Study of Structural Variation in MECP2 Duplication Syndrome and Its Phenotypic Variability

Academic Background

MECP2 Duplication Syndrome (MRXSL) is an X-linked genomic disorder primarily caused by an increase in the copy number of the MECP2 gene on the X chromosome. This condition predominantly affects males, and its clinical features vary widely, including infantile hypotonia, severe developmental delay, intellectual disability (ID), absence of speech, progressive spasticity, gastrointestinal issues, frequent respiratory infections, and epilepsy. Despite the significant clinical heterogeneity observed among MRXSL cases, the specific link between genomic structural variations and clinical phenotypes has remained unclear. Additionally, complex genomic rearrangements (CGRs) have been identified in up to 38% of MRXSL families, further complicating our understanding of the disorder’s complexity. This study aims to explore the relationship between genomic structural variations, phenotypic variability, and disease severity in MRXSL through comprehensive genomics, transcriptomics, and deep phenotyping analyses.

Study Source

This study was published in Genome Medicine (2024, 16:146), authored by Davut Pehlivan, Jesse D. Bengtsson, Sameer S. Bajikar, and collaborators from institutions such as Texas Children’s Hospital, Baylor College of Medicine, the National Genomics Infrastructure in Stockholm, Sweden, and others.

Research Methods

This study analyzed 137 MRXSL cases using quantitative phenotypic data and a multi-layered genomic approach to uncover the pathological mechanisms underlying MECP2 duplication and the role of gene dosage on disease phenotypes.

1. Study Subjects

• Sample Source: 82 cases were collected from the Texas Children’s Hospital Rett Center, and 55 cases were gathered via telemedicine or local care providers.
• Previously Published Cases: A total of 137 individuals (125 families) were included, 136 males and 1 female. The female patient had an unbalanced translocation, leading to classical MRXSL phenotypes.

2. Genomic Analysis Workflow

Customized genomic platforms were used, including short-read sequencing, high-resolution array comparative genomic hybridization (Array CGH), optical genome mapping (OGM), and long-read sequencing. Key genomic findings included: - Genomic Rearrangement Types: Categorized into five groups: tandem duplications (48%), inverted triplications (20%), terminal duplications (22%), interspersed duplications (5%), and other complex rearrangements (5%). - Duplication Sizes: Ranged from 64.6 kb to 16.5 Mb, with 87% of de novo variants being terminal duplications, revealing a strong bias toward this genomic configuration.

3. Phenotypic Evaluation and Analysis

Patients were categorized by different genomic rearrangements to analyze the relationship between genetic structures and clinical phenotypic patterns. Key clinical domains include developmental features, infections, physical characteristics, neurological abnormalities, gastrointestinal and genitourinary system anomalies, among others.

a) Developmental Parameters

All patients exhibited severe developmental delay, with the highest developmental skills typically below 24 months. Developmental quotients (DQs) decreased progressively from tandem duplication to triplication cases, with triplication patients having the most severe developmental restrictions.

b) Infection and Immune Abnormalities

Frequent infections, especially pneumonia and upper respiratory infections, were a core feature of MRXSL. Urinary tract infections (UTIs) were observed at higher-than-normal rates and were significantly more common in patients with complex genomic structures.

c) Neurological System

Epilepsy was present in 50%-60% of patients, with earlier onset in cases with more complex rearrangements. Abnormal muscle tone (either hypotonia or hypertonia) was prevalent. Movement disorders, such as spasticity and ataxia, were also observed with varying frequencies. Autistic spectrum disorder (ASD)-like behaviors were reported in 85.8% of individuals, alongside sensory abnormalities (e.g., high pain tolerance, bruxism).

d) Genitourinary and Other Systems

Genitourinary system abnormalities were present in 45.2% of cases, increasing to 80%-100% in patients with more complex structures or triplications. Brain imaging abnormalities were notable in all translocation and triplication cases. Severe vision and hearing impairments were also documented in triplication cases.

4. Transcriptomics Analysis

RNA sequencing revealed that MECP2 and IRAK1 gene expression levels were significantly increased in MECP2 duplication cases, correlating with copy number variations. Transcriptomic clustering indicated distinct gene expression patterns between rearrangement types. MECP2 and IRAK1 RNA expression levels correlated strongly with protein levels, supporting a gene dosage effect.

5. Survival Analysis

Kaplan-Meier survival analysis revealed genomic rearrangements significantly influenced patient survival. Patients with tandem duplications had the best survival outcomes, while triplications had the poorest survival rates with a median survival under four years. Survival duration declined progressively with increasing genomic complexity.

Research Significance

This study provides several major insights into MECP2 duplication syndrome, including: 1. Structure Variations and Phenotypic Severity: The study demonstrates the impact of MECP2 gene dosage and genomic structural variations on phenotypic variability and disease severity, systematically quantifying these effects across different categories. 2. Genotype-Phenotype Associations and Clinical Implications: The findings highlight the need for personalized diagnostic and therapeutic strategies based on specific genetic rearrangements. 3. Transcriptomics and Gene Dosage Effects: The study provides direct evidence of the dose-dependent effects of MECP2 duplication on RNA and protein levels, leading to broader transcriptomic dysregulation.

Conclusion

This comprehensive study highlights the complex interplay between gene dosage, genomic structural rearrangements, and phenotypic traits in MECP2 duplication syndrome, revealing structure-specific patterns of disease manifestation. By integrating genomics, transcriptomics, and quantitative phenotyping, the findings enhance our understanding of MRXSL and provide valuable insights for guiding clinical decision-making and optimizing therapeutic strategies.