37 research outputs found
Phenotype-specific association of the TGFBR3 locus with nonsyndromic cryptorchidism
PURPOSE:
Based on a genome-wide association study of testicular dysgenesis syndrome showing a possible association with TGFBR3, we analyzed data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal.
MATERIALS AND METHODS:
We excluded samples based on strict quality control criteria, leaving 844 cases and 2,718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform (ie Illumina® HumanHap550, version 1 or 3, or Human610-Quad, version 1 BeadChip in group 1 and Human OmniExpress 12, version 1 BeadChip platform in group 2). Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of data for groups 1 and 2, and selective genotyping of independent cases (330) and controls (324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum.
RESULTS:
We identified suggestive (p ≤ 1× 10(-4)) association of markers in/near TGFBR3, including rs9661103 (OR 1.40; 95% CI 1.20, 1.64; p = 2.71 × 10(-5)) and rs10782968 (OR 1.58; 95% CI 1.26, 1.98; p = 9.36 × 10(-5)) in groups 1 and 2, respectively. In subgroup analyses we observed strongest association of rs17576372 (OR 1.42; 95% CI 1.24, 1.60; p = 1.67 × 10(-4)) with proximal and rs11165059 (OR 1.32; 95% CI 1.15, 1.38; p = 9.42 × 10(-4)) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior genome-wide association study signal (rs12082710) was marginal (OR 1.13; 95% CI 0.99, 1.28; p = 0.09 for group 1), and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild-type and cryptorchid rat fetal gubernaculum.
CONCLUSIONS:
These data suggest complex or phenotype specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling
Inferring Parametric Energy Consumption Functions at Different Software Levels:ISA vs. LLVM IR
The static estimation of the energy consumed by program
executions is an important challenge, which has applications in program
optimization and verification, and is instrumental in energy-aware software
development. Our objective is to estimate such energy consumption
in the form of functions on the input data sizes of programs. We have developed
a tool for experimentation with static analysis which infers such
energy functions at two levels, the instruction set architecture (ISA) and
the intermediate code (LLVM IR) levels, and re
ects it upwards to the
higher source code level. This required the development of a translation
from LLVM IR to an intermediate representation and its integration
with existing components, a translation from ISA to the same representation,
a resource analyzer, an ISA-level energy model, and a mapping
from this model to LLVM IR. The approach has been applied to programs
written in the XC language running on XCore architectures, but
is general enough to be applied to other languages. Experimental results
show that our LLVM IR level analysis is reasonably accurate (less than
6:4% average error vs. hardware measurements) and more powerful than
analysis at the ISA level. This paper provides insights into the trade-off
of precision versus analyzability at these levels
Metals in some dominant vascular plants, mosses, lichens, algae, and the biological soil crust in various types of terrestrial tundra, SW Spitsbergen, Norway
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Barriers to implementation of guidelines for the diagnosis and management of undescended testis
Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function Variant
Context: Autosomal dominant and rarely de novo gain-of-function variants in the gene are associated with precocious male puberty, while somatic variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the gene. Digital droplet polymerase chain reaction of the variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in . The gain-of-function nature of the variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys
Expanding the reproductive organ phenotype of CHD7-spectrum disorder
CHD7 disorder is a multiple congenital anomaly syndrome with a highly variable phenotypic spectrum, and includes CHARGE syndrome. Internal and external genital phenotypes frequently seen in CHD7 disorder include cryptorchidism and micropenis in males, and vaginal hypoplasia in females, both thought to be secondary to hypogonadotropic hypogonadism. Here, we report 14 deeply phenotyped individuals with known CHD7 variants (9 pathogenic/likely pathogenic and 5 VOUS) and a range of reproductive and endocrine phenotypes. Reproductive organ anomalies were observed in 8 of 14 individuals and were more commonly noted in males (7/7), most of whom presented with micropenis and/or cryptorchidism. Kallmann syndrome was commonly observed among adolescents and adults with CHD7 variants. Remarkably, one 46,XY individual presented with ambiguous genitalia, cryptorchidism with Müllerian structures including uterus, vagina and fallopian tubes, and one 46,XX female patient presented with absent vagina, uterus and ovaries. These cases expand the genital and reproductive phenotype of CHD7 disorder to include two individuals with genital/gonadal atypia (ambiguous genitalia), and one with Müllerian aplasia