Bridging Genotype to Phenotype in-Related Syndrome: Evidence from RNA-Seq,FDG-PET, Clinical Deep Phenotyping in Two New Cases, and a Literature Review.

Researchers studied two teenagers with a rare genetic condition affecting brain development caused by changes in the KMT5B gene. Both children had autism, movement coordination problems, and difficulties with planning and language, but normal intelligence. Brain scans showed reduced activity in areas controlling movement and memory. The study helps explain how this genetic change affects brain function and development, providing better understanding of why children with this condition have specific challenges.

This study examined two adolescents with KMT5B gene variants causing autosomal dominant intellectual developmental disorder 51. Using comprehensive clinical assessments, brain imaging (MRI, PET/CT), and RNA sequencing, researchers identified specific patterns of brain dysfunction and molecular changes. Both patients showed autism spectrum disorder, developmental coordination disorder, and executive function difficulties without intellectual disability. Brain imaging revealed reduced activity in cerebellar and temporal regions, which correlated with symptom severity.

RNA analysis identified dysregulated pathways, particularly DDIT4 upregulation, potentially linked to synaptic dysfunction. The study provides new insights into how KMT5B gene mutations affect brain development and function, highlighting cerebellar involvement in movement coordination and autism symptoms.

This research advances understanding of KMT5B-related disorders, suggesting specific clinical features and brain patterns to monitor. The identification of cerebellar involvement may inform targeted interventions for movement coordination difficulties. However, larger studies are needed before clinical applications.

Very small sample size (only two patients) limits generalizability. As a case study with literature review, findings need replication in larger cohorts. The molecular findings from RNA sequencing require validation in additional patients and functional studies.

Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features.Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI andFDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype-phenotype correlations.Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances.

PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models.The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype-phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders.