Novel KDM3B Variants in Two Chinese Patients With Global Developmental Delay and Autism

Area of Science:

• Genetics
• Neuroscience
• Developmental Biology

Background:

• Haploinsufficiency of KDM3B is associated with developmental delay, intellectual disability, autism spectrum disorder (ASD), and immunodeficiency (DIJOS syndrome).
• The full phenotypic spectrum and genotype-phenotype correlations of KDM3B-related disorders require further investigation.

Purpose of the Study:

• To investigate the genetic basis of global developmental delay and autistic features in two unrelated patients.
• To expand the understanding of the KDM3B gene's role in neurodevelopment and associated disorders.

Main Methods:

• Detailed clinical evaluation of two patients, including neuroimaging, electrophysiology, and neurodevelopmental assessments.
• Whole exome sequencing (WES) to identify genetic variants, followed by Sanger sequencing for confirmation.
• Variant interpretation according to ACMG guidelines.

Main Results:

• Identified a de novo pathogenic nonsense variant (p.Ser657*) in KDM3B in Patient 1, presenting with severe developmental delay, deafness, and autistic features.
• Identified a likely pathogenic splice-site variant in KDM3B in Patient 2, presenting with milder developmental delay and autistic behaviors with normal hearing.
• Demonstrated phenotypic heterogeneity in KDM3B-related disorder, with variant type and location potentially influencing disease severity.

Conclusions:

• The findings broaden the mutational and phenotypic spectrum of KDM3B-related disorders.
• KDM3B plays a crucial role in neurodevelopment, cognition, and optic nerve formation.
• Further research is needed to elucidate the molecular mechanisms underlying the clinical heterogeneity observed in KDM3B-related conditions.