MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study

Area of Science:

• Genetics
• Developmental Biology
• Clinical Medicine

Background:

• Kabuki syndrome (KS) is a rare congenital disorder.
• Pathogenic variants in the MLL2 gene are the most frequent cause of KS.
• Understanding genotype-phenotype correlations is crucial for KS diagnosis and management.

Purpose of the Study:

• To investigate the genotype-phenotype correlation in a large cohort of Kabuki syndrome patients.
• To identify and characterize MLL2 gene mutations in clinically diagnosed KS patients.
• To correlate MLL2 mutation status with clinical severity and specific phenotypic features.

Main Methods:

• A cohort of 86 clinically defined Kabuki syndrome patients was studied.
• Patients were assessed using a standardized phenotype list and a novel clinical scoring system (MLL2-Kabuki score).
• Full coding region and intron-exon boundaries of the MLL2 gene were sequenced.

Main Results:

• Likely pathogenic MLL2 mutations were identified in 52% (45/86) of patients, including 31 nonsense, 10 missense, and 4 splice-site mutations.
• Patients with pathogenic MLL2 mutations exhibited significantly higher MLL2-Kabuki scores (median 6) compared to those without mutations (median 5).
• Specific facial features, including dysplastic ears, arched eyebrows, blue sclerae, and characteristic lip and nose shapes, were more prevalent in mutation-positive patients.

Conclusions:

• Pathogenic MLL2 mutations are confirmed as the predominant cause of Kabuki syndrome.
• MLL2 mutation status significantly correlates with clinical severity and specific facial dysmorphisms in KS.
• These findings enhance the understanding of MLL2's role in KS and aid in genotype-based clinical assessment.