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A Novel Deep Intronic Variant in NSD1 Causing Sotos Syndrome
Alejandro Parra1,2,3,4, Mario Cazalla1,2,3,4, Juan A Jimenez-Estrada2
1CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
American Journal of Medical Genetics. Part A
|April 3, 2025
Summary
Whole genome sequencing identified a novel deep intronic variant in NSD1, leading to Sotos syndrome. Methylation analysis confirmed the diagnosis, highlighting advanced genetic testing
Area of Science:
- Genetics
- Molecular Biology
- Epigenetics
Background:
- Sotos syndrome is a genetic disorder often caused by pathogenic variants in the NSD1 gene.
- Conventional diagnostic methods may not always detect all causative genetic alterations.
- Whole Genome Sequencing (WGS) offers comprehensive genomic analysis.
Observation:
- A female patient presented with a clear clinical phenotype suggestive of Sotos syndrome.
- Deep intronic variant in the NSD1 gene was identified using WGS.
- RNA sequencing (RNA-seq) demonstrated the creation of a novel exon (exonization) due to the variant.
Findings:
- Methylation analysis revealed an episignature pattern consistent with Sotos syndrome.
- The identified deep intronic variant in NSD1 was confirmed as pathogenic.
- The combination of WGS, RNA-seq, and methylation analysis successfully diagnosed Sotos syndrome.
Implications:
- This case underscores the utility of WGS for diagnosing genetic disorders with complex presentations.
- Methylation profiling is emerging as a valuable diagnostic tool for Sotos syndrome and potentially other genetic conditions.
- Advanced molecular techniques are crucial for identifying novel variants and improving diagnostic yield in rare diseases.
Keywords:
NSD1RNA‐seqSotos syndromeepisignatureintronic variantmethylation patternwhole genome sequencingMore Related Videos
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