| Affiliation: | 1. Department of Paediatrics and Adolescent Medicine, Center for Rett Syndrome, Rigshospitalet, Copenhagen, Denmark;2. Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;3. Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark;4. Department of Pediatrics, Kolding Hospital, Kolding, Denmark;5. Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark;6. Medical Genetics Department, National and Kapodistrian University of Athens, “Aghia Sophia” Children's Hospital, Athens, Greece;7. Department of Medical Genetics, Hacettepe Medical School, Ankara, Turkey;8. Department of Paediatrics, Murdoch Children's Research Institute, University of Melbourne, Melbourne, Australia;9. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark;10. Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark |
| 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. |
