Male With Mosaicism for Supernumerary Ring X Chromosome

Baker, Peter R.; Tsai, Anne Chun Hui; Springer, Michelle; Swisshelm, Karen; March, Jennifer R.; Brown, Kathleen; Bellus, Gary A.

doi:10.1097/scs.0b013e3181ec6ac0

Cited by 9 publications

(5 citation statements)

References 34 publications

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“…Analogous to the situation in females, where heterozygous duplication of EFNB1 was shown to be associated with mild CFNS features (26), a case was recently reported of a male with mosaicism for a supernumerary ring X chromosome containing a normal EFNB1 gene copy [karyotype 46,XY/47,XY,r(X)]. The affected individual exhibited several clinical features suggestive of CFNS, and the authors of the paper noted several other reminiscent, but less well-characterized cases in older literature (27). …”

Section: Discussionmentioning

confidence: 99%

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Twigg¹,

Babbs²,

Elzen

et al. 2013

Human Molecular Genetics

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Craniofrontonasal syndrome (CFNS), an X-linked disorder caused by loss-of-function mutations of EFNB1, exhibits a paradoxical sex reversal in phenotypic severity: females characteristically have frontonasal dysplasia, craniosynostosis and additional minor malformations, but males are usually more mildly affected with hypertelorism as the only feature. X-inactivation is proposed to explain the more severe outcome in heterozygous females, as this leads to functional mosaicism for cells with differing expression of EPHRIN-B1, generating abnormal tissue boundaries—a process that cannot occur in hemizygous males. Apparently challenging this model, males occasionally present with a more severe female-like CFNS phenotype. We hypothesized that such individuals might be mosaic for EFNB1 mutations and investigated this possibility in multiple tissue samples from six sporadically presenting males. Using denaturing high performance liquid chromatography, massively parallel sequencing and multiplex-ligation-dependent probe amplification (MLPA) to increase sensitivity above standard dideoxy sequencing, we identified mosaic mutations of EFNB1 in all cases, comprising three missense changes, two gene deletions and a novel point mutation within the 5′ untranslated region (UTR). Quantification by Pyrosequencing and MLPA demonstrated levels of mutant cells between 15 and 69%. The 5′ UTR variant mutates the stop codon of a small upstream open reading frame that, using a dual-luciferase reporter construct, was demonstrated to exacerbate interference with translation of the wild-type protein. These results demonstrate a more severe outcome in mosaic than in constitutionally deficient males in an X-linked dominant disorder and provide further support for the cellular interference mechanism, normally related to X-inactivation in females.

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Section: Discussionmentioning

confidence: 99%

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Twigg¹,

Babbs²,

Elzen

et al. 2013

Human Molecular Genetics

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“…Several chromosomal aberrations have been observed in 30%-60% of PM cases, and in more than 80% of cases, chromosomal abnormalities are present in a mosaic state (Salas-Labadía et al, 2019). The presence of SMCs in PM patients has been reported previously and the most representative chromosomes involved are: 3, 5, 6, 9, 10, 13, 15, 18, 20, and X (Stanley et al, 1993;Boon et al, 1996;Portnoï et al, 1999;Hansen et al, 2003;Akahoshi et al, 2004;Lloveras et al, 2004;Gimelli et al, 2007;Villa, 2007;Murthy et al, 2008;Dhar et al, 2009;González-Enseñat et al, 2009;Baker et al, 2010;Oiso et al, 2010;Cappanera et al, 2011;Kraoua et al, 2011;Brock et al, 2012;Patil et al, 2012;Faletra et al, 2013;Myers et al, 2015;Cunha et al, 2016;Naoki et al, 2017;Samanta and Schaefer, 2020;Nisson et al, 2021). However, the genotype-phenotype correlations of most sSMCs remain unknown and need to be established (Liehr et al, 2011).…”

Section: Introductionmentioning

confidence: 83%

“…Another report described duplication Xp11.2-p21.3, which shares similar clinical manifestations with our patient, including DD and cutaneous manifestations ( Gustashaw et al, 1994 ). It is important to consider that genetic counseling should be recommended to parents ( Baker et al, 2010 ; Kromann et al, 2018 ; Liehr, 2021 ; Liehr, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism

Navarrete-Meneses,

Ochoa-Mellado,

Gutiérrez-Álvarez

et al. 2024

Front. Genet.

