Heterozygous Deletion of the SHOX Gene Enhancer in two Females With Clinical Heterogeneity Associating With Skewed XCI and Escaping XCI

Sun, Yixi; Luo, Yuqin; Qian, Yeqing; Chen, Min; Wang, Liya; Li, Hongge; Zou, Yu

doi:10.3389/fgene.2019.01086

Cited by 10 publications

(9 citation statements)

References 43 publications

(47 reference statements)

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“…This indicates partial XCI on SHOX. Consistent with this, Sun et al reported diverse phenotypes of two women with the same SHOX deletion, who had extremely skewed XCI (12).…”

Section: Discussionmentioning

confidence: 59%

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Hattori

Seki

Inaba

et al. 2021

Preprint

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Adult men are, on average, ~13 cm taller than adult women. Although previous studies have suggested a significant contribution of sex chromosomal genes to sexual dimorphism in height, all attempts to identify a male-specific growth gene have failed. In the present study, we analyzed transcripts from cartilage tissues, and found that the expression of SHOX, a growth-promoting gene in the pseudoautosomal region on the X and Y chromosomes, was lower in females than in males. DNA methylation analyses showed that SHOX has some characteristics of genes subjected to X chromosome inactivation (XCI). These findings indicate that sex difference in human height is mainly ascribed to incomplete spreading of XCI on a pseudoautosomal gene. More importantly, RT-PCR of fibroblast clones revealed XCI-independent random clonal monoallelic expression of SHOX. We presume that during eutherian evolution, SHOX translocated from an autosome to the proto-sex chromosome without losing the epigenetic memory of random clonal monoallelic expression and subsequently underwent partial XCI. This study provides a novel model of epigenetic gene regulation leading to phenotypic diversity in humans.

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“…This indicates partial XCI on SHOX. Consistent with this, Sun et al reported diverse phenotypes of two women with the same SHOX deletion, who had extremely skewed XCI (12).…”

Section: Discussionmentioning

confidence: 59%

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Hattori

Seki

Inaba

et al. 2021

Preprint

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“…This can be explained by the haplo-insufficiency of the short stature homeobox gene ( SHOX ), that is in the pseudoautosomal region (PAR1) (refractory to X inactivation) in the short arm of X chromosome ( 13 , 14 , 15 , 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…The most common feature is short stature, which is found in 95% of patients, especially in patients with 46,X,i(Xq). This can be explained by the haplo-insufficiency of the short stature homeobox gene (SHOX), that is in the pseudoautosomal region (PAR1) (refractory to X inactivation) in the short arm of X chromosome (13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

Double isochromosome X, A rare cytogenetic variant of turner syndrome: A case report and a review of the literature

Zerrouki

Babakhouya

Tajir

2022

Balkan Journal of Medical Genetics

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Turner Syndrome (TS) is a genetic disorder caused by total or partial loss of an X chromosome. The isochromosome X (i(X)) is a known variant of TS, however, double i(X) is a very rare variant, reported very few times in the literature. We report on a rare case of TS with double i(X). This is an 11-year-old female patient , addressed to the medical genetics consultation for short stature and facial features suggestive of TS. We performed a constitutional postnatal karyotype from a peripheral blood sample, with lymphocyte culture, and an R band analysis, performed on 70 metaphases. Metaphases analysis in our patient identified the presence of three cell populations: 45,X[22]/46,X,i(X)(q10)[30]/47,X,i(X)(q10),i(X)(q10) [18]. The first has total chromosome X monosomy, the second with a normal X chromosome and one isochromosome of the long arm of the other X chromosome and the third with a normal X chromosome and two isochromosomes of the long arm of the X chromosome. A control cell culture was performed from a second blood sample of the patient and confirmed the abnormality. This paper will discuss this case in comparison with other rare cases described, as well as the formation of the double isochromosome, based on the literature.

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“…Skewed XCI plays an important role in the phenotypic heterogeneities of many X-linked disorders, even involving in diseases caused by XCI-escaping genes ( Sun et al, 2019 ). Although XCI-escaping genes are expressed from the inactive X chromosome (Xi) in all cells, their expression levels relative to active X chromosome (Xa) levels are usually reduced ( Carrel and Willard, 1999 ).…”

Section: Introductionmentioning

confidence: 99%

Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele

et al. 2022

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Skewed XCI plays an important role in the phenotypic heterogeneities of many X-linked disorders, even involving in diseases caused by XCI-escaping genes. DDX3X-related intellectual disability is more common in females and less common in males, who usually inherit from unaffected heterozygous mothers. As an X inactivation (XCI) escaping gene, the role of skewed XCI in the phenotype of DDX3X mutant female is unknown. Here we reported a DDX3X: c.694_711dup18 de novo heterozygous mutation in a female with intellectual disability on the maternal X chromosome on the basis of SNPs detected by PCR-sanger sequencing. AR assay revealed that the maternal mutant X chromosome was extremely inactivated in the proband. Using RNA sequencing and whole-exome sequencing, we quantified allelic read counts and allele-specific expression, and confirmed that the mutant X chromosome was inactive. Further, we verified that the mutant DDX3X allele had a lower expression level by RNA sequencing and RT-PCR, and the normal and mutated DDX3X expression accounted for respectively 70% and 30% of total. In conclusion, we found a symptomatic female with extreme skewing XCI in the DDX3X mutant allele. It was discovered that XCI in the mutant allele was insufficient to reverse the phenotype of DDX3X-related neurodevelopmental disorder. It contributed to a better understanding of the role of skewed XCI in phenotypic differences, which can aid in the genetic counseling and prenatal diagnosis of disorders in females with DDX3X defects.

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Heterozygous Deletion of the SHOX Gene Enhancer in two Females With Clinical Heterogeneity Associating With Skewed XCI and Escaping XCI

Cited by 10 publications

References 43 publications

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Pseudoautosomal gene SHOX exhibits sex-biased random monoallelic expression and contributes to sex difference in height

Double isochromosome X, A rare cytogenetic variant of turner syndrome: A case report and a review of the literature

Case Report: De novo DDX3X mutation caused intellectual disability in a female with skewed X-chromosome inactivation on the mutant allele

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