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Unmasking Turner Syndrome in a Patient with Long QT Syndrome: A Case Report and Review of Clinical Implications

Clinical Genetics and Therapeutics
  • Primary Categories:
    • Clinical Genetics
  • Secondary Categories:
    • Clinical Genetics
Introduction
Long QT syndrome (LQTS) is characterized by QT prolongation and T wave abnormalities on the EKG. It increases the risk of life-threatening arrhythmic events, particularly in young individuals. Molecular genetic testing identifies a genetic cause in approximately 80% of cases, most commonly in genes linked to autosomal dominant LQTS.



Turner syndrome, is the most common sex chromosomal abnormality found in females. It results when one of the X chromosomes is missing, partially or completely. Individuals with Turner syndrome present with a variable phenotype which commonly includes short stature, ovarian failure, characteristic facial features, edema of hands or feet, webbed neck, broad chest, and low posterior hairline. Additional features include hypothyroidism, hearing loss, digital, renal, and cardiac abnormalities, as well as variable neurocognitive and psychosocial issues. Mosaic Turner syndrome occurs due to a random event during the cell division stage in the early fetal development of the affected individual. As a result, some of a person's cells have the usual two sex chromosomes, while other cells contain only one copy of the X chromosome. Rarely, Turner syndrome can result from a partial deletion of the X chromosome, and can be inherited.



This report introduces a novel variant involving a mosaic, multi-gene deletion involving at least 155065 kb within cytogenetic band Xp22.33q28 including KCNE5 gene underscoring the complexity of clinical decisions arising from uncertain genetic results.  

 

Case Presentation
A 16-year-old F presented for a murmur evaluation was found to have a QTc of 473 msec and a structurally and functionally normal heart.  A subsequent stress test showed significant QTc prolongation to 487msec with exercise despite peak QTc being unable to be calculated due to artifact.  She was referred to Cardiogenomics Program to discuss genetic testing. Her family history included a paternal grandfather who experienced sudden cardiac death at the age of 40. The details of his condition were unknown.

 

Diagnostic Workup
Patient underwent genetic testing via GeneDx Arrhythmia Sequencing and Deletion/Duplication Panel and was found positive for a mosaic loss of Chromosome X pathogenic variant involving deletion of at least 155065 kb within cytogenetic band Xp22.33q28. Genomic coordinates: chrX:168547_155233846 [GRCh37] including KCNE5 gene. The chromosome X multi-gene copy number variant including the KCNE5 gene may contribute to the Long QT in this proband.  Her follow-up EKG revealed a QTc interval of 477 msec.

 

Treatment and Management
Patient was started on Nadolol 40 mg po q day. Fluorescence in situ hybridization (FISH) testing was recommended to clarify the cytogenetic structure of the aberration. Correlation of this finding with the patient clinical features was recommended.

 

Outcome and Follow-Up
She continues to be on beta blockers. Constitutional mosaic monosomy X is consistent with mosaic Turner syndrome hence patient is scheduled for a comprehensive clinical evaluation to assess for symptoms of Turner syndrome. Additionally, targeted testing for the copy number variant involving the KCNE5 gene was proposed for family members to assess potential risk.

 

Discussion
The clinical significance, disease associations, and associated risks can vary depending on whether the variant is constitutional or acquired. When present as a constitutional variant, this finding has been linked to Turner syndrome; however, the panel assay used in this case could not differentiate between the two. Additionally, the extent of mosaicism cannot be precisely determined by this assay. To address these issues, FISH testing is typically  recommended to further clarify the cytogenetic structure of the aberration.

 

Conclusion
The chromosome X multi-gene copy number variant including the KCNE5 gene may contribute to the LQT in this proband. If constitutional, the variant is consistent with mosaic Turner syndrome. Correlation of these findings with the clinical features of this proband is recommended. FISH testing may be considered to clarify the cytogenetic structure of the aberration.

 

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