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

BACKGROUND

HMGXB4 (additionally known as HMG2L1) is a non-histone DNA-binding protein that contains a single HMG-box domain. HMGXB4 was originally described in Xenopus where it was seen to negatively regulate the Wnt/β-catenin signaling pathway.

MATERIALS AND METHODS

In this study, we conducted a genetic and clinical evaluation of a single family with three affected individuals suffering from intellectual disability (ID), global developmental delay (GDD) and dysmorphic facial features.Whole genome sequencing (WGS) and Sanger sequencing were performed on the affected individuals' DNA to identify genetic variations. Additionally, a reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to assess gene expression in both the affected and unaffected individuals in the family.

RESULT

WGS identified a homozygous frameshift variant c.1193_1196del p. (Lys398Argfs × 25) in exon 5 of the gene (OMIM 604702), which completely segregated the disease phenotype in the family. Furthermore, RT-qPCR revealed a substantial decrease in the gene expression in the affected individuals as compared to the unaffected individuals of the family.

CONCLUSIONS

The current study is the first evidence linking a genetic variant in the gene to ID, GDD, and dysmorphic facial features. Therefore, it is possible that contributes significantly to developmental milestones and may be responsible for neurodevelopmental disorders in humans.