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Updated: May 31, 2026
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Identification and Functional Analysis of a Novel NSD2 Missense Variant in a Patient With Rauch-Steindl Syndrome
Shixuan Xu1,2,3, Guoqaing Li1,2,3, Yimin He1,2
1The International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Molecular Genetics & Genomic Medicine
|May 30, 2026
Summary
Rauch-Steindl syndrome (RAUST) is a rare neurodevelopmental disorder. A novel NSD2 missense variant was found to cause aberrant splicing, leading to protein truncation and aiding in RAUST diagnosis.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Rauch-Steindl syndrome (RAUST) is a rare neurodevelopmental disorder caused by pathogenic variants in the NSD2 gene.
- Phenotypic overlap with Wolf-Hirschhorn syndrome (WHS) often leads to misdiagnosis.
- Interpreting missense variants in NSD2 requires functional validation.
Purpose of the Study:
- To identify the genetic cause of RAUST in a patient with overlapping features of WHS.
- To functionally characterize a novel de novo missense variant in NSD2.
- To improve diagnostic accuracy and differentiate between RAUST and WHS.
Main Methods:
- Trio-whole-exome sequencing (WES) was performed.
- Sanger sequencing was used for validation.
- RNA splicing impact was assessed using reverse transcription PCR and TA-cloning.
Main Results:
- A novel de novo missense variant (c.2137G>C, p.Gly713Arg) in NSD2 was identified in a patient with RAUST.
- Functional analysis revealed this variant causes exon 11 skipping, leading to a frameshift and premature protein truncation.
- The identified variant was present in 53% of transcripts.
Conclusions:
- This study reports the first NSD2 missense variant acting as a splicing mutation.
- RNA-level functional assays are crucial for accurate variant interpretation.
- Findings reinforce genotype-phenotype distinctions between RAUST and WHS.
