Higher CNV Frequencies in Chromosome 14 of Girls With Turner Syndrome Phenotype

Context: Precise genotype-phenotype correlations in Turner syndrome (TS) have not yet been deciphered. The chromosomal basis of the clinical TS phenotype in the absence of X chromosome aberrations on conventional karyotyping remains more and less unexplored. Objective: To elucidate the high-resolution chromosomal picture and analyze the genotype-phenotype associations in girls with clinical phenotype of TS by chromosomal microarray. Design and Patients: Cross sectional observational study conducted between October 2018 and January 2020 on 47 girls presenting the clinical TS phenotype and fulfilling the criteria for chromosomal analysis. Setting: Outpatient department at Department of Endocrinology and the Molecular Research Lab at tertiary care teaching institution. Results: The copy number variation (CNV) polymorphs were more frequent on autosomes than X chromosomes, and they were detected in 89.3%, 61.7%, and 92.8% of patients, respectively, on chromosome 14 or X or both. A total 445 and 64 CNV polymorphs were discovered on chromosome X and 14, respectively. The latter exhibited either gain at 14q32.33, loss at 14q11.2, or both. Karyotype was available for 27 patients; 55.6% of cases displayed X chromosome abnormalities while 44.4% cases had a normal karyotype. Functional interactomes of the genes that were present in chromosome 14 CNVs and those known to be associated with TS showed an overlap of 67% and enriched various development-related cellular pathways underlying TS phenotype. Conclusions: On high-resolution karyotype analysis, clinical phenotype of TS can be associated with CNV defects in autosomes, specifically chromosome 14 or X chromosome or both. The syndrome of chromosome 14 CNV defects with and without X-chromosomal defects clinically mimics TS and shares a common genomic network that deserves further investigations.

Automated summary

This study used chromosomal microarray to elucidate high-resolution chromosomal patterns and analyze genotype-phenotype associations in girls with the clinical phenotype of Turner syndrome (TS). The results showed that copy number variations (CNVs) on autosomes were more common than on the X chromosome, with CNVs detected on chromosome 14 and X in a large percentage of patients. Functional interactions between genes in chromosome 14 CNVs and known TS-associated genes were identified, revealing a potential common genomic network underlying the TS phenotype. This suggests that CNV defects in autosomes, particularly chromosome 14 or X, may play a role in the clinical presentation of TS, warranting further investigation.