The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype

Abstract

SUMMARYThe Klinefelter syndrome (KS) is the most frequent sex chromosomal disorder in males, characterized by at least one supernumerary X chromosome (most frequent karyotype 47,XXY). This syndrome presents with a broad range of phenotypes. The common characteristics include small testes and infertility, but KS subjects are at increased risk of hypogonadism, cognitive dysfunction, obesity, diabetes, metabolic syndrome, osteoporosis, and autoimmune disorders, which are present in variable proportion. Although part of the clinical variability might be linked to a different degree of testicular function observed in KS patients, genetic mechanisms of the supernumerary X chromosome might contribute. Gene-dosage effects and parental origin of the supernumerary X chromosome have been suggested to this regard. No study has been performed analyzing the genetic constitution of the X chromosome in terms of copy number variations (CNVs) and their possible involvement in phenotype of KS. To this aim, we performed a SNP arrays analysis on 94 KS and 85 controls. We found that KS subjects have more frequently than controls X-linked CNVs (39/94, [41.5%] with respect to 12/ 42, [28.6%] of females, and 8/43, [18.6%] of males, p < 0.01). The number of X-linked CNVs in KS patients was 4.58 AE 1.92 CNVs/subject, significantly higher with respect to that found in control females (1.50 AE 1.29 CNVs/subject) and males (1.14 AE 0.37 CNVs/subject). Importantly, 94.4% X-linked CNVs in KS subjects were duplications, higher with respect to control males (50.0%, p < 0.001) and females (83.3%, p = 0.1). Half of the X-linked CNVs fell within regions encompassing genes and most of them (90%) included genes escaping X-inactivation in the regions of X-Y homology, particularly in the pseudoautosomal region 1 (PAR1) and Xq21.31. This study described for the first time the genetic properties of the X chromosome in KS and suggests that X-linked CNVs (especially duplications) might contribute to the clinical phenotype.

Klinefelter syndrome comorbidities linked to increased X chromosome gene dosage and altered protein interactome activity

“…LEP and EPO appear relevant to the increased prevalence of at least diabetes and obesity in KS patients (43) and might be used as biomarkers for the clinical management of KS in the future. An interesting observation was that both LEP and LEPR were down-regulated.…”

Copy Number Variations in Candidate Genes and Intergenic Regions Affect Body Mass Index and Abdominal Obesity in Mexican Children

“…In terms of CNVs, Rocca et al found that this region is associated with the phenotypes of the Klinefelter syndrome (KS) [37], which has a wide range of phenotypes. The common characteristics include small testes and infertility, but KS subjects are at increased risk of hypogonadism, cognitive dysfunction, obesity, T2D, osteoporosis, and autoimmune disorders [38].…”

The Sex Chromosome Hypothesis of Schizophrenia: Alive, Dead, or Forgotten? A Commentary and Review

“…In this report of over 21,000 cases, CNVs were found in various locations throughout the genome, but also included 2 Mol Neuropsychiatry 2018;4:83-89 DOI: 10.1159/000491489 significant duplications on Xq28 (one of which was in MAGEA11) and suggestive, although not significant, deletions on Xp21.2 (DMD). It is also interesting that a study of CNVs in Klinefelter's individuals [62] showed an overall increase in CNVs when compared with normal males or females, and half of the X-linked CNVs fell within regions encompassing genes. Most of these genes (90%) escape X inactivation and are within the regions of X-Y homology, particularly the pseudoautosomal region 1 (PAR1) and Xq21.…”