Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Hu, Jie; Ou, Zhishuo; Infante, Elena; Kochmar, Sally J.; Madan‐Khetarpal, Suneeta; Hoffner, Lori; Parsazad, Shafagh; Surti, Urvashi

doi:10.1186/s13039-017-0326-4

Cited by 7 publications

(3 citation statements)

References 14 publications

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“…Based upon the above data, we hypothesize that SP1 is a candidate hypospadias associated gene. Considering that SP1 is likely to be dosage sensitive [43], rs11170516 may affect proximal SP1 gene expression in a minor effect, which can disturb a variety of downstream pathways including: androgen production and signaling, estrogen production and signaling, gonad development and signaling and estrogen pathway. Additional genetic and functional characterization of this SNP and other loci are needed to further delineate the mechanism by which the 12q13.13 locus contributes to the etiology and expression of hypospadias.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

et al. 2019

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BackgroundHypospadias risk–associated gene variants have been reported in populations of European descent using genome-wide association studies (GWASs). There is little known at present about any possible hypospadias risk associations in Han Chinese populations.MethodsTo systematically investigate hypospadias risk–associated gene variants in Chinese patients, we performed the first GWAS in a Han Chinese cohort consisting of 197 moderate-severe hypospadias cases and 933 unaffected controls. Suggestive loci (p < 1 × 10− 4) were replicated in 118 cases and 383 controls, as well as in a second independent validation population of 137 cases and 190 controls. Regulatory and protein-protein interactions (PPIs) were then conducted for the functional analyses of candidate variants.ResultsWe identified rs11170516 with the risk allele G within the SP1/SP7 region that was independently associated with moderate-severe hypospadias [SP1/SP7, rs11170516, Pcombine = 3.5 × 10− 9, odds ratio (OR) = 1.96 (1.59–2.44)]. Results also suggested that rs11170516 is associated with the expression of SP1 as a cis-expression quantitative trait locus (cis-eQTL). Protein SP1 could affect the risk of hypospadias via PPIs.ConclusionsWe performed the first GWAS of moderate-severe hypospadias in a Han Chinese cohort, and identified one novel susceptibility cis-acting regulatory locus at 12q13.13, which may regulate a variety of hypospadias-related pathways by affecting proximal SP1 gene expression and subsequent PPIs. This study complements known common hypospadias risk-associated variants and provides the possible role of cis-acting regulatory variant in causing hypospadias.

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Section: Discussionmentioning

confidence: 99%

Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

et al. 2019

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“…However, Patt and and exon 2 of the AAAS gene, the second is the g.16166_17813delinTGAGGCCTGCTG homozygous indel mutation encompassing introns 7 to 10 of the AAAS gene, the third is the recently reported g. 53306793_53321761del homozygous deletion of the exon 7 of C12orf10 and all exons of the AAAS gene 61,97,127 . Furthermore, a few heterozygous AAAS gene microdeletions implicating also the HOX gene clusters and neighboring genes have been reported causing psychomotor retardation and skeletal abnormalities but not causing TAS symptoms, despite being possible conductors for the syndrome if another disease-causing mutation were to occur [128][129][130] .…”

Section: Oral Disorders and Other Clinical Manifestationsmentioning

confidence: 99%

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

Pogliaghi

Cangiano

Duminuco

et al. 2020

PPL

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: Triple-A Syndrome (TAS) is a rare autosomal recessive disorder characterized by three cardinal symptoms: alacrimia, achalasia and adrenal insufficiency due to ACTH insensitivity. Various progressive neurological abnormalities and skin changes have been described in association with the syndrome. The disease is caused by mutation in the AAAS gene on chromosome 12q13. Mutations in AAAS were identified in more than 90% of individuals and families with TAS. The protein encoded by AAAS was termed ALADIN and is part of the WD repeat family of proteins, that have been found to be involved in many different functions such as protein-protein interaction, RNA processing, cytoskeleton assembly, control of cell division, signal transduction and apoptosis. Immunohistochemical analysis showed that mutated or truncated ALADIN localizes to the cytoplasm rather than to the nuclear pore complex. The exact function of ALADIN and the mechanisms that lead to the ACTH-resistant adrenal phenotype remains largely unknown. Nonetheless, recent studies provided some insights on the role of ALADIN as a member of the Nuclear Pore Complex not only implicated in the import of proteins involved in DNA repair and oxidative stress homeostasis but also in the strengthening of the mitotic spindle assembly. Early identification of the syndrome is challenging, given the rarity of the condition and high phenotypic heterogeneity even among members of the same family. In this review, we aim to summarize the current knowledge of clinical and molecular profile of patients with TAS and recommendations for the diagnosis, management, and follow-up of patients.

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“…Moreover, animal and human studies have demonstrated that mutations in genes involved in testis descent, such as androgen receptor (AR), insulin-like factor 3 (INSL3) and its receptor relaxin family peptide receptor 2 (RXFP2), might be the cause of some cases of non-syndromic cryptorchidism (Kumagai et al, 2002;Ferlin et al, 2003Ferlin et al, , 2008Foresta & Ferlin, 2004;Bogatcheva & Agoulnik, 2005). Furthermore, patients affected by microdeletion or microduplication syndrome have been reported to be at higher risk of undescended testes among syndromic features (Kashevarova et al, 2014;Hu et al, 2017), suggesting that structural variations might contribute to the etiology of cryptorchidism. Indeed, the possible involvement of genetic factors in human cryptorchidism constitutes the research topic of many studies in recent years (Gurney et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

E2F1 copy number variations contribute to spermatogenic impairment and cryptorchidism by increasing susceptibility to heat stress

et al. 2019

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Background: Copy number variations (CNVs) play an important role in the onset of several diseases, and recently research focused on the relationship between these structural variants and diseases of the reproductive tract, including male infertility and cryptorchidism. Objectives: To evaluate the contribution of copy number variations of E2F1 gene to idiopathic male infertility and the factors influencing expression of this gene. Materials and Methods: We performed a retrospective study on 540 subjects recruited from September 2014 to February 2015. TaqMan CNV assay was used to analyze E2F1 CNV. Real-time PCR was used to assess E2F1 and HSP70 expression level in heat stressed and transfected cells with three E2F1 copies. Results: We found a significant difference in the frequency of altered E2F1 copies in patients (12/343, 3.5%) compared with controls (0/197) (p = 0.005). Six patients with E2F1 CNV had history of cryptorchidism, but the prevalence between men with idiopathic infertility (6/243, 2.5%) and infertile men with history of cryptorchidism (6/100, 6.0%) was not statistically different (p = 0.1). E2F1 expression increased under heat stress conditions, especially in cells carrying more copies of gene and this was associated with increased expression of HSP70. Discussion: Our data suggest that an abnormal E2F1 expression caused by multiple copies of E2F1 gene predisposes to the onset of infertility and that the risk further increases if subjects with altered E2F1 copies have stressful conditions, such as heat stress or history of cryptorchidism. Conclusion: This study shows a link between E2F1 CNV and male infertility, suggesting that the increased risk of spermatogenic impairment associated with higher E2F1 copies might be due to higher susceptibility to stressful conditions.

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Chromosome 12q13.13q13.13 microduplication and microdeletion: a case report and literature review

Cited by 7 publications

References 14 publications

Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

Genome-wide association study in Chinese cohort identifies one novel hypospadias risk associated locus at 12q13.13

Triple-A Syndrome (TAS): An In-Depth Overview on Genetic and Phenotype Heterogeneity

E2F1 copy number variations contribute to spermatogenic impairment and cryptorchidism by increasing susceptibility to heat stress

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