ESPE Abstracts (2022) 95 P1-322

1UCL Great Ormond Street Institute of Child Health, London, United Kingdom; 2University College London Hospital, London, United Kingdom; 3UCL Zayed Centre for Research into Rare Disease in Children, London, United Kingdom

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.

Volume 95

60th Annual ESPE (ESPE 2022)

Rome, Italy
15 Sep 2022 - 17 Sep 2022

European Society for Paediatric Endocrinology 

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