ANKRD11 variants: KBG syndrome and beyond.

Area of Science:

• Genetics
• Developmental Biology
• Molecular Medicine

Background:

• Mutations in Ankyrin Repeat Domain 11 (ANKRD11) are linked to KBG syndrome and Cornelia de Lange syndrome (CdLS).
• ANKRD11 variants are part of a broader class of chromatinopathies, affecting gene regulation and development.
• Functional overlap among chromatin regulators leads to shared, often overlapping, clinical features, complicating differential diagnosis.

Purpose of the Study:

• To clinically characterize individuals with ANKRD11 variants.
• To investigate the phenotypic spectrum associated with ANKRD11 mutations.
• To explore diagnostic challenges and potential co-occurring molecular diagnoses.

Main Methods:

• Clinical assessment of 23 individuals with ANKRD11 variants.
• Phenotypic evaluation including developmental delay, intellectual disability, and dysmorphic features.
• Review of initial clinical diagnoses (KBG syndrome, CdLS) and potential evolution of phenotype over time.

Main Results:

• Individuals presented with developmental delay, intellectual disability, and dysmorphic features.
• Most subjects initially received diagnoses of KBG syndrome or CdLS.
• Phenotypic variability was significant, with overlapping clinical signs and severity.
• The broad spectrum of phenotypes may be influenced by additional molecular diagnoses or distinct pathogenic mechanisms.

Conclusions:

• ANKRD11 variants contribute to a spectrum of developmental disorders, often presenting with overlapping features of KBG syndrome and CdLS.
• The phenotypic variability underscores the complexity of diagnosing chromatinopathies.
• Further investigation into co-occurring genetic factors may explain the broad range of clinical presentations.