Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

Bitten Schönewolf-Greulich; Anne Marie Bisgaard; Morten Dunø; Cathrine Jespersgaard; Mette Rokkjær; Lars K. Hansen; Eirini Tsoutsou; Christalena Sofokleous; Meral Topcu; Simran Kaur; Nicole J. Van Bergen; Karen Brøndum-Nielsen; Martin J. Larsen; Kristina P. Sørensen; John Christodoulou; Christina R. Fagerberg; Zeynep Tümer

doi:10.1111/cge.13473

Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

Bitten Schönewolf-Greulich^*, Anne Marie Bisgaard, Morten Dunø, Cathrine Jespersgaard, Mette Rokkjær, Lars K. Hansen, Eirini Tsoutsou, Christalena Sofokleous, Meral Topcu, Simran Kaur, Nicole J. Van Bergen, Karen Brøndum-Nielsen, Martin J. Larsen, Kristina P. Sørensen, John Christodoulou, Christina R. Fagerberg, Zeynep Tümer

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

3 Citationer (Scopus)

Abstract

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

Originalsprog	Engelsk
Tidsskrift	Clinical Genetics
Vol/bind	95
Udgave nummer	3
Sider (fra-til)	403-408
ISSN	0009-9163
DOI	https://doi.org/10.1111/cge.13473
Status	Udgivet - 2019

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10.1111/cge.13473

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Schönewolf-Greulich, B., Bisgaard, A. M., Dunø, M., Jespersgaard, C., Rokkjær, M., Hansen, L. K., Tsoutsou, E., Sofokleous, C., Topcu, M., Kaur, S., Van Bergen, N. J., Brøndum-Nielsen, K., Larsen, M. J., Sørensen, K. P., Christodoulou, J., Fagerberg, C. R., & Tümer, Z. (2019). Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements. Clinical Genetics, 95(3), 403-408. https://doi.org/10.1111/cge.13473

Schönewolf-Greulich, B, Bisgaard, AM, Dunø, M, Jespersgaard, C, Rokkjær, M, Hansen, LK, Tsoutsou, E, Sofokleous, C, Topcu, M, Kaur, S, Van Bergen, NJ, Brøndum-Nielsen, K, Larsen, MJ, Sørensen, KP, Christodoulou, J, Fagerberg, CR & Tümer, Z 2019, 'Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements', Clinical Genetics, bind 95, nr. 3, s. 403-408. https://doi.org/10.1111/cge.13473

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title = "Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements",

abstract = "Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.",

keywords = "male, MECP2, mosaicism, NGS, Rett syndrome",

author = "Bitten Sch{\"o}newolf-Greulich and Bisgaard, {Anne Marie} and Morten Dun{\o} and Cathrine Jespersgaard and Mette Rokkj{\ae}r and Hansen, {Lars K.} and Eirini Tsoutsou and Christalena Sofokleous and Meral Topcu and Simran Kaur and {Van Bergen}, {Nicole J.} and Karen Br{\o}ndum-Nielsen and Larsen, {Martin J.} and S{\o}rensen, {Kristina P.} and John Christodoulou and Fagerberg, {Christina R.} and Zeynep T{\"u}mer",

year = "2019",

doi = "10.1111/cge.13473",

language = "English",

volume = "95",

pages = "403--408",

journal = "Clinical Genetics",

issn = "0009-9163",

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TY - JOUR

T1 - Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

AU - Schönewolf-Greulich, Bitten

AU - Bisgaard, Anne Marie

AU - Dunø, Morten

AU - Jespersgaard, Cathrine

AU - Rokkjær, Mette

AU - Hansen, Lars K.

AU - Tsoutsou, Eirini

AU - Sofokleous, Christalena

AU - Topcu, Meral

AU - Kaur, Simran

AU - Van Bergen, Nicole J.

AU - Brøndum-Nielsen, Karen

AU - Larsen, Martin J.

AU - Sørensen, Kristina P.

AU - Christodoulou, John

AU - Fagerberg, Christina R.

AU - Tümer, Zeynep

PY - 2019

Y1 - 2019

N2 - Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

AB - Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

KW - male

KW - MECP2

KW - mosaicism

KW - NGS

KW - Rett syndrome

U2 - 10.1111/cge.13473

DO - 10.1111/cge.13473

M3 - Journal article

C2 - 30417326

AN - SCOPUS:85058056185

SN - 0009-9163

VL - 95

SP - 403

EP - 408

JO - Clinical Genetics

JF - Clinical Genetics

IS - 3

ER -

Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

Abstract

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