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Introduction:The combination of gene content on the marker chromosome, chromosomal origin, level of mosaicism, origin mechanism (chromothripsis), and uniparental disomy can influence the final characterization of sSMCs. Several chromosomal aberrations, including sSMCs, have been observed in 30%–60% of patients with pigmentary mosaicism, and in more than 80%, chromosomal abnormalities are present in the mosaic state. In patients with pigmentary mosaicism the most representative chromosomes involved in sSMCs are 3, 5, 6, 9, 10, 13, 15, 18, 20, and X. In this study, we included the complete clinical, cytogenetic, and molecular characterization of seven patients with pigmentary mosaicism associated with the presence of SMCs of different chromosomal origins.Methods:The patients were diagnosed by the Genetics and Dermatology Department of three different hospitals. Cytogenetic and FISH analyses were performed on peripheral blood, light skin, and dark skin. FISH analysis was performed using different probes, depending on the marker chromosome description. Different array analysis was performed.Results:To date, of the seven cases studied, the chromosomal origins of six were successfully identified by FISH or array analysis. The chromosomes involved in SMCs were 6, 9, 15, and 18, X. The most frequently found was the centric minute structure.Discussion:To date, this group of seven patients constitutes the largest clinical and cytogenetically finely described study of cases with pigmentary mosaicism associated with sSMCs. Undoubtedly, analysis of the two skin types is a fundamental part of our study, as numerical differences may occur in the cell lines found in each skin type. The knowledge generated in this study will help delineate a very heterogeneous entity more accurately, and in the future, analyzing more patients with PM will likely establish a more definite association with the presence of this genetic alteration.

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“…Although marker chromosomes may be frequently identified in patients with gonadal dysgenesis, a detailed molecular characterization of 46,XY patients with mosaicism of a supernumerary X chromosome has been rarely reported in the literature. Baker et al [2010] described a male with the mosaicism 46,XY/47,XY,r(X) that had multiple congenital anomalies, including features of craniofrontonasal dysplasia of the central nervous system, as well as cardiac, urogenital (hypospadia, cryptorchidism, and the presence of uterus and fallopian tubes), limb, and cutaneous anomalies. Array-CGH mapping previously determined that a derivative X chromosome consisted of a 24-Mb genomic segment that contains regions of Xp11.3 through Xq13.1, but not Xp21, and also lacks XIST [Baker et al, 2010].…”

Section: Discussionmentioning

confidence: 99%

“…Baker et al [2010] described a male with the mosaicism 46,XY/47,XY,r(X) that had multiple congenital anomalies, including features of craniofrontonasal dysplasia of the central nervous system, as well as cardiac, urogenital (hypospadia, cryptorchidism, and the presence of uterus and fallopian tubes), limb, and cutaneous anomalies. Array-CGH mapping previously determined that a derivative X chromosome consisted of a 24-Mb genomic segment that contains regions of Xp11.3 through Xq13.1, but not Xp21, and also lacks XIST [Baker et al, 2010]. Gonadal histology and the hormonal profile of this previous patient was not reported.…”

Section: Discussionmentioning

confidence: 99%

A Small Supernumerary Xp Marker Chromosome Including Genes NR0B1 and MAGEB Causing Partial Gonadal Dysgenesis and Gonadoblastoma

Nishi

Júnior

Krepischi

et al. 2021

Sex Dev

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Copy number variations of several genes involved in the process of gonadal determination have been identified as a cause of 46,XY differences of sex development. We report a non-syndromic 14-year-old female patient who was referred with primary amenorrhea, absence of breast development, and atypical genitalia. Her karyotype was 47,XY,+mar/46,XY, and FISH analysis revealed the X chromosome origin of the marker chromosome. Array-CGH data identified a pathogenic 2.0-Mb gain of an Xp21.2 segment containing NR0B1/DAX1 and a 1.9-Mb variant of unknown significance from the Xp11.21p11.1 region. This is the first report of a chromosomal microarray analysis to reveal the genetic content of a small supernumerary marker chromosome detected in a 47,XY,+der(X)/46,XY karyotype in a non-syndromic girl with partial gonadal dysgenesis and gonadoblastoma. Our findings indicate that the mosaic presence of the small supernumerary Xp marker, encompassing the NR0B1/DAX1 gene, may have been the main cause of dysgenetic testes development, although the role of MAGEB and other genes mapped to the Xp21 segment could not be completely ruled out.

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Male With Mosaicism for Supernumerary Ring X Chromosome

Cited by 9 publications

References 34 publications

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Cellular interference in craniofrontonasal syndrome: males mosaic for mutations in the X-linked EFNB1 gene are more severely affected than true hemizygotes

Cytogenomic characterization of small supernumerary marker chromosomes in patients with pigmentary mosaicism

A Small Supernumerary Xp Marker Chromosome Including Genes <b><i>NR0B1</i></b> and <b><i>MAGEB</i></b> Causing Partial Gonadal Dysgenesis and Gonadoblastoma

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