Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

Fieremans, Nathalie; Esch, Hilde Van; Holvoet, Maureen; Goethem, Gert Van; Devriendt, Koenraad; Roselló, Mónica; Mayo, Sonia; Martı́nez, Francisco; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; Lupski, James R.; Vermeesch, Joris Robert; Marynen, Peter; Froyen, Guy

doi:10.1002/humu.23012

Cited by 81 publications

(93 citation statements)

References 71 publications

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“…The preferential activation of the paternal X then lead to the expression of the mutated PQBP1 gene, which we postulate to be located on the paternal chromosome (Figure b). This phenomenon has been reported in other XLIDs typically expressed in males; extreme skewing (>90%) is more frequent in females with XLID and causal variants have been identified in several patients with extreme skewing (Fieremans et al, ). In this case, mother and daughter could appear to be skewed in opposite directions around the PQBP1 locus if a crossover event(s) occurred outside of the informative assayed regions (Xp22.12‐Xq13.1) containing the PQBP1 locus.…”

Section: Discussionmentioning

confidence: 59%

Renpenning syndrome in a female

Cho

Peñaherrera

Souich

et al. 2019

American J of Med Genetics Pt A

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Renpenning syndrome (OMIM: 309500) is a rare X‐linked disorder that causes intellectual disability, microcephaly, short stature, a variety of eye anomalies, and characteristic craniofacial features. This condition results from pathogenic variation of PQBP1, a polyglutamine‐binding protein involved in transcription and pre‐mRNA splicing. Renpenning syndrome has only been reported in affected males. Carrier females do not usually have clinical features, and in reported families with Renpenning syndrome, most female carriers exhibit favorable skewing of X‐chromosome inactivation. We describe a female with syndromic features typical of Renpenning syndrome. She was identified by exome sequencing to have a de novo heterozygous c.459_462delAGAG mutation in PQBP1 (Xp11.23), affecting the AG hexamer in exon 4, which is the most common causative mutation in this syndrome. Streaky hypopigmentation of the skin was observed, supporting a hypothesized presence of an actively expressed, PQBP1 mutation‐bearing X‐chromosome in some cells. X‐inactivation studies on peripheral blood cells demonstrated complete skewing in both the proband and her mother with preferential inactivation of the maternal X chromosome in the child. We demonstrated expression of the PQBP1 mutant transcript in leukocytes of the affected girl. Therefore, it is highly likely that the PQBP1 mutation arose from the paternal X chromosome.

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Section: Discussionmentioning

confidence: 59%

Renpenning syndrome in a female

Cho

Peñaherrera

Souich

et al. 2019

American J of Med Genetics Pt A

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“…Although our patient had some phenotypic features that differed from those of typical CdLS patients, she also had intellectual disability, a common feature of CdLS patients with HDAC8 mutation. Previous studies indicated that atypical phenotypes of female CdLS patients with HDAC8 mutation might be due to SXCI [6,7,16]. In view of this, SXCI analysis of the present patient was also carried out and confirmed the presence of SXCI, which could explain the atypical phenotype of the patient.…”

Section: Discussionmentioning

confidence: 78%

“…Other phenotypic features, including small hands and feet and feeding difficulties in infancy, were also observed in CdLS patients with HDAC8 mutation. Harakalova et al [14] Kaiser et al [7] Feng et al [15] Fieremans et al [16] Parenti et al [17] Total …”

Section: Phenotypic Features Of Cdls Patients With Hdac8 Mutationmentioning

confidence: 99%

A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome

Gao¹,

Huang²,

Fan³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cornelia de Lange Syndrome (CdLS) is a rare genetic disorder classically characterized by distinctive facies, growth retardation, intellectual disability, feeding difficulties, and multiple organ system anomalies. Previously, the diagnosis of CdLS was based mainly on identifying the typical phenotype in patients. However, with the advances in clinical molecular genetic diagnostic techniques, more patients, especially patients with milder phenotypes, are being diagnosed from detecting pathogenic mutation. Methods: Pathogenic mutation in a female patient with a milder phenotype was detected using whole-exome sequencing (WES), and was further characterized using bioinformatic analysis and in vitro functional experiments, including X-chromosome inactivation analysis, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and enzyme activity assay. Results: This patient was found to harbor a novel missense mutation (c.806T>G, p.I269R) in the coding region of the HDAC8 gene, which was predicted to be pathogenic. Compared with other CdLS patients with HDAC8 mutation, the patient lacked typical facies, including synophrys and arched eyebrows. In vitro functional experiments showed the presence of skewed X-chromosome inactivation. Furthermore, the novel mutation decreased the dissolubility and enzymatic activity of HDAC8 protein. Conclusions: The present study identified a novel missense mutation (c.806T>G, p.I269R) in the HDAC8 gene leading to CdLS, which not only provided strong evidence for diagnosis in this present patient, but also expanded the spectrum of pathogenic mutations for CdLS.

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“…However, exceptions to this rule have been noted since the first descriptions of males with X‐linked intellectual disability (XLID) . In the first report of the fragile X syndrome [MIM: 300806] in 1943 by Martin and Bell, the authors noted that “… the milder form of deficiency, exhibited by females … would remind the reader, however, that occasionally genes appear to be incompletely recessive, in that they may manifest to a less severe degree in heterozygotes …“ Moreover, while it has become clear that some female carriers of XLID conditions show variable cognitive dysfunction similar to male patients, the mechanisms driving this variability in females are still unclear …”

Section: Introductionmentioning

confidence: 99%

“…Protection from phenotypic expression in carrier females of XLID conditions has been largely attributed to skewed inactivation of the X chromosome and compensation by the normal allele, with evidence for this coming from studies showing more frequent skewing of X‐inactivation (XI) in female carriers of XLID syndromes as compared to non‐carrier females . X‐inactivation is established in the blastocyst stage of embryonic development and is responsible for random transcriptional downregulation of one of the two X‐chromosomes in somatic cells .…”

Section: Introductionmentioning

confidence: 99%

X‐linked intellectual disability: Phenotypic expression in carrier females

et al. 2019

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To better understand the landscape of female phenotypic expression in X‐linked intellectual disability (XLID), we surveyed the literature for female carriers of XLID gene alterations (n = 1098) and combined this with experience evaluating XLID kindreds at the Greenwood Genetic Center (n = 341) and at the University of Adelaide (n = 157). One‐hundred forty‐four XLID genes were grouped into nine categories based on the level of female phenotypic expression, ranging from no expression to female only expression. For each gene, the clinical presentation, gene expression in blood, X‐inactivation (XI) pattern, biological pathway involved, and whether the gene escapes XI were noted. Among the XLID conditions, 88 (61.1%) exhibited female cognitive phenotypic expression only, while 56 (38.9%) had no female phenotypic expression (n = 45), phenotype expression with normal cognition in females (n = 8), or unknown status for female phenotypic expression (n = 3). In twenty‐four (16.6%) XLID genes, XI was consistently skewed in female carriers, in 54 (37.5%) XI showed variable skewing, and in 33 (22.9%) XI was consistently random. The XI pattern was unknown in 33 (22.9%) XLID conditions. Therefore, there is evidence of a female carrier phenotype in the majority of XLID conditions although how exactly XI patterns influence the female phenotype in XLID conditions remains unclear.

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Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern

Cited by 81 publications

References 71 publications

Renpenning syndrome in a female

Renpenning syndrome in a female

A Functional Mutation in HDAC8 Gene as Novel Diagnostic Marker for Cornelia De Lange Syndrome

X‐linked intellectual disability: Phenotypic expression in carrier females

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