Familial NSD1 Exon 3 Deletion Associated with Phenotypic and Epigenetic Variability

Area of Science:

• Genetics and Epigenetics
• Developmental Biology
• Molecular Biology

Background:

• NSD1 pathogenic variants cause Sotos syndrome, a developmental disorder with overgrowth and intellectual disability.
• Familial Sotos syndrome cases are rare, with limited genotype-phenotype correlation data.
• NSD1, an epigenetic regulator, is linked to a specific DNA methylation pattern (episignature).

Purpose of the Study:

• To investigate a family with an NSD1 exon 3 deletion and atypical Sotos syndrome phenotype.
• To correlate genotype with phenotype and DNA methylation patterns within the family.
• To assess the utility of DNA methylation episignature profiling in understanding intrafamilial variability.

Main Methods:

• DNA episignature profiling using a next-generation sequencing approach.
• Comparative analysis of DNA methylation patterns in affected family members, Sotos syndrome patients, and controls.

Main Results:

• Affected family members exhibited clinical variability, with the proband being most severely affected.
• Genome-wide DNA hypomethylation was observed in Sotos syndrome patients and the affected family members.
• The proband's DNA methylation pattern most closely resembled classical Sotos syndrome, with milder patterns in less affected relatives.

Conclusions:

• A familial germline NSD1 exon 3 deletion is associated with mild Sotos syndrome exhibiting variable expressivity.
• DNA methylation episignature analysis revealed a less pronounced pattern in milder cases.
• Methylation episignature analysis is valuable for exploring intrafamilial variability in chromatin disorders.