represent a major source of genetic variation contributing to human disease. Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease, but to date little is known about the role of CNVs in the etiology of TOF. Using high-resolution genome-wide microarrays and stringent calling methods, we investigated rare CNVs in a prospectively recruited cohort of 433 unrelated adults with TOF and/or pulmonary atresia at a single centre. We excluded those with recognized syndromes, including 22q11.2 deletion syndrome. We identified candidate genes for TOF based on converging evidence between rare CNVs that overlapped the same gene in unrelated individuals and from pathway analyses comparing rare CNVs in TOF cases to those in epidemiologic controls. Even after excluding the 53 (10.7%) subjects with 22q11.2 deletions, we found that adults with TOF had a greater burden of large rare genic CNVs compared to controls (8.82% vs. 4.33%, p = 0.0117). Six loci showed evidence for recurrence in TOF or related congenital heart disease, including typical 1q21.1 duplications in four (1.18%) of 340 Caucasian probands. The rare CNVs implicated novel candidate genes of interest for TOF, including PLXNA2, a gene involved in semaphorin signaling. Independent pathway analyses highlighted developmental processes as potential contributors to the pathogenesis of TOF. These results indicate that individually rare CNVs are collectively significant contributors to the genetic burden of TOF. Further, the data provide new evidence for dosage sensitive genes in PLXNA2-semaphorin signaling and related developmental processes in human cardiovascular development, consistent with previous animal models.

RASopathies are autosomal dominant disorders caused by mutations in more than 10 known genes that regulate the RAS/MAPK pathway. Noonan syndrome (NS) is a RASopathy characterized by a distinctive facial appearance, musculoskeletal abnormalities, and congenital heart defects. We have recently identified mutations in RIT1 in patients with NS. To delineate the clinical manifestations in RIT1 mutation-positive patients, we further performed a RIT1 analysis in RASopathy patients and identified 7 RIT1 mutations, including two novel mutations, p.A77S and p.A77T, in 14 of 186 patients. Perinatal abnormalities, including nuchal translucency, fetal hydrops, pleural effusion, or chylothorax and congenital heart defects, are observed in all RIT1 mutation-positive patients. Luciferase assays in NIH 3T3 cells demonstrated that the newly identified RIT1 mutants, including p.A77S and p.A77T, and the previously identified p.F82V, p.T83P, p.Y89H, and p.M90I, enhanced Elk1 transactivation. Genotype-phenotype correlation analyses of previously reported NS patients harboring RIT1, PTPN11, SOS1, RAF1, and KRAS revealed that hypertrophic cardiomyopathy (56 %) was more frequent in patients harboring a RIT1 mutation than in patients harboring PTPN11 (9 %) and SOS1 mutations (10 %). The rates of hypertrophic cardiomyopathy were similar between patients harboring RIT1 mutations and patients harboring RAF1 mutations (75 %). Short stature (52 %) was less prevalent in patients harboring RIT1 mutations than in patients harboring PTPN11 (71 %) and RAF1 (83 %) mutations. These results delineate the clinical manifestations of RIT1 mutation-positive NS patients: high frequencies of hypertrophic cardiomyopathy, atrial septal defects, and pulmonary stenosis; and lower frequencies of ptosis and short stature.

