Whole-Exome Sequencing Identifies Loci Associated with Blood Cell Traits and Reveals a Role for Alternative GFI1B Splice Variants in Human Hematopoiesis.
The American Journal of Human Genetics 99(2):481 (2016)
Circulating blood cell counts and indices are important indicators of hematopoietic function and a number of clinical parameters, such as blood oxygen-carrying capacity, inflammation, and hemostasis. By performing whole-exome sequence association analyses of hematologic quantitative traits in 15...
Novel patient-derived xenograft and cell line models for therapeutic testing of pediatric liver cancer.
Journal of Hepatology 65(2):325 (2016)
Pediatric liver cancer is a rare but serious disease whose incidence is rising, and for which the therapeutic options are limited. Development of more targeted, less toxic therapies is hindered by the lack of an experimental animal model that captures the heterogeneity and metastatic capability ...
Association of the IGF1 gene with fasting insulin levels.
European Journal of Human Genetics 24(9):1337 (2016)
Insulin-like growth factor 1 (IGF-I) has been associated with insulin resistance. Genome-wide association studies (GWASs) of fasting insulin (FI) identified single-nucleotide variants (SNVs) near the IGF1 gene, raising two hypotheses: (1) these associations are mediated by IGF-I levels and (2) t...
Molecular diagnostic experience of whole-exome sequencing in adult patients.
Genetics in Medicine 18(7):678 (2016)
Whole-exome sequencing (WES) is increasingly used as a diagnostic tool in medicine, but prior reports focus on predominantly pediatric cohorts with neurologic or developmental disorders. We describe the diagnostic yield and characteristics of WES in adults.
We performed a retrospective analysis ...
Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine.
The American Journal of Human Genetics 98(6):1051 (2016)
Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium inclu...
Multilevel Genomics-Based Taxonomy of Renal Cell Carcinoma.
Cell Reports 14(10):2476 (2016)
On the basis of multidimensional and comprehensive molecular characterization (including DNA methalylation and copy number, RNA, and protein expression), we classified 894 renal cell carcinomas (RCCs) of various histologic types into nine major genomic subtypes. Site of origin within the nephron...
Monoallelic and Biallelic Variants in EMC1 Identified in Individuals with Global Developmental Delay, Hypotonia, Scoliosis, and Cerebellar Atrophy.
The American Journal of Human Genetics 98(3):562 (2016)
The paradigm of a single gene associated with one specific phenotype and mode of inheritance has been repeatedly challenged. Genotype-phenotype correlations can often be traced to different mutation types, localization of the variants in distinct protein domains, or the trigger of or escape from...
A t(5;16) translocation is the likely driver of a syndrome with ambiguous genitalia, facial dysmorphism, intellectual disability, and speech delay.
Genetic studies grounded on monogenic paradigms have accelerated both gene discovery and molecular diagnosis. At the same time, complex genomic rearrangements are also appreciated as potent drivers of disease pathology. Here, we report two male siblings with a dysmorphic face, ambiguous genitali...
Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk.
Circulation: Cardiovascular Genetics 9(1):64 (2016)
Rare genetic variants influence blood pressure (BP).
Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4...
Comprehensive Molecular Characterization of Papillary Renal-Cell Carcinoma.
New England Journal of Medicine 374(2):135 (2016)
Papillary renal-cell carcinoma, which accounts for 15 to 20% of renal-cell carcinomas, is a heterogeneous disease that consists of various types of renal cancer, including tumors with indolent, multifocal presentation and solitary tumors with an aggressive, highly lethal phenotype. Little is kno...
An open access pilot freely sharing cancer genomic data from participants in Texas.
Scientific data 3:160010 (2016)
Genomic data sharing in cancer has been restricted to aggregate or controlled-access initiatives to protect the privacy of research participants. By limiting access to these data, it has been argued that the autonomy of individuals who decide to participate in data sharing efforts has been super...
Whole-Exome Sequencing in Familial Parkinson Disease.
JAMA Neurology 73(1):68 (2016)
Parkinson disease (PD) is a progressive neurodegenerative disease for which susceptibility is linked to genetic and environmental risk factors.
To identify genetic variants contributing to disease risk in familial PD.
A 2-stage study design that included a discovery cohort of families with PD an...
Rare variants in the notch signaling pathway describe a novel type of autosomal recessive Klippel-Feil syndrome.
American Journal of Medical Genetics Part A 167A(11):2795 (2015)
Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported ...
The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.
The American Journal of Human Genetics 97(2):199 (2015)
Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological...
Exome sequencing reveals homozygous TRIM2 mutation in a patient with early onset CMT and bilateral vocal cord paralysis.
Humangenetik 134(6):671 (2015)
Charcot-Marie-Tooth disease is a heterogeneous group of inherited distal symmetric polyneuropathies associated with mutations in genes encoding components essential for normal functioning of the Schwann cell and axon. TRIM2, encoding a ligase that ubiquitinates the neurofilament light chain, was...
Analysis of loss-of-function variants and 20 risk factor phenotypes in 8,554 individuals identifies loci influencing chronic disease.
Nature Genetics 47(6):640 (2015)
A typical human exome harbors dozens of loss-of-function (LOF) variants, which can lower disease risk factor levels and affect drug efficacy. We hypothesized that LOF variants are enriched in genes influencing risk factor levels and the onset of common chronic diseases, such as cardiovascular di...
Homozygous loss-of-function mutations in SOHLH1 in patients with nonsyndromic hypergonadotropic hypogonadism.
Journal of Clinical Endocrinology & Metabolism 100(5):E808 (2015)
Hypergonadotropic hypogonadism presents in females with delayed or arrested puberty, primary or secondary amenorrhea due to gonadal dysfunction, and is further characterized by elevated gonadotropins and low sex steroids. Chromosomal aberrations and various specific gene defects can lead to hype...
FBN1 contributing to familial congenital diaphragmatic hernia.
American Journal of Medical Genetics Part A 167A(4):831 (2015)
Congenital diaphragmatic hernia (CDH) is a relatively common, life--threatening birth defect. We present a family with recurrent CDH--paraesophageal and central--for whom exome sequencing (ES) revealed a frameshift mutation (c.4969_4970insA, p.Ile1657Asnfs*30) in the fibrillin 1 gene (FBN1) that...
Association of Rare Loss-Of-Function Alleles in HAL, Serum Histidine: Levels and Incident Coronary Heart Disease.
Circulation: Cardiovascular Genetics 8(2):351 (2015)
Histidine is a semiessential amino acid with antioxidant and anti-inflammatory properties. Few data are available on the associations between genetic variants, histidine levels, and incident coronary heart disease (CHD) in a population-based sample.
By conducting whole exome sequencing on 1152 A...
New mutations in the RAB28 gene in 2 Spanish families with cone-rod dystrophy.
JAMA Ophthalmology 133(2):133 (2015)
The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.
To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutati...