Genotype-phenotype correlations in individuals with pathogenic RERE variants

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Molecular Biology

Background:

• Heterozygous variants in the arginine-glutamic acid dipeptide repeats gene (RERE) are linked to neurodevelopmental disorder with or without anomalies of the brain, eye, or heart (NEDBEH).
• Understanding genotype-phenotype correlations in RERE-related disorders is crucial for accurate diagnosis and patient management.

Observation:

• Nine individuals with NEDBEH carrying partial deletions or deleterious sequence variants in RERE were identified.
• These RERE variants were de novo in all cases with available parental samples.
• A significant proportion of pathogenic RERE variants affect a histidine-rich region within the Atrophin-1 domain.

Findings:

• Point mutations in RERE's Atrophin-1 domain are associated with increased risks of eye, heart, and renal anomalies, and sensorineural hearing loss compared to loss-of-function variants.
• A recurrent two-amino-acid duplication in the histidine-rich region of RERE is linked to a CHARGE syndrome-like phenotype.
• Mutations in RERE lead to a spectrum of clinical phenotypes with identifiable genotype-phenotype correlations.

Implications:

• Genotype-phenotype correlations in RERE variants can guide clinical decision-making for NEDBEH.
• Individuals meeting CHARGE syndrome criteria but lacking CHD7 variants should be screened for RERE variants.
• Further research into RERE's role in neurodevelopment and associated anomalies is warranted.