Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-gen... Plain language summary The authors compared the DNA methylation patterns in blood from individuals with two rare neurodevelopmental disorders (childhood-onset dystonia [DYT-KMT2B] and Kabuki syndro...

Spontaneous pneumothorax is a common respiratory presentation that may signal underlying genetic disease. Familial pneumothorax occurs in ~10% of primary cases, yet 75% remain genetically unclassified. We report identical twin brothers presenting with spontaneous pneumothoraces in adulthood, leading to a diagnosis of Tatton-Brown-Rahman syndrome (TBRS), a DNMT3A-related overgrowth disorder not previously associated with pneumothorax. Both individuals exhibited tall stature, mild intellectual disability, hypermobility, and cardiac abnormalities. Whole genome sequencing identified a rare de novo DNMT3A missense variant (c.1585 G > A, p.D529N) absent from population databases and predicted to be damaging. Methylation profiling confirmed genome-wide hypomethylation consistent with impaired DNMT3A function, supporting pathogenicity. No variants were found in known familial pneumothorax genes. Apical blebs observed at surgery and connective tissue features suggest a mechanistic link between TBRS and pneumothorax, analogous to other monogenic connective tissue disorders. This case expands the phenotypic spectrum of TBRS and highlights the importance of genetic evaluation in familial pneumothorax. Diagnosis enables personalised care, including surveillance for extrapulmonary complications such as aortic root dilatation and haematological malignancy. Our findings suggest that TBRS should be considered in patients presenting with pneumothorax, tall stature, and neurodevelopmental features. Further cases are needed to confirm this association and refine clinical management strategies.

Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific histone methyltransferase, is an important epigenetic regulator and pathogenic variants in NSD1 are associated with a distinctive blood DNA methylation pattern (episignature). We described a family with an NSD1 exon 3 deletion and an atypical clinical phenotype. Methods: DNA episignature profiling was undertaken with a next generation sequencing-based approach. Results: Within the family, the three affected individuals showed clinical variability with the proband being most severely affected, although none showed unequivocal macrocephaly or the characteristic facial features of Sotos syndrome. DNA methylation profiling was performed in the three affected family members, eight individuals with Sotos syndrome, and compared to control samples. The eight individuals with Sotos syndrome displayed genome-wide hypomethylation as previously described. DNA hypomethylation was also apparent in the three family members with the NSD1 exon 3 deletion with the proband being most similar to the episignature observed in confirmed Sotos syndrome patients. The two more mildly affected relatives had less pronounced DNA hypomethylation. Conclusions: A familial germline exon 3 NSD1 deletion was associated with mild Sotos syndrome phenotype with variable expressivity and a DNA methylation episignature that was less marked in milder cases than in individuals with classical Sotos syndrome. These findings support the use of methylation episignature analysis to explore intrafamilial variability in chromatin disorders.