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Ten years of Genome Medicine

further on the rich source of rare variant genomic data and on human phenotyping of the perturbations of biological homeostasis that present as disease. James R. Lupski Section Editor, Genomics and

Novel parent-of-origin-specific differentially methylated loci on chromosome 16

BackgroundCongenital malformations associated with maternal uniparental disomy of chromosome 16, upd(16)mat, resemble those observed in newborns with the lethal developmental lung disease, alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV). Interestingly, ACDMPV-causative deletions, involving FOXF1 or its lung-specific upstream enhancer at 16q24.1, arise...

From genes to genomes in the clinic

Next-generation sequencing is revolutionizing medical genetics and in the near future will pervade all medical fields. To maximize the potential clinical utility of this approach, global data sharing and phenotyping are needed, and the role of the geneticist in the interpretation of variation is vital.

De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith–Magenis syndrome

BackgroundNeurodevelopmental disorders are genetically and phenotypically heterogeneous encompassing developmental delay (DD), intellectual disability (ID), autism spectrum disorders (ASDs), structural brain abnormalities, and neurological manifestations with variants in a large number of genes (hundreds) associated. To date, a few de novo mutations potentially disrupting TCF20...

From genomic medicine to precision medicine: highlights of 2015

0 6 7 Matthias Schwab 0 4 10 11 0 James R. Lupski, Section Editor, Genomics and epigenomics of disease 1 European Institute for Systems Biology and Medicine, CNRS-ENS-UCBL, Université de Lyon , 69007

Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns

Background Left-sided lesions (LSLs) account for an important fraction of severe congenital cardiovascular malformations (CVMs). The genetic contributions to LSLs are complex, and the mutations that cause these malformations span several diverse biological signaling pathways: TGFB, NOTCH, SHH, and more. Here, we use whole exome sequence data generated in 342 LSL cases to identify...

A visual and curatorial approach to clinical variant prioritization and disease gene discovery in genome-wide diagnostics

BackgroundGenome-wide data are increasingly important in the clinical evaluation of human disease. However, the large number of variants observed in individual patients challenges the efficiency and accuracy of diagnostic review. Recent work has shown that systematic integration of clinical phenotype data with genotype information can improve diagnostic workflows and...

Increased genome instability in human DNA segments with self-chains: homology-induced structural variations via replicative mechanisms

Weichen Zhou Feng Zhang Xiaoli Chen Yiping Shen James R. Lupski Li Jin Environmental factors including ionizing radiation and chemical agents have been known to be able to induce DNA rearrangements

Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations

participated in this study. CNV Study Group James R. Lupski (Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA), Claudia Carvalho (Department of Molecular and Human

Curcumin facilitates a transitory cellular stress response in Trembler-J mice

We have previously shown that oral administration of curcumin significantly decreases the percentage of apoptotic Schwann cells and partially mitigates the severe neuropathy phenotype of the Trembler-J (Tr-J) mouse model in a dose-dependent manner. Here we compared the gene expression in sciatic nerves of 2-week-old pups and adult Tr-J with the same age groups of wild-type mice...

Genomic disorders ten years on

It is now becoming generally accepted that a significant amount of human genetic variation is due to structural changes of the genome rather than to base-pair changes in the DNA. As for base-pair changes, knowledge of gene and genome function has been informed by structural alterations that convey clinical phenotypes. Genomic disorders are a class of human conditions that result...

Enriched rearing improves behavioral responses of an animal model for CNV-based autistic-like traits

Potocki–Lupski syndrome (PTLS; MIM #610883), characterized by neurobehavioral abnormalities, intellectual disability and congenital anomalies, is caused by a 3.7-Mb duplication in 17p11.2. Neurobehavioral studies determined that ∼70–90% of PTLS subjects tested positive for autism or autism spectrum disorder (ASD). We previously chromosomally engineered a mouse model for PTLS (Dp...

Schizophrenia: Incriminating genomic evidence

. ? James R. Lupski is in the Departments of Molecular and Human Genetics, and of Pediatrics, Baylor College of Medicine and Texas Children?s Hospital, Houston, Texas 77030, USA. e-mail: 1. Burmeister , M

PacBio-LITS: a large-insert targeted sequencing method for characterization of human disease-associated chromosomal structural variations

Background Generation of long (>5 Kb) DNA sequencing reads provides an approach for interrogation of complex regions in the human genome. Currently, large-insert whole genome sequencing (WGS) technologies from Pacific Biosciences (PacBio) enable analysis of chromosomal structural variations (SVs), but the cost to achieve the required sequence coverage across the entire human...

Replicative mechanisms of CNV formation preferentially occur as intrachromosomal events: evidence from Potocki–Lupski duplication syndrome

Copy number variations (CNVs) in the human genome contribute significantly to disease. De novo CNV mutations arise via genomic rearrangements, which can occur in ‘trans’, i.e. via interchromosomal events, or in ‘cis’, i.e. via intrachromosomal events. However, what molecular mechanisms occur between chromosomes versus between or within chromatids has not been systematically...

Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics

Donna M. Muzny Richard A. Gibbs Jacques Rougemont Ioannis Xenarios 0 James R. Lupski Alexandre Reymond 0 0 Center for Integrative Genomics, University of Lausanne , 1015 Lausanne , Switzerland

Phenotypic and molecular characterisation of CDK13-related congenital heart defects, dysmorphic facial features and intellectual developmental disorders

Background De novo missense variants in CDK13 have been described as the cause of syndromic congenital heart defects in seven individuals ascertained from a large congenital cardiovascular malformations cohort. We aimed to further define the phenotypic and molecular spectrum of this newly described disorder. Methods To minimise ascertainment bias, we recruited nine additional...

Charcot–Marie–Tooth disease

Charcot-Marie-Tooth (CMT) disease is a heterogeneous group of genetic disorders presenting with the phenotype of a chronic progressive neuropathy affecting both the motor and sensory nerves. During the last decade over two dozen genes have been identified in which mutations cause CMT. The disease illustrates a multitude of genetic principles, including diverse mutational...