Biallelic HMGXB4 loss-of-function variant causes intellectual disability, developmental delay, and dysmorphic...

Area of Science:

• Genetics
• Neurodevelopmental Biology
• Molecular Biology

Background:

• HMGXB4 (HMG2L1) is a DNA-binding protein with an HMG-box domain.
• HMGXB4 negatively regulates the Wnt/β-catenin signaling pathway in Xenopus.

Purpose of the Study:

• To investigate the genetic and clinical basis of intellectual disability (ID), global developmental delay (GDD), and dysmorphic facial features in a single family.
• To identify the genetic cause of these neurodevelopmental disorders.

Main Methods:

• Whole genome sequencing (WGS) and Sanger sequencing were performed on affected and unaffected family members.
• Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to analyze HMGXB4 gene expression.

Main Results:

• A homozygous frameshift variant (c.1193_1196del p.Lys398Argfs×25) in the HMGXB4 gene was identified in affected individuals.
• Affected individuals exhibited a significant decrease in HMGXB4 gene expression compared to unaffected individuals.

Conclusions:

• This study provides the first evidence linking HMGXB4 gene variants to ID, GDD, and dysmorphic facial features.
• HMGXB4 is implicated as a significant contributor to human neurodevelopmental milestones and disorders.