Morphological alterations in the brains of schizophrenia patients suggest that neurodevelopmental dysfunction is involved in the etiology of the disease. 1 Such dysfunction may be due to functional alterations of cell adhesion molecules, which play important roles in cell migration, axonal growth, fasciculation, synaptogenesis, and synaptic remodeling. We screened for mutations in the coding region of the close homologue to L1 gene (CHL1), which is located on human chromosome 3p26, in 24 Japanese patients with schizophrenia. A missense polymorphism (Leu17Phe) in the signal peptide region was identified. A case-control comparison revealed significantly higher frequencies of the Leu/Leu genotype (P = 0.004) and the Leu allele (P = 0.006) in 282 Japanese schizophrenic patients than in 229 Japanese control subjects. The estimated odds ratio for schizophrenia was 1.83 (95% CI, 1.28-2.26) for the Leu/Leu genotype compared with the other genotypes. An association between this CHL1 gene polymorphism and schizophrenia supports the notion that cell adhesion molecules are involved in the etiology of schizophrenia. Molecular Psychiatry (2002) 7, 412-415. DOI: 10.1038/ sj/mp/4000973Cell adhesion molecules (CAMs) play important roles in specifying cell-cell interactions during development, regeneration, and modification of synaptic activity. In humans, mutations in the L1 cell adhesion molecule (L1CAM) are associated with a neurological syndrome termed CRASH, which includes corpus callosum agenesis, mental retardation, adducted thumbs, spasticity, hydrocephalus, and a wide spectrum of other clinical features. A mouse model with null mutation in the L1CAM gene suggests roles for L1CAM in the mechanism of cortical dendrite differentiation as well as in guidance of callosal axons and regulation of hippocampal development. 2 An abnormality in expression of one of the CAMs could result in the histologic abnormalities observed in the brains of individuals with schizophrenia. 3 Increased neural CAM (NCAM) and decreased L1CAM immunoreactivities have been observed in the cerebrospinal fluid (CSF) of schizophrenic patients in comparison to immunoreactivities in normal control subjects. 4,5 A selective increase in levels of 105-to 115-kDa NCAM in the hippocampi and prefrontal cortices of patients with schizophrenia was found, though levels of other NCAMs and L1CAM were not altered. 6,7 Since NCAMs function can be impaired by viral neuroaminidase associated with maternal influenza infection during embryonic development, 8 and since increased CSF NCAM and decreased CSF L1CAM levels were found in affected but not non-affected twins in a study of monozygotic discordant twins, the changes in NCAMs observed in schizophrenia may not contribute to the genetic predisposition to schizophrenia. 4 However, schizophrenia is known to have a genetic component, and a cohort study suggested an interaction between genetic risk for schizophrenia and obstetric complications. 9,10 It is possible that mutations in the genes encoding CAMs are part of the gene...

Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1 kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10 kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10 kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint-resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions.

Background: The β₂-adrenergic receptor (ADRB2) is the most common adrenergic receptor in the lung, and associations between ADRB2 polymorphisms and intermediate phenotypes of asthma have been reported. Four missense polymorphisms (Arg16Gly, Gln27Glu, Val34Met, and Thr164Ile) and one polymorphism in the 5′ leader cistron of the ADRB2 messenger RNA has been identified. In vitro studies have shown that these missense polymorphisms can affect ADRB2 function. Methods: To examine possible associations of ADRB2 polymorphisms with asthma susceptibility, we performed transmission disequilibrium tests (TDT) of 137 Japanese families identified through children with atopic asthma. Results: We did not find associations between any alleles of the ADRB2 polymorphisms and asthma by TDT (p > 0.1). We also performed a meta-analysis of data from all available studies. The random-effects model showed no significant odds ratio for the Arg16Gln (odds ratio = 1.05, p = 0.53) or Gln27Glu (odds ratio = 1.12, p = 0.22) polymorphism. Conclusion: Our data indicate that ADRB2 does not contribute substantially to susceptibility to asthma, but it is possible that these polymorphisms influence disease activity and drug responses in individuals with asthma.

Here we report on a 5-year-old Japanese girl with developmental delay and microcephaly. Although she had a normal karyotype, a bacterial artificial chromosome-based array-comparative genome hybridization analysis detected a de novo 4.0-Mb heterozygous deletion at Xp11.3-p11.4 harboring nine genes. By comparison with a healthy carrier mother of a boy with atypical Norrie disease having a smaller deletion in the same region, we excluded four genes as candidates whose haploinsufficiency would be causative for developmental delay. Among the other five genes, CASK seems to be the most likely candidate for a causative gene, because it is strongly expressed in fetal brain and plays important roles in neural development and synaptic function. We confirmed that the expression of CASK mRNA was decreased in the patient compared with healthy controls and the patient's X-chromosomal inactivation was not skewed. These results suggested that the genetic deletion of CASK results in haploinsufficiency, which might be causative for the patient's developmental delay or mental retardation. (c) 2008 Wiley-Liss, Inc.