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Identification of a Novel Variant in the MAD1L1 Gene in an Individual with Mosaic Variegated Aneuploidy Syndrome

Laboratory Genetics and Genomics
  • Primary Categories:
    • Laboratory Genetics
  • Secondary Categories:
    • Laboratory Genetics
Introduction
Mosaic Variegated Aneuploidy Syndrome (MVAS) is an autosomal recessive condition characterized by mosaic aneuploidy and a range of clinical manifestations including growth delays, developmental delays, congenital malformations, and an increased risk for cancer.  Variants in MVAS-related genes lead to defects in the spindle assembly checkpoint, a key mechanism that ensures chromosomes are correctly distributed to daughter cells during mitosis. Affected individuals often exhibit chromosomal instability and mosaicism, with cells having varying number of chromosomes thus contributing to the syndrome's heterogeneity. The presence of mosaic aneuploidy in the patient's cells is crucial for confirming the diagnosis, making cytogenetic analysis essential for identifying the disease's aneuploid nature. This case describes a patient presenting with MAD1L1-related MVAS, which has only been documented in the literature once before. 

 

Case Presentation
This patient is a 7-year-old male presenting with myelodysplastic syndrome, global developmental delay, hyperpigmented skin lesions, congenital anomalies, and multiple nodules in the kidney and lung.  There was no significant family history that pertained to the current medical conditions or concerns. Whole genome sequencing was ordered to investigate the underlying cause of the individual’s varying clinical features.

Diagnostic Workup
The patient underwent whole genome sequencing in 2022 that was negative for any phenotype-related variants. Re-analysis two years later revealed a novel homozygous missense variant in the MAD1L1 gene: c.1948C>T (p.Arg650Trp) that was classified as a VUS. The reanalysis results were due to the documented findings of one MAD1L1-related MVAS case. Both parents were heterozygous for this variant.  Karyotype analysis of skin fibroblasts uncovered significant chromosomal instability, confirming the presence of mosaic aneuploidy and the diagnosis of MAD1L1-related MVAS. 

This novel variant is in the C-terminal region of the protein MAD1, which is critical for binding MAD2 to form the spindle assembly checkpoint. This variant does not appear in gnomAD as homozygous in the healthy population, and it has not been described in ClinVar, supporting its rarity and likely pathogenicity. Bioinformatic analysis predicted that this variant affects a highly conserved region of the gene and in silico tools (CADD and REVEL) predict it to be deleterious. The identified c.1948C>T (p.Arg650Trp) variant in the MAD1L1 gene was re-classified from a VUS to likely pathogenic according to ACMG guidelines after chromosome confirmation. The individual’s clinical presentation, variant characteristics, and karyotyping results are consistent with a diagnosis of MVAS. 

 

Treatment and Management
The individual was referred to a multidisciplinary team for management and treatment, including oncology, dermatology, allergy and immunology, cardiovascular and orthopedics. Additionally, the family was provided with genetic counseling and information regarding the inheritance pattern and recurrence risks.

Outcome and Follow-Up
The individual is currently undergoing a specialized treatment protocol for the myelodysplastic syndrome. Follow-up evaluations will be conducted to monitor for any additional complications. 

 

Discussion
This study reports a novel MAD1L1 variant which expands the known spectrum of variants associated with MVAS. Whole genome sequencing revealed a novel homozygous missense variant in the MAD1L1 gene (c.1948C>T, p.Arg650Trp), which disrupts the protein’s interaction with MAD2, impairing chromosome segregation during mitosis which was supported by orthogonal testing. This variant, not previously reported, was classified as likely pathogenic based on its rarity, in silico predictions, MAD1L1-related MVAS literature and the patient’s clinical and cytogenetic findings. 

 

Conclusion
This case underscores the importance of genetic testing and cytogenetic analysis in diagnosing MVAS. The multidisciplinary management strategy, alongside genetic counseling, is essential for addressing both the clinical manifestations of MVAS and the associated genetic risks for family members. This case contributes to the growing understanding of MVAS and emphasizes the value of continuous genetic research to identify novel variants that may contribute to the syndrome. Regular follow-up and cancer surveillance remain integral to the management of these patients, given their increased risk for malignancy.  

 

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