Refining the Phenotypic Spectrum of KMT5B-Associated Developmental Delay

Area of Science:

• Genetics
• Neurodevelopmental Disorders
• Chromatin Biology

Background:

• Lysine methyltransferases (KMTs) and demethylases (KDMs) are crucial for chromatin modification.
• Heterozygous variants in KMT5B have been linked to intellectual disability (ID) and autism spectrum disorder (ASD).

Purpose of the Study:

• To investigate the role of KMT5B in neurodevelopmental disorders.
• To identify and characterize novel KMT5B variants in patients with global developmental delay (GDD) or ID, macrocephaly, and other features.

Main Methods:

• Whole exome sequencing (WES) was performed on three unrelated patients.
• Clinical presentations were analyzed and compared to previously reported cases.
• Three-dimensional computational modeling was used to predict the structural effects of missense variants.

Main Results:

• Three distinct de novo heterozygous pathogenic variants in KMT5B were identified in the probands: c.541C > G (p.His181Asp), c.833A > T (p.Asn278Ile), and c.391_394delAAAG (p.Lys131GlufsTer6).
• The identified variants are associated with GDD/ID, macrocephaly, and additional clinical features.
• Computational modeling predicted the structural impact of the missense variants.

Conclusions:

• De novo missense and nonsense variants in KMT5B are implicated in GDD/ID.
• KMT5B should be considered in the differential diagnosis of neurodevelopmental disorders, especially when accompanied by macrocephaly or overgrowth.