Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe speech delay*

Weimer, Jörg; Metzke-Heidemann, Simone; Plendl, Hansjörg; Caliebe, Almuth; Grunewald, Regina; Õunap, Katrin; Tammur, Pille; Jonat, W.; Bartsch, Oliver; Siebert, Reiner; Arnold, Norbert

doi:10.1002/ajmg.a.31104

Cited by 6 publications

(5 citation statements)

References 36 publications

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“…This, then, must happen in such a way that, preferentially, ring chromosomes are formed. First, a model proposing that the multiple sSMCs are the result of fertilization by 2 spermatozoa [Beverstock et al, 2003] is not supported by the DNA marker studies in our patient (although such a scenario may provide an explanation for other patients with a r(Y) as 1 of the multiple sSMCs, see the case described by Weimer et al [2006]). Another model is based on the incomplete degradation of a nonextruded second polar body during meiosis II [Daniel and Malafiej, 2003].…”

Section: Discussionmentioning

confidence: 52%

Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

Hochstenbach

Gijn²,

Krijtenburg³

et al. 2012

Mol Syndromol

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In a 24-year-old man with mild intellectual disability, congenital heart defects and obesity, we identified up to 4 small supernumerary marker chromosomes (sSMCs) in blood metaphases. The ring-shaped sSMCs were derived from chromosomes 11, 12 and X as well as a fourth, unidentified chromosome. In interphase nuclei of epithelial cells from the urinary tract and buccal mucosa, the presence of the r(11), r(12) and r(X) was confirmed by FISH. Using Illumina Infinium 317K SNP-arrays, we detected 3 copies of the pericentromeric regions of chromosomes 11, 12 and X. The r(X) was present in 84–89% of cells in the various tissues examined, lacks the XIST gene, but contains FAM123B, a potential dosage-sensitive candidate gene for congenital cardiac abnormalities, and ARHGEF9, a candidate gene for intellectual disability. ARHGEF9 encodes collybistin (CB), which is required for localization of the inhibitory receptor-anchoring protein gephyrin and for formation and maintenance of postsynaptic GABA_A and glycine receptors. We propose that the 2-fold increase in dosage of ARHGEF9 disturbs the stoichiometry of CB with its interacting proteins at inhibitory postsynapses. SNP alleles and short tandem repeat markers on the r(11) and r(X) were compatible with a maternal origin of both sSMCs through a meiosis II error. The sSMCs may have resulted from predivision chromatid nondisjunction, leading to anaphase lagging, followed by incomplete degradation of the supernumerary chromosomes.

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Section: Discussionmentioning

confidence: 52%

Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

Hochstenbach

Gijn²,

Krijtenburg³

et al. 2012

Mol Syndromol

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“…In numerically abnormal karyotypes, sSMCs were most often observed for individuals with Turner, Down, Klinefelter syndromes and Triple X(2,7). The present case is the 4 thKlinefelter syndrome case with a small supernumerary marker chromosome reported in the literature.The first Klinefelter case with a marker chromosome was presented in 1997 by Maneaet al That patient was 2.5 years old and had a mos 48 XXY, + r(?X)/47 XXY karyotype.…”

mentioning

confidence: 61%

“…Signs vary with age (1). Most individuals with Klinefelter syndrome are of normal intelligence, but they may have low verbal scores and diminished speech abilities (2).…”

Section: Introductionmentioning

confidence: 99%

Another Small Supernumerary Marker Chromosome Derived from Chromosome 9 in a Klinefelter Patient

