EHMT2 as a Candidate Gene for an Autosomal Recessive Neurodevelopmental Syndrome

Area of Science:

• Genetics
• Epigenetics
• Neurodevelopmental Disorders

Background:

• Neurodevelopmental disorders (NDDs) exhibit genetic heterogeneity, with many involving chromatin regulation genes.
• EHMT1 mutations cause Kleefstra syndrome 1 (KS1); EHMT2's role in NDDs is unknown.
• The EHMT1/2 complex is vital for tissue-specific gene repression.

Purpose of the Study:

• To investigate the role of EHMT2 variants in neurodevelopmental disorders.
• To determine if EHMT2 mutations can cause a Kleefstra-like syndrome.

Main Methods:

• Whole exome sequencing identified a homozygous EHMT2 splice site variant (c.328+2 T>G).
• RNA sequencing analyzed the variant's impact on EHMT2 splicing.
• Epigenetic analysis using the EpiSign assay assessed the KS1 episignature.

Main Results:

• The patient presented with a phenotype resembling KS1, including intellectual disability and dysmorphisms.
• RNAseq revealed aberrant splicing of EHMT2 due to the variant.
• The patient tested positive for the KS1 episignature, confirming epigenetic changes.

Conclusions:

• The EHMT2 splice variant likely causes loss-of-function, leading to a novel autosomal recessive Kleefstra-like syndrome.
• EHMT2 is a potential novel gene implicated in neurodevelopmental disorders.
• Further studies and case identification are needed to confirm EHMT2's role.