Hidden mosaicism in patients with Klinefelter's syndrome: implications for genetic reproductive counselling

Garcia-Quevedo, L.; Blanco, Joan; Sarrate, Zaida; Català, Vicenç; Bassas, Lluís; Vidal, Francesca

doi:10.1093/humrep/der351

Cited by 33 publications

(26 citation statements)

References 35 publications

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“…These data could also explain why mosaic Klinefelter (mos 47,XXY/46XY) patients display oligospermia or cryptozoospermia more frequently. Given that more 46,XY spermatocytes are expected to be present in the testis, they would tend to achieve spermatogenesis, as confirmed recently for 5 mosaic KS patients (Garcia‐Quevedo et al, 2011) and observed for mosaic 45,X/46,XY patients (Giltay et al, 2000).…”

Section: Discussionsupporting

confidence: 60%

The High Frequency of Sperm Aneuploidy in Klinefelter Patients and in Nonobstructive Azoospermia Is Due to Meiotic Errors in Euploid Spermatocytes

Vialard

Bailly

Bouazzi

et al. 2012

Journal of Andrology

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For nonobstructive azoospermic (NOA) patients with a normal karyotype or for Klinefelter syndrome (47,XXY) patients, intracytoplasmic sperm injection is associated with an increased aneuploidy risk in offspring. We examined testicular cells from patients with different azoospermia etiologies to determine the origin of the aneuploid spermatozoa. The incidence of chromosome abnormalities was investigated in all types of azoospermia. Four study subgroups were constituted: Klinefelter patients (group 1), NOA patients with spermatogenesis failure but a normal karyotype (group 2), obstructive azoospermic patients with normal spermatogenesis (group 3), and control patients with normal sperm (group 4). The pachytene stage (in the three azoospermic groups) and postmeiotic cells (in all groups) were analyzed with fluorescence in situ hybridization. No aneuploid pachytene spermatocytes were observed. Postmeiotic aneuploidy rates were higher in the two groups with spermatogenesis failure (5.3% and 4.0% for groups 1 and 2, respectively) than in patients with normal spermatogenesis (0.6% for group 3 and group 4). Whatever the etiology of the azoospermia, the spermatozoa originated from euploid pachytene spermatocytes. These results strengthen the hypothesis whereby sperm aneuploidy in both Klinefelter patients and NOA patients with a normal karyotype results from meiotic abnormalities and not from aneuploid spermatocytes. The fact that sperm aneuploidy was more frequent when spermatogenesis was altered suggests a deleterious testicular environment. The study results also provide arguments for offering preimplantation genetic diagnosis or prenatal diagnosis when a pregnancy occurs for fathers with NOA (whatever the karyotype).

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Section: Discussionsupporting

confidence: 60%

The High Frequency of Sperm Aneuploidy in Klinefelter Patients and in Nonobstructive Azoospermia Is Due to Meiotic Errors in Euploid Spermatocytes

Vialard

Bailly

Bouazzi

et al. 2012

Journal of Andrology

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“…Each sample was submitted for direct DNA sequencing and underwent an AciI restriction enzyme assay that selectively cuts CACNA1C-wild type (WT). The lymphocytederived gDNA was assessed for mutant and WT copy numbers, using a method previously described by Etheridge et al, 8 to quantify the degree of mosaicism present in the mother.…”

Section: Figurementioning

confidence: 99%

“…Interestingly, mosaicism also contributes to the inheritance of other multisystem disorders, such as Klinefelter' s syndrome. 8 With such a wide variety of phenotypic manifestations in TS1, somatic and germline mosaicism provides limitless possibilities for presenting and concealing TS1-causative mutations.…”

