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Comprehensive Phenotypic Spectrum of MED13L Syndrome: Insights from Literature and the National Brain Gene Registry

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction:
Pathogenic variants in MED13L cause neurodevelopmental disorders characterized by cognitive, motor, behavioral, and systemic features. MED13L encodes a key component of the mediator complex, which regulates transcription critical to cellular development. This study integrates data from a systematic review of published cases with five participants from the National Brain Gene Registry to expand the understanding of the phenotypic variability and clinical implications of MED13L syndrome.

Methods:
A systematic review of 93 published cases was performed to identify recurrent and unique clinical features. Detailed clinical, genetic, and imaging data from five registry participants were analyzed to further characterize the phenotypic spectrum. Three pathogenic variants identified in the registry participants are novel and not previously reported in the literature. Findings were compared across both data sources to assess commonalities, variability, and genotype-phenotype correlations.

Results:
Motor and Language Development:

Hypotonia was reported in 57% of published cases and all registry participants, often presenting as delayed gross and fine motor milestones. Ataxic gait was observed in 29% of published cases. Language development was significantly delayed, with 35% of published cases being non-verbal and 25% limited to a few words. Among registry participants, three were non-verbal, and two exhibited mixed receptive-expressive language delays. Additional findings included motor coordination difficulties and structural anomalies such as metatarsus adductus.

Cognitive and Behavioral Features:

Intellectual disability (ID) was present in 69% of published cases, ranging from mild (6 cases) to severe (4 cases). All registry participants demonstrated global developmental delays, with ID severity ranging from mild to profound. Autism spectrum disorder (ASD) was observed in 27% of published cases and three registry participants. Additional behavioral findings included stereotypies (12%), anxiety (4%), self-harm (8%), and sleep disturbances, including insomnia and restless sleep. Behavioral challenges often necessitated tailored therapies and multidisciplinary care approaches.

Structural and Systemic Anomalies:

Structural anomalies reported in the literature included ventriculomegaly and hydrocephalus. Among registry participants, congenital diaphragmatic hernia, epilepsy with continuous spike-wave during sleep, bicuspid aortic valve, and aortic insufficiency were notable findings. One participant required a ventriculoperitoneal shunt due to hydrocephalus, while another presented with cortical visual impairment secondary to prematurity. These systemic findings highlight the potential for multisystem involvement in MED13L syndrome.

Novel Variants:

Three pathogenic variants identified in the Brain Gene Registry participants are novel and expand the mutational spectrum of MED13L syndrome. These findings emphasize the need for continued variant curation and functional studies to better understand genotype-phenotype relationships.

Conclusion:
MED13L syndrome represent a heterogeneous phenotypic spectrum with shared features such as intellectual disability, hypotonia, and language delays, but also unique structural and systemic anomalies that underscore the complexity of the condition. The inclusion of novel variants and underreported systemic findings from registry cases highlights the importance of integrating clinical data with existing literature to inform diagnostic strategies and therapeutic interventions. This study underscores the critical need for multidisciplinary care to address the diverse challenges faced by individuals with MED13L syndrome.

Agenda

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