Resumé
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 | |
| Status | Udgivet - mar. 2019 |
Fingeraftryk
Bibliografisk note
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.Citer dette
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Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements. / Schönewolf-Greulich, Bitten; Bisgaard, Anne-Marie; Dunø, Morten; Jespersgaard, Cathrine; Rokkjaer, Mette; Hansen, Lars Kjaersgaard; Tsoutsou, Eirini; Sofokleous, Christalena; Topcu, Meral; Kaur, Simran; Van Bergen, Nicole J; Brøndum-Nielsen, Karen; Larsen, Martin J; Sørensen, Kristina P; Christodoulou, John; Fagerberg, Christina R; Tümer, Zeynep.
I: Clinical Genetics, Bind 95, Nr. 3, 03.2019, s. 403-408.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review
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 - Rokkjaer, Mette
AU - Hansen, Lars Kjaersgaard
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
N1 - © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2019/3
Y1 - 2019/3
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 - MECP2
KW - NGS
KW - Rett syndrome
KW - male
KW - mosaicism
U2 - 10.1111/cge.13473
DO - 10.1111/cge.13473
M3 - Journal article
C2 - 30417326
VL - 95
SP - 403
EP - 408
JO - Clinical Genetics
JF - Clinical Genetics
SN - 0009-9163
IS - 3
ER -