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confidence: 99%

Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome

Dufendach¹,

Giudicessi

Boczek

et al. 2013

Pediatrics

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The presence of 2 distinct populations of somatic or germline cells within a single individual harboring different genotypes is termed mosaicism. Recent reports suggest that parental mosaicism is involved in the heritability of type 1 Timothy syndrome (TS1), an extremely rare and life-threatening multisystem disorder characterized by severe QT interval prolongation, syndactyly, and several other complications. Although full TS1 is caused by a single missense mutation in the CACNA1C-encoded cardiac calcium channel, mosaic TS1 parents can display isolated syndactyly without additional phenotypic manifestations. A newborn boy presented with syndactyly at birth. The presence of syndactyly in his mother led to a diagnosis of benign familial syndactyly. However, at 9 months of age, during his first syndactyly-corrective surgery, intraoperative electrocardiograms revealed extreme QT prolongation and 2:1 atrioventricular block. A comprehensive cardiac evaluation was performed, and both mother and child were tested genetically, confirming a clinical suspicion of TS1. Only the patient tested positive for the TS1 mutation; however, more extensive molecular testing revealed a limited presence of the mutation in maternally-derived DNA. This case illustrates the potential of parental mosaicism to confound the diagnosis of potentially life-threatening genetic diseases, such as TS1. Here, a mother with a partial TS1 phenotype and genetically confirmed mosaicism transmitted the TS1-causative mutation to her son, resulting in fully expressive TS1. Thus, a shared partial phenotype should not be dismissed as a benign or insignificant finding, but should be evaluated further to rule out the possibility of parental mosaicism concealing a potentially fatal heritable disease.

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“…However, a number of factors complicate the use of human SCA syndromes as a model for examination of sex chromosome gene-dosage effects, including background genetic and environmental diversity, karyotypic mosaicism (Wolff et al 2010; Garcia-Quevedo et al 2011), and X chromosome parent of origin (Lepage et al 2013). These considerations make murine SCA models an attractive complement to the study of SCA in humans.…”

Section: Introductionmentioning

confidence: 99%

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

et al. 2014

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Murine sex chromosome aneuploidies (SCAs) provide powerful models for charting sex chromosome influences on mammalian brain development. Here, building on prior work in X-monosomic (XO) mice, we use spatially non-biased high-resolution imaging to compare and contrast neuroanatomical alterations in XXY and XO mice relative to their wild-type XX and XY littermates. First, we show that carriage of a supernumerary X chromosome in XXY males (1) does not prevent normative volumetric masculinization of the bed nucleus of the stria terminalis (BNST) and medial amygdala, but (2) causes distributed anatomical alterations relative to XY males, which show a statistically unexpected tendency to be colocalized with and reciprocal to XO-XX differences in anatomy. These overlaps identify the lateral septum, BNST, ventral group thalamic nuclei and periaqueductal gray matter as regions with replicable sensitivity to X chromosome dose across two SCAs. We then harness anatomical variation across all four karyotype groups in our study—XO, XX, XY and XXY—to create an agnostic data-driven segmentation of the mouse brain into five distributed clusters which (1) recover fundamental properties of brain organization with high spatial precision, (2) define two previously uncharacterized systems of relative volume excess in females vs. males (“forebrain cholinergic” and “cerebelo-pontine-thalamo-cortical”), and (3) adopt stereotyped spatial motifs which delineate ordered gradients of sex chromosome and gonadal influences on volumetric brain development. Taken together, these data provide a new framework for the study of sexually dimorphic influences on brain development in health and disrupted brain development in SCA.

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Hidden mosaicism in patients with Klinefelter's syndrome: implications for genetic reproductive counselling

Cited by 33 publications

References 35 publications

The High Frequency of Sperm Aneuploidy in Klinefelter Patients and in Nonobstructive Azoospermia Is Due to Meiotic Errors in Euploid Spermatocytes

The High Frequency of Sperm Aneuploidy in Klinefelter Patients and in Nonobstructive Azoospermia Is Due to Meiotic Errors in Euploid Spermatocytes

Maternal Mosaicism Confounds the Neonatal Diagnosis of Type 1 Timothy Syndrome

Triangulating the sexually dimorphic brain through high-resolution neuroimaging of murine sex chromosome aneuploidies

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