Gulten

Gorukmez²,

Karkucak³

et al. 2012

West Indian Med J

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Marker chromosomes are very rare in Klinefelter patients and phenotypic findings are related to the affected chromosomal region. The phenotypic effects of small supernumerary marker chromosomes (sSMC) range from multiple malformations/mental retardation to no effect (ie a normal phenotype). This wide spectrum of phenotypes is due to the origin, structure and gene content of the marker chromosome. The first Klinefelter case with sSMC 9 was published by Liehr et al in 2005. The present case was referred for chromosomal analysis because of dysmorphic features, speech delay and mild mental retardation. Conventional cytogenetic analysis revealed the 47 XXY karyotype in 17 metaphases and the 48 XXY + marker karyotype in eight metaphases. Fluorescence in situ hybridization (FISH) analysis to identify the marker chromosome was performed using the LSI p16 (9p21) Spectrum Orange/CEP 9 SpectrumGreen Probe (Vysis CDKN2A/CEP 9 FISH Probe) partial trisomy 9 mosaicism was confirmed in this patient. To our knowledge, this is the second Klinefelter syndrome case with a small supernumerary marker chromosome derived from chromosome 9.

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“…The r(Y) chromosome was transmitted via ICSI from the oligospermic but otherwise unremarkable father to the child. Apart from this article we found another one which described a case of an additional r(Y) chromosome [Weimer et al, 2006]. The patient showed signs of KS including gynecomastia, decreased body hair, hypergonadotropic hypogonadism, learning difficulties, an increased value of FSH, and a decreased value of testosterone.…”

Section: Klinefelter Patients With Additional Aberrations On the Y Chmentioning

confidence: 99%

Chromosomal Variants in Klinefelter Syndrome

Frühmesser

Kotzot²

2011

Sex Dev

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Klinefelter syndrome (KS) describes the phenotype of the most common sex chromosome abnormality in humans and occurs in one of every 600 newborn males. The typical symptoms are a tall stature, narrow shoulders, broad hips, sparse body hair, gynecomastia, small testes, absent spermatogenesis, normal to moderately reduced Leydig cell function, increased secretion of follicle-stimulating hormone, androgen deficiency, and normal to slightly decreased verbal intelligence. Apart from that, amongst others, osteoporosis, varicose veins, thromboembolic disease, or diabetes mellitus are observed. Some of the typical features can be very weakly pronounced so that the affected men often receive the diagnosis only at the adulthood by their infertility. With a frequency of 4%, KS is described to be the most common genetic reason for male infertility. The most widespread karyotype in affected patients is 47,XXY. Apart from that, various other karyotypes have been described, including 46,XX in males, 47,XXY in females, 47,XX,der(Y), 47,X,der(X),Y, or other numeric sex chromosome abnormalities (48,XXXY, 48,XXYY, and 49,XXXXY). The focus of this review was to abstract the different phenotypes, which come about by the various karyotypes and to compare them to those with a ‘normal’ KS karyotype. For that the patients have been divided into 6 different groups: Klinefelter patients with an additional isochromosome Xq, with additional rearrangements on 1 of the 2 X chromosomes or accordingly on the Y chromosome, as well as XX males and true hermaphrodites, 47,XXY females and Klinefelter patients with other numeric sex chromosome abnormalities. In the latter, an almost linear increase in height and developmental delay was observed. Men with an additional isochromosome Xq show infertility and other minor features of ‘normal’ KS but not an increased height. Aside from the infertility, in male patients with other der(X) as well as der(Y) rearrangements and in XXY women no specific phenotype is recognizable amongst others due to the small number of cases. The phenotype of XX males depends on the presence of SRY (sex-determining region Y) and the level of X inactivation at which SRY-negative patients are generally rarely observed.

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Characterization of two supernumerary marker chromosomes in a patient with signs of Klinefelter syndrome, mild facial anomalies, and severe speech delay*

Cited by 6 publications

References 36 publications

Gain of <b><i>FAM123B</i></b> and <b><i>ARHGEF9 </i></b>in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

Gain of <b><i>FAM123B</i></b> and <b><i>ARHGEF9 </i></b>in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes

Another Small Supernumerary Marker Chromosome Derived from Chromosome 9 in a Klinefelter Patient

Chromosomal Variants in Klinefelter Syndrome

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