Y-chromosome microdeletions are not associated with SHOX haploinsufficiency

Chianese, Chiara; Giacco, Deborah Lo; Tüttelmann, Frank; Ferlin, Alberto; Ntostis, Panagiotis; Vinci, Serena; Balercia, Giancarlo; Ars, Elisabet; Ruíz-Castañé, Eduard; Giglio, Sabrina; Forti, Gianni; Kliesch, Sabine; Krausz, Csilla

doi:10.1093/humrep/det322

Cited by 13 publications

(9 citation statements)

References 19 publications

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“…They raised the question about the importance of screening for SHOX ‐linked copy number variations in men carrying Yq microdeletions. However, a subsequent much larger multicentre study did not find an association between Y‐chromosomal microdeletions and SHOX haploinsufficiency, implying that deletion carriers have no augmented risk of SHOX ‐related pathologies (short stature and skeletal anomalies) (Chianese et al ., ).…”

Section: Genetic Counsellingmentioning

confidence: 97%

EAA/EMQN best practice guidelines for molecular diagnosis of Y‐chromosomal microdeletions: state‐of‐the‐art 2013

et al. 2013

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The molecular diagnosis of Y-chromosomal microdeletions is a common routine genetic test which is part of the diagnostic workup of azoospermic and severe oligozoospermic men. Since 1999, the European Academy of Andrology (EAA) and the European Molecular Genetics Quality Network (EMQN) have been actively involved in supporting the improvement of the quality of the diagnostic assays by publication of the laboratory guidelines for molecular diagnosis of Y-chromosomal microdeletions and by offering external quality assessment trials. The present revision of the 2004 laboratory guidelines summarizes all the clinical novelties related to the Y chromosome (classic, partial and gene-specific deletions, genotype–phenotype correlations, methodological issues) and provides an update on the results of the quality control programme. These aspects also reflect the consensus of a large group of specialists present at a round table session during the recent Florence-Utah-Symposium on ‘Genetics of male infertility’ (Florence, 19–21 September, 2013). During the last 10 years the gr/gr deletion has been demonstrated as a significant risk factor for impaired sperm production. However, the screening for this deletion type in the routine diagnostic setting is still a debated issue among experts. The original basic protocol based on two multiplex polymerase chain reactions remains fully valid and appropriate for accurate diagnosis of complete AZF deletions and it requires only a minor modification in populations with a specific Y chromosome background. However, in light of novel data on genotype–phenotype correlations, the extension analysis for the AZFa and AZFb deletions is now routinely recommended. Novel methods and kits with excessively high number of markers do not improve the sensitivity of the test, may even complicate the interpretation of the results and are not recommended. Annual participation in an external quality control programme is strongly encouraged. The 12-year experience with the EMQN/EAA scheme has shown a steep decline in diagnostic (genotyping) error rate and a simultaneous improvement on reporting practice.

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Section: Genetic Counsellingmentioning

confidence: 97%

EAA/EMQN best practice guidelines for molecular diagnosis of Y‐chromosomal microdeletions: state‐of‐the‐art 2013

et al. 2013

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“…Indeed, this information raised the question about the importance of screening for SHOX-linked CNVs in men carrying Y-chromosome microdeletions. Our group performed a large multicenter study in order to evaluate whether such an alarming hypothesis was actually true (Chianese et al 2013). No association was found between Y-chromosome microdeletions and SHOX haploinsufficiency, implying that deletion carriers have no augmented risk of SHOX-related pathologies (short stature and skeletal anomalies).…”

Section: R167mentioning

confidence: 99%

Genetics of male infertility: from research to clinic

Krausz¹,

Riera-Escamilla²,

Chianese³

2015

Reproduction

190

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Male infertility is a multifactorial complex disease with highly heterogeneous phenotypic representation and in at least 15% of cases, this condition is related to known genetic disorders, including both chromosomal and single-gene alterations. In about 40% of primary testicular failure, the etiology remains unknown and a portion of them is likely to be caused by not yet identified genetic anomalies. During the last 10 years, the search for 'hidden' genetic factors was largely unsuccessful in identifying recurrent genetic factors with potential clinical application. The armamentarium of diagnostic tests has been implemented only by the screening for Y chromosomelinked gr/gr deletion in those populations for which consistent data with risk estimate are available. On the other hand, it is clearly demonstrated by both single nucleotide polymorphisms and comparative genomic hybridization arrays, that there is a rare variant burden (especially relevant concerning deletions) in men with impaired spermatogenesis. In the era of next generation sequencing (NGS), we expect to expand our diagnostic skills, since mutations in several hundred genes can potentially lead to infertility and each of them is likely responsible for only a small fraction of cases. In this regard, system biology, which allows revealing possible gene interactions and common biological pathways, will provide an informative tool for NGS data interpretation. Although these novel approaches will certainly help in discovering 'hidden' genetic factors, a more comprehensive picture of the etiopathogenesis of idiopathic male infertility will only be achieved by a parallel investigation of the complex world of gene environmental interaction and epigenetics.Reproduction (2015) 150 R159-R174

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“…This finding led to hypothesis that microdeletion carriers undergoing ART would expose their future sons to the risk of having not only fertility problems but also SHOX-linked pathologies. However, these alarming data have been contradicted by a more recent study performed on an almost doubled study population [13], in which none of the microdeletion carriers displayed SHOX deletion. This discrepancy might depend on either methodological issues or the different ethnic background of the two examined study populations.…”

Section: Genetic Counsellingmentioning

confidence: 85%

Genetic testing and counselling for male infertility

Krausz

Chianese

2014

Current Opinion in Endocrinology, Diabetes &Amp; Obesity

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As for Klinefelter patients, novel preventive measures to preserve fertility have been proposed although they are not yet applicable in the routine setting. Y-chromosome deletions have both diagnostic and prognostic values and their testing is advised to be performed according to the new European Academy of Andrology/European Molecular Genetics Quality Network guidelines. Among monogenic diseases, major advances have been obtained in the identification of novel genes of hypogonadotrophic hypogonadism. Pharmacogenetic approaches of hormonal treatment in infertile men with normal values of follicle-stimulating hormone (FSH) are promising and based on FSHR and FSHB polymorphisms. X chromosome-linked deletions are relevant for impaired spermatogenesis. In about 40% of male infertility, the cause is unknown and novel genetic factors are expected to be discovered in the near future.

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Y-chromosome microdeletions are not associated with SHOX haploinsufficiency

Cited by 13 publications

References 19 publications

EAA/EMQN best practice guidelines for molecular diagnosis of Y‐chromosomal microdeletions: state‐of‐the‐art 2013

EAA/EMQN best practice guidelines for molecular diagnosis of Y‐chromosomal microdeletions: state‐of‐the‐art 2013

Genetics of male infertility: from research to clinic

Genetic testing and counselling for male infertility

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