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

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.

A Female Patient with Xq28 Microduplication Presenting with Myotubular Myopathy, Confirmed with a Custom-Designed X-array.

X-linked myotubular myopathy (XLMTM) is a rare inherited neuromuscular disorder associated with mutations in the MTM1 gene on the Xq28 region. We report a severely affected girl with XLMTM, caused by maternally inherited 661 kb Xq28 microduplication identified by chromosomal microarray analysis and confirmed also on DNA from muscle biopsy with a custom-designed X-chromosome-specific microarray. X-inactivation analysis revealed a skewed inactivation pattern on the proband's muscle biopsy. Muscle biopsy histopathology was indicative of increased variability in fiber diameter, marked and diffuse endomysial proliferation of adipose and connective tissues, as well as predominance of type 1 fibers.