Y-chromosome microdeletions are not associated with SHOX haploinsufficiency

studyquestion: Are Y-chromosome microdeletions associated with SHOX haploinsufficiency, thus representing a risk of skeletal anomalies
for the carriers and their male descendents?
summary answer: The present study shows that SHOX haploinsufficiency is unlikely to be associated with Y-chromosome microdeletions.
what is known already: Y-chromosome microdeletions are not commonly known as a major molecular genetic cause of any pathological
condition except spermatogenic failure. However, it has been recently proposed that they are associated not only with infertility but also
with anomalies in the pseudoautosomal regions (PAR), among which SHOX haploinsufficiency stands out with a frequency of 5.4% in microdeletion
carriers bearing a normal karyotype. This finding implies that sons fathered by men with Y-chromosome defects will not only exhibit fertility
problems, but might also suffer from SHOX-related conditions.
study design: Five European laboratories (Florence, Mu¨nster, Barcelona, Padova and Ancona), routinely performing Y-chromosome
microdeletion screening, were enrolled in a multicenter study.
participants/materials, setting, methods: PAR-linked and SHOX copy number variations (CNVs) were analyzed in 224
patients carrying Y-chromosome microdeletions and 112 controls with an intact Y chromosome, using customized X-chromosome-specific
array-CGH platforms and/or qPCR assays for SHOX and SRY genes.
main results and the role of chance: Our data show that 220 out of 224 (98.2%) microdeletion carriers had a normal SHOX
copy number, as did all the controls. No SHOX deletionswere found in any of the examined subjects (patients as well as controls), thus excluding
an association with SHOX haploinsufficiency. SHOX duplications were detected in 1.78% of patients (n ¼ 4), of whom two had an abnormal and
two a normal karyotype. This might suggest that Y-chromosome microdeletions have a higher incidence forSHOXduplications, irrespective of the
patient’s karyotype. However, the only clinical condition observed in our four SHOX-duplicated patients was infertility.
limitations, reasons for caution: The number of controls analyzed is rather low to assess whether the SHOX duplications
found in the two men with Y-chromosome microdeletions and a normal karyotype represent a neutral polymorphism or are actually associated
with the presence of the microdeletion.
wider implications of the findings: Men suffering from infertility due to the presence of Y-chromosome microdeletions can
resort to artificial reproductive technology (ART) to father their biological children. However, infertile couples must be aware of the risks implied
and this makes genetic counseling a crucial step in the patient’s management. This study does not confirm previous alarming data that showed an
association between Y-chromosome microdeletions and SHOX haploinsufficiency. Our results imply that deletion carriers have no augmented risk of SHOX-related pathologies (short stature and skeletal anomalies) and indicate that there is no need for radical changes in genetic counseling
of Yq microdeletion carriers attempting ART, since the only risk established so far for their male offspring remains impaired spermatogenesis.