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• W4241480813 abstract "Copy-number variation (CNV) at the 7q11.23 locus results in two distinct neurodevelopmental disorders: deletions give rise to Williams syndrome (WS), whereas the reciprocal CNV causes 7q11.23 duplication syndrome (Dup7). Because the same genes are altered in each, the study of these two disorders can provide insight into the ways in which gene dosage influences human development. In this issue, Strong et al. question whether DNA-methylation changes occur in children with WS and Dup7. Their analyses identified genome-wide, dose-dependent alterations in DNA methylation in both groups of children. Moreover, the differentially methylated genes were enriched with imprinted genes and genes previously associated with autism spectrum disorder (ASD). An important caveat to this study is that the authors analyzed whole-blood samples, which might not represent the most relevant cell type for these disorders. Nonetheless, the altered gene-expression profiles are suggestive of epigenetic changes occurring very early in development and perhaps altering crucial steps in brain development. These results, together with recent findings in schizophrenia and ASD, suggest the need for additional investigation of how the epigenome contributes to neurodevelopment. Coronary artery disease (CAD) represents a major health issue in developed nations. This complex, polygenic disorder, which results from the buildup of arterial plaque and increases risk for heart attack and stroke, is the leading cause of death in North America. Previous genome-wide association studies, which assume an additive mode of inheritance, have identified dozens of variants associated with CAD risk. Here, drawing upon recent work that has implicated long stretches of homozygous genotypes—or runs of homozygosity (ROHs)—in the etiology of complex traits, most notably those related to neurodevelopmental disorders, Christofidou et al. sought to study the potential role for ROHs in CAD risk. In their analysis of over 20,000 Europeans, the authors noted enrichment of both the number and length of ROHs in individuals with CAD. Their analyses also demonstrated significant differences in gene-expression patterns in monocytes and macrophages in individuals harboring ROHs. Recent work has highlighted an enrichment of predicted deleterious variation in long ROHs, so although the authors failed to detect any discrete stretches of DNA significantly associated with CAD, it is possible that the overall accumulation of recessive variants might represent a key component in the overall genetic architecture of CAD. One confounding factor for sequencing studies is the accidental contamination of a sample with additional DNA from other individuals. When these mixed samples are included in sequencing studies, the overall result is an increase in seemingly heterozygous genotypes; this problem can be made worse with increasing levels of contamination and sequencing depth. In this issue, Flickinger et al. developed cleanCall, a model that calls genotypes from sequencing data while accounting for DNA-sample contamination. In their analyses, calls made by cleanCall showed higher concordance between sequencing and array genotypes than did calls made without the model. Furthermore, the read depth from the contaminated samples and the level of contamination decreased the concordance between the genotype calls, and this could be improved when the adjustment for contamination was implemented in cleanCall. In the future, cleanCall will be expanded so that it can be used for additional types of sequencing data, including RNA sequencing data and multiallelic SNPs. Nearly all teenagers can recount a visit to their nurse or doctor for a scoliosis check, and for good reason: adolescent idiopathic scoliosis (AIS) is the most commonly observed spinal deformity. A polygenic inheritance pattern has been suggested, and genome-wide association studies (GWASs) have identified loci associated with this disorder. Now, Ogura et al. have expanded upon previous GWASs and identified BNC2 SNPs that are associated with AIS. Follow-up analyses revealed that the risk SNPs increase BNC2 expression. The authors uncovered a functional role for one of the SNPs: its presence increases BNC2 enhancer activity through amplified binding to the transcription factor YY1. Moreover, overexpression of this variant allele in fish altered body curvature in a dose-dependent manner. Studies in null mice have revealed a role for BNC2 in craniofacial development, as well as in the proliferation of a variety of mesenchymal cell types. Further study is needed to establish the manner by which BNC2 expression predisposes to AIS, but these results nominate the fine tuning of regulatory pathways crucial for musculoskeletal development as a strong candidate. Intellectual disability (ID) occurs at a much lower frequency in females than in males, in part because of the prevalence of X chromosome mutations that can cause this disorder. Indeed, over 100 X chromosome genes are known to harbor mutations that cause ID in males. In this issue, Blok et al. undertook a study aimed at defining the genetic cause of simplex cases of ID in females. Through a combination of sequencing approaches, the authors identified 38 females harboring de novo mutations in DDX3X, an X chromosome gene whose protein product plays a role in the Wnt signaling pathway, as well as a variety of other cellular processes. Functional studies pointed to a loss-of-function effect for the de novo variants. Notably, de novo DDX3X variants were not detected in males. However, the authors did identify three families who harbor segregating DDX3X missense variants; interestingly, these variants performed identically to the wild-type protein in functional assays. Further work will be required for gaining a full understanding of the gender differences present in DDX3X pathology; this information, in turn, could prove helpful in the search for other genetic causes of ID in females." @default.
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• W4241480813 date "2015-08-01" @default.
• W4241480813 modified "2023-09-26" @default.
• W4241480813 title "This Month in The Journal" @default.
• W4241480813 doi "https://doi.org/10.1016/j.ajhg.2015.07.005" @default.
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