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Critical genes involved in embryonic development are often transcription factors, regulating many downstream genes. LMX1B is a homeobox gene that is involved in formation of the limbs, eyes and kidneys, heterozygous loss‐of‐function sequence variants and deletions cause Nail‐Patella syndrome. Most of the reported variants are localised within the gene's coding sequence, however, approximately 5%–10% of affected individuals do not have a pathogenic variant identified within this region. In this study, we present a family with four affected individuals across two generations with a deletion spanning a conserved upstream LMX1B‐binding sequence. This deletion is de novo in the mother of three affected children. Furthermore, in this family, the manifestations appear limited to the nails and limbs, and therefore may reflect an attenuated phenotype of the classic Nail‐Patella phenotype that includes ophthalmological and renal manifestations. [ABSTRACT FROM AUTHOR]

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. Even very low‐grade mosaicim in methyl‐CPG‐binding protein 2 (MECP2) can cause Rett syndrome in males. The c.1308dupT variant of a male patient was present in 4.2% in blood and 23.8% in muscle tissue (encircled). Analysis of MECP2 in males should be carried out with very high read depth and variant call threshold should be low. A negative finding blood should be repeated using other tissues. [ABSTRACT FROM AUTHOR]

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., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)