Epigenotype-genotype-phenotype correlations in SETD1A and SETD2 chromatin disorders

Area of Science:

• Genetics and Epigenetics
• Neurodevelopmental Disorders
• Chromatin Biology

Background:

• Germline pathogenic variants in SETD1A and SETD2 genes are linked to neurodevelopmental disorders (NDDs), characterized by developmental delay and congenital anomalies.
• SETD1A and SETD2 proteins are crucial for chromatin-mediated gene expression regulation.
• Methylation episignatures are increasingly used to interpret variant pathogenicity in NDDs.

Approach:

• Genome-wide methylation profiling of over 2 million CpGs using next-generation sequencing was performed on patients with SETD1A or SETD2 variants.
• Methylation profiles of SETD1A variant patients were compared to identify potential episignatures.
• Clinical and genetic features of SETD2 patient subgroups were reviewed and correlated with methylation data.

Key Points:

• No strong methylation episignature was detected in patients with SETD1A variants.
• SETD2 variants showed distinct methylation episignatures, with hypomethylation in truncating mutations (Luscan-Lumish syndrome) and hypermethylation in missense codon 1740 variants.
• Within the SETD2 codon 1740 subgroup, p.Arg1740Trp variants exhibited more severe methylation changes and clinical phenotypes compared to p.Arg1740Gln variants.

Conclusions:

• Novel epigenotype-genotype-phenotype correlations were identified in SETD2-related NDDs.
• The findings suggest a gain-of-function mechanism for pathogenic SETD2 codon 1740 variants.
• Two out of 10 SETD2-NDD cases developed neoplasms, highlighting a potential link between these variants and cancer.