Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions

Barthold, Julia Spencer; Wang, Yanping; Kolon, Thomas F.; Kollin, Claude; Nordenskjöld, Agneta; Fisher, Alicia Olivant; Figueroa, T. Ernesto; Bani-Hani, Ahmad H.; Hagerty, Jennifer A.; González, R. Jiménez; Noh, Paul H.; Chiavacci, Rosetta M.; Harden, Kisha R.; Abrams, Debra; Kim, Chong; Jin, Li; Hákonarson, Hákon; Devoto, Marcella

doi:10.1093/humrep/dev180

Cited by 22 publications

(32 citation statements)

References 69 publications

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“…cryptorchidism in the absence of other congenital anomalies). 197 In a GWAS of 844 boys with cryptorchidism and 2,718 controls, no individual SNPs reached a level of genome-wide significance. Pathway analysis, however, suggested that loci important in cyptoskeleton-dependent function may be of importance.…”

Section: Geneticsmentioning

confidence: 99%

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Risk factors for cryptorchidism

et al. 2017

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The condition known as cryptorchidism – undescended testis – is one of the most common congenital abnormalities found among males, and is one of the few known risk factors for testicular cancer (TC). Like testicular cancer, the key exposures in the occurrence of cryptorchidism remain elusive. Testicular descent is thought to occur during two hormonally-controlled phases – between 8–15 weeks and 25–35 weeks gestation – and while it is clear that a failure of testes to descend permanently is likely due to disruptions to one or both of these phases, the cause(s) and mechanism(s) of such disruption are still unclear. In this manuscript, we review the broad range of putative risk factors that have been evaluated in relation to the development of cryptorchidism to date, discuss their plausibility, and make suggestions regarding further approaches to understand aetiology. There are few exposures for which there is consistent evidence of an association with cryptorchidism; and in those cases where evidence appears unequivocal – for example, the relationship between cryptorchidism and gestational measures such as low birth weight – the measured exposure is likely to be a surrogate for the true causal exposure. The relative importance of each risk factor may vary considerably between mother/son pairs depending on an array of genetic, maternal, placental and foetal factors – all of which could vary between regions.

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Section: Geneticsmentioning

confidence: 99%

“…The authors noted that their findings might reflect the fact that susceptibility to this disease is highly heterogeneous and possibly driven by environmental causes and/or rare genetic variants. 197 …”

Section: Geneticsmentioning

confidence: 99%

Risk factors for cryptorchidism

et al. 2017

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“…Using these bioinformatics resources in our previous study, we associated cryptorchidism-associated genomic variations with musclecontraction pathway (Cannistraci et al, 2013). Additionally, cytoskeleton-dependent molecular and cellular functions were found to be prevalent using pathway analysis of suggestive GWAS signals, and may implicate loci encoding cytoskeletal proteins that participate in androgen receptor signaling (Barthold et al, 2015).…”

Section: Discussionmentioning

confidence: 98%

Molecular mechanisms of cryptorchidism development: update of the database, disease comorbidity, and initiative for standardization of reporting in scientific literature

Urh

Kunej

2016

Andrology

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SUMMARYCryptorchidism is a frequent urogenital abnormality that may be present at birth (congenital form) or develop later in life (acquired form). It represents 2-4% full-term male births. It has a potential effect on health; defects in testes descent usually cause impaired spermatogenesis resulting in reduced fertility and increased rates of testicular neoplasia, and testicular torsion. In our previous study, we developed a cryptorchidism gene database which consists of 217 genomic variations associated with development of cryptorchidism in seven mammalian species. The number of studies and study approaches in this field are increasing; therefore, update of the database was needed. The search of multi-omics data was performed and the updated database includes 280 genomic variations associated with cryptorchidism in seven species. The catalog has been complemented with additional data including: number of participants (patients/controls), race/ethnicity, clinical data (age period at diagnosis), congenital/acquired cryptorchidism, unilateral (left/right)/bilateral cryptorchidism, disease comorbidity, and disease ontology. Collected data revealed that cryptorchidism has been reported to be co-present with 150 comorbid conditions, including several syndromes, reproductive, cardiovascular, ophthalmologic, dermatologic, mental, and bone disorders, deafness, and cancer. However, updating the database is time-consuming because of the heterogeneity of results and methodology in scientific literature. The field lacks a standardized format for reporting associations between genotype and phenotype which would enable faster development of the database, data integration, sharing, and facilitate biomarker development. Therefore, in this study, we updated a database of cryptorchidism genes and suggested a first step toward standardization of the format for reporting results of original as well as review studies which we suggest implementing into the scientific literature that reports genotype-cryptorchidism associations.

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“…It is possible that some of the 57 patients without any CNV detected in this study harbor RIT1 CNVs. On the other hand, recent evidence from breeding studies of a cryptorchid rat strain (Barthold et al ., ); and from association studies in both pigs (Elansary et al ., ) and man (Barthold et al ., ) have suggested that cryptorchidism is inherited as a polygenic trait, whit different variants contributing to susceptibility. Therefore, we suggest that the RAF1 microduplication detected in this study represents one of these variants.…”

Section: Discussionmentioning

confidence: 99%

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism

et al. 2017

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Cryptorchidism is the most common congenital disorder in boys, but the cause for most cases remains unknown. Patients with Noonan Syndrome are characterized by a typical face, growth retardation, congenital heart defects, learning disabilities and cryptorchidism. Copy number variations of Ras/MAPK pathway genes are unusual in patients with several clinical features of Noonan Syndrome; however, they have not been studied in patients with only one feature of this condition, such as cryptorchidism. Our aim was to determine whether patients with isolated cryptorchidism exhibit Ras/MAPK pathway gene copy number variations (CNVs). Fifty-nine patients with isolated cryptorchidism and negative for mutations in genes associated with Noonan Syndrome were recruited. Determination of Ras/MAPK pathway gene CNVs was performed by Comparative Genome Hybridization array. A CNV was identified in two individuals, a ~175 kb microduplication at 3p25.2, partially including RAF1. A similar RAF1 microduplication has been observed in a patient with testicular aplasia. This suggests that some patients with isolated cryptorchidism may harbor Ras/MAPK pathway gene CNVs.

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Pathway analysis supports association of nonsyndromic cryptorchidism with genetic loci linked to cytoskeleton-dependent functions

Cited by 22 publications

References 69 publications

Risk factors for cryptorchidism

Risk factors for cryptorchidism

Molecular mechanisms of cryptorchidism development: update of the database, disease comorbidity, and initiative for standardization of reporting in scientific literature

Copy number variants of Ras/MAPK pathway genes in patients with isolated cryptorchidism

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