MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome

Area of Science:

• Genetics
• Molecular Biology
• Developmental Biology

Background:

• Kabuki syndrome (KS) is a rare genetic disorder characterized by congenital malformations, distinctive facial features, and developmental delays.
• Mutations in the MLL2 gene are the primary cause of KS, accounting for the majority of diagnosed cases.
• A significant portion of KS cases remain genetically unsolved, indicating the need for broader diagnostic approaches.

Observation:

• This study investigated five patients with clinically diagnosed Kabuki syndrome.
• All five patients presented with novel types of mutations within the MLL2 gene, including mosaic deletions and duplications.
• These mutations were not detectable through standard sequencing methods.

Findings:

• The study identified previously unreported MLL2 mutation types in Kabuki syndrome patients, including mosaic small deletions, whole-gene deletions, multi-exon deletions, and multi-exon duplications.
• These findings highlight the importance of considering MLL2 gene dosage abnormalities in KS diagnosis.
• The prevalence of these complex MLL2 mutations may be significant, potentially rivaling that of KDM6A deletions.

Implications:

• The discovery of novel MLL2 mutation types expands the genetic understanding of Kabuki syndrome.
• Recommending MLL2 dosage studies for unsolved KS cases can improve diagnostic yield.
• Further research into these MLL2 mutations will elucidate disease mechanisms and inform potential therapeutic strategies.