ESPE Abstracts

Background: Turner syndrome (TS) affects 1:2,500 females and results from complete or partial loss of one of the X chromosomes. Typical traits associated with TS include short stature, primary ovarian insufficiency (POI), autoimmune diseases, and cardiovascular and endocrine disorders. Long-term follow-up is needed from the time of presentation into adult life. Several genetic mechanisms have been proposed to account for the development of TS-associated features. These include haploinsufficiency of pseudoautosomal region (PAR) genes, gene dosage effects of factors that escape X-inactivation, exposure of traits with a single X, or secondary effects of X chromosome loss on autosomal gene regulation. In this study we explored the possibility that a deficit of X-chromosome material associated with TS could have a secondary effect on genetic stability across the genome.

Aims: We aimed to investigate whether there are differences in genetic variability in the autosomes and X chromosome in women with TS compared to control groups, as a consequence of disrupted DNA replication/repair mechanisms secondary to loss of X gene(s).

Methods: Whole Exome Sequencing (Nonacus ExomeCG) was carried out in a cohort of 134 women with TS (karyotype groups: monosomy=75; ring=20; isochromosome=34; complex=5) and three control groups (46,XX=23; 46,XX non-TS POI=101; 46,XY=11). Next generation sequencing was carried out to a read depth of ~ 110X on an Illumina NovaSeq. Variant calling (Platypus 0.8.1), annotation (Qiagen Clinical Insight) and filtering (R 4.1.1) was used to assess the number of variants in the autosomes and X chromosomes of TS women and control cohorts, as well as translation impact and pathogenicity (ACMG).

Results: Overall, 6,600,120 variants were detected after filtering. The total number of autosomal variants was not significantly different between TS groups (median monosomy=23,532; ring=23,632; isochromosome=23,538; complex=23,713) and controls (46,XX=23,625; 46,XX non-TS POI=23,374; 46,XY=23,376). In depth analysis of missense, frameshift, synonymous and stop gain/loss variants, and pathogenicity also showed no significant differences. For the X chromosome, the number of variations was proportional to the amount of X chromosome material present within each group, with no excess of disruption seen in TS cohorts, for total variants and subgroup/pathogenicity analysis.

Conclusions: No significant differences in genetic variability within the autosomes were found in this large cohort of TS women compared to controls. The number of X-chromosome variants was related to the complement of X chromosome material. These data suggest that morbidity in TS is not likely to be linked to global changes in genetic variability.