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

ABSTRACT Background Haploinsufficiency of KDM3B has also been linked to developmental delay, intellectual disability, autism spectrum disorder (ASD) and immunodeficiency known as developmental delay, intellectual disability, joint contractures and facial dysmorphism; immunodeficiency; and short stature (DIJOS) syndrome. However, the phenotypic spectrum is not fully defined, and genotype–phenotype associations need to be further studied. Methods Here we report on two unrelated patients with global developmental delay and autistic features and provide detailed clinical information of both patients, including cranial magnetic resonance imaging (MRI), electroencephalography (EEG), metabolic screening, hearing assessment and neurodevelopmental testing. Whole exome sequencing (WES) was performed for potential genetic causes, and candidate variants were verified via Sanger sequencing. Interpretation of variants was performed in accordance with ACMG guidelines. Results For Patient 1, we detected a de novo pathogenic heterozygous nonsense variant in KDM3B (c.1970C > G, p.Ser657*). The canonical splice‐site variant (c.3973‐1G > C) in KDM3B that we found in Patient 2 was classified as likely pathogenic. Clinically, Patient 1 had severe developmental retardation, deafness and autistic tilt, whereas Patient 2 had milder retardation and autistic behaviours with normal hearing. The splice‐site variant in Patient 2 may disrupt an upstream intron and is predicted to influence splicing, which may elicit nonsense‐mediated mRNA decay and contribute a more severe interference, comparatively. Conclusion Our results broaden the mutational and phenotypic spectrum of KDM3B‐related disorder and highlight the phenotypic heterogeneity even in patients with the same type of variant. Functional analysis underscores the importance of KDM3B in neurodevelopment, optic nerve formation and cognition. Additional studies will be required to define the differences in clinical phenotype at the molecular level.