Human phenotype caused by biallelic KDM4B frameshift variant.

Area of Science:

• Genetics
• Developmental Biology
• Human Disease

Background:

• KDM4B (Lysine Demethylase 4B) encodes a histone demethylase regulating gene expression.
• Loss-of-function variants in KDM4B cause autosomal dominant intellectual developmental disorder 65.
• Previously, only heterozygous KDM4B variants were reported, with no cases of biallelic variants.

Purpose of the Study:

• To report the first case of a patient with biallelic KDM4B pathogenic variants.
• To investigate the phenotypic consequences of homozygous KDM4B variants in humans.
• To compare the phenotype of a homozygous patient with her heterozygous mother.

Main Methods:

• Clinical evaluation of a female patient and her heterozygous mother.
• Genetic analysis to identify KDM4B variants.
• Review of existing literature on KDM4B variants and associated disorders.

Main Results:

• A female patient presented with a biallelic KDM4B frameshift variant (c.1384_1394delinsGGG, p.(Leu462Glyfs*43)).
• The patient exhibited developmental and language delays, hypotonia, and a characteristic facial appearance.
• The patient's phenotype was more severe than her heterozygous mother's, suggesting viability of homozygous variants in females.

Conclusions:

• Homozygous KDM4B frameshift variants can be viable in humans, particularly in females.
• This case expands the known spectrum of KDM4B-related disorders and challenges previous assumptions about embryonic lethality in homozygous states.
• Further research is needed to understand the full implications of biallelic KDM4B variants.