The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

Bitten Schönewolf-Greulich; Maria-Isabel Tejada; K Stephens; K Hadzsiev; J Gauthier; Karen Brøndum-Nielsen; R Pfundt; Kirstine Johanne Theresia Ravn; H Maortua; B Gener; C Martínez-Bouzas; A Piton; G Rouleau; J Clayton-Smith; T Kleefstra; Anne-Marie Bisgaard; Zeynep Tümer

doi:10.1111/cge.12769

The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

Bitten Schönewolf-Greulich, Maria-Isabel Tejada, K Stephens, K Hadzsiev, J Gauthier, Karen Brøndum-Nielsen, R Pfundt, Kirstine Johanne Theresia Ravn, H Maortua, B Gener, C Martínez-Bouzas, A Piton, G Rouleau, J Clayton-Smith, T Kleefstra, Anne-Marie Bisgaard, Zeynep Tümer

Department of Clinical Medicine

10 Citations (Scopus)

Abstract

Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

Original language	English
Journal	Clinical Genetics
Volume	89
Issue number	6
Pages (from-to)	733-738
Number of pages	6
ISSN	0009-9163
DOIs	https://doi.org/10.1111/cge.12769
Publication status	Published - 1 Jun 2016

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10.1111/cge.12769

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Schönewolf-Greulich, B., Tejada, M.-I., Stephens, K., Hadzsiev, K., Gauthier, J., Brøndum-Nielsen, K., Pfundt, R., Ravn, K. J. T., Maortua, H., Gener, B., Martínez-Bouzas, C., Piton, A., Rouleau, G., Clayton-Smith, J., Kleefstra, T., Bisgaard, A.-M., & Tümer, Z. (2016). The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. Clinical Genetics, 89(6), 733-738. https://doi.org/10.1111/cge.12769

Schönewolf-Greulich, B, Tejada, M-I, Stephens, K, Hadzsiev, K, Gauthier, J, Brøndum-Nielsen, K, Pfundt, R, Ravn, KJT, Maortua, H, Gener, B, Martínez-Bouzas, C, Piton, A, Rouleau, G, Clayton-Smith, J, Kleefstra, T, Bisgaard, A-M & Tümer, Z 2016, 'The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome', Clinical Genetics, vol. 89, no. 6, pp. 733-738. https://doi.org/10.1111/cge.12769

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abstract = "Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.",

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T1 - The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

AU - Schönewolf-Greulich, Bitten

AU - Tejada, Maria-Isabel

AU - Stephens, K

AU - Hadzsiev, K

AU - Gauthier, J

AU - Brøndum-Nielsen, Karen

AU - Pfundt, R

AU - Ravn, Kirstine Johanne Theresia

AU - Maortua, H

AU - Gener, B

AU - Martínez-Bouzas, C

AU - Piton, A

AU - Rouleau, G

AU - Clayton-Smith, J

AU - Kleefstra, T

AU - Bisgaard, Anne-Marie

AU - Tümer, Zeynep

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N2 - Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

AB - Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.

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The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome

Abstract

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