Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature

Heide, Solveig; Afenjar, Alexandra; Edery, Patrick; Sanlaville, Damien; Keren, Boris; Lavillaureix, Alinoë; Hyon, Capucine; Doummar, Diane; Siffroi, Jean‐Pierre; Chantot‐Bastaraud, Sandra

doi:10.1016/j.ejmg.2015.04.003

Cited by 15 publications

(18 citation statements)

References 22 publications

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“…These data are in accordance with previous studies that describe ratios from 2.5% to 17%. 3,7 There is clinical overlap between symptomatic female carriers with dystrophinopathy and limb-girdle muscular dystrophy. [2][3][4][5][6] The differential diagnosis between both is of the utmost importance for adequate genetic counseling because limb-girdle muscular dystrophy presents with dominant or recessive autosomal inheritance and dystrophinopathy presents an X-linked inheritance.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Cotta

Paim

Carvalho

et al. 2017

Can. J. Neurol. Sci.

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Section: Discussionmentioning

confidence: 99%

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Cotta

Paim

Carvalho

et al. 2017

Can. J. Neurol. Sci.

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“…Moser and Emery cites the first case of a manifesting carrier of DMD was in 1934 by Kryschowa and Abowjan [6]. While the majority of female carriers do not manifest symptoms, studies have shown that 2-17% develop DMD symptomology [5,7,8]. Similar to males with DMD, manifesting carriers present with skeletal muscle weakness and cardiomyopathy, with the gravity of skeletal muscle weakness ranging from mild muscle weakness to more severe DMD-like progression [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Literature on female carriers and manifesting carriers of DMD is comprised of cohort studies, case studies, and meta-analyses, focused on X-chromosome inactivation and phenotype characterization with the majority of information on cardiomyopathy and limited information on skeletal muscle weakness [5,7,8,[12][13][14][15][16][17]. The vast majority of research using rodent models of DMD, such as the commonly used mdx mouse, has used males to investigate the pathogenesis of and treatments for DMD, with literature on DMD signs in females being sparse [18].…”

Section: Introductionmentioning

confidence: 99%

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

et al. 2021

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Female carriers of Duchenne muscular dystrophy (DMD) presenting with DMD symptomology similar to males with DMD, such as skeletal muscle weakness and cardiomyopathy, are termed manifesting carriers. There is phenotypic variability among manifesting carriers including the age of onset, which can range from the first to fourth decade of life. In females, estrogen levels typically begin to decline during the fourth decade of life and estrogen deficiency contributes to loss of muscle strength and recovery of strength following injury. Thus, we questioned whether the decline of estrogen impacts the development of DMD symptoms in females. To address this question, we studied 6–8 month-old homozygous mdx female mice randomly assigned to a sham or ovariectomy (OVX) surgical group. In vivo whole-body plethysmography assessed ventilatory function and diaphragm muscle strength was measured in vitro before and after fatigue. Anterior crural muscles were analyzed in vivo for contractile function, fatigue, and in response to eccentric contraction (ECC)-induced injury. For the latter, 50 maximal ECCs were performed by the anterior crural muscles to induce injury. Body mass, uterine mass, hypoxia-hypercapnia ventilatory response, and fatigue index were analyzed by a pooled unpaired t-test. A two-way ANOVA was used to analyze ventilatory measurements. Fatigue and ECC-injury recovery experiments were analyzed by a two-way repeated-measures ANOVA. Results show no differences between sham and OVX mdx mice in ventilatory function, strength, or recovery of strength after fatigue in the diaphragm muscle or anterior crural muscles (p ≥ 0.078). However, OVX mice had significantly greater eccentric torque loss and blunted recovery of strength after ECC-induced injury compared to sham mice (p ≤ 0.019). Although the results show that loss of estrogen has minimal impact on skeletal muscle contractile function in female mdx mice, a key finding suggests that estrogen is important in muscle recovery in female mdx mice after injury.

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“…Various types of mutation in ARX and IL1RAPL1 are associated with intellectual disability . Some female carriers of a non‐functional DMD gene, with skewed X‐inactivation, show signs of muscle weakness . If the X chromosomes, affected by this molecular alteration, were not fully subjected to random X inactivation in all tissues, we could speculate that intellectual disability and hypotonia in this patient are the consequence.…”

Section: Discussionmentioning

confidence: 91%

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring

et al. 2016

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Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield.

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Xp21 deletion in female patients with intellectual disability: Two new cases and a review of the literature

Cited by 15 publications

References 22 publications

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Impact of estrogen deficiency on diaphragm and leg muscle contractile function in female mdx mice

Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring

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