Analysis of genetic variability in Turner syndrome linked to long-term clinical features

Background: Women with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management. // Objective: We investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a “two-hit” hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated. // Methods: Whole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA. // Results: Standard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p<0.02). // Conclusions: Women with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated

Characterisation of Turner Syndrome with focus on the pathogenesis of diabetes mellitus

Introduction: Turner Syndrome (TS) is a complex condition, affecting every system in the body (Elsheikh, Conway, & Wass, 1999; Gravholt et al., 2017). Caused by a complete or partial lack of one X chromosome TS is associated with a variety of morbidities such as diabetes mellitus (DM). A literature review found that DM is poorly characterised in TS and DM risk is reported to be higher than that of females in the general population (Gravholt, Juul, Naeraa, & Hansen, 1998). The results from glucose homeostasis reports have been conflicting reporting both insulin deficiency (V. K. Bakalov et al., 2004) and resistance (Salgin et al., 2006) to be the mechanism behind pathogenesis as well as a possible association with the isochromosome karyotype (V. K. Bakalov, Cheng, C., Zhou, J., and Bondy, C.A., 2008). Furthermore, those with established DM have often been excluded from analysis and therefore remain largely unexplored. The overall aim my doctoral research was to identify the factors involved in TS-associated DM using a multipronged approach. Methodologies A series of methodologies were implemented to address the characterisation of the DM phenotype experienced by women with TS. Studies 1 & 2 Statistical characterisation of adult health parameter data derived from the Turner Syndrome Life Course Project against; karyotype, paediatric treatments and long-term oestrogen use. Study 3 A prospective study of the characterisation of glucose homeostasis and DM-risk factors in affected and women with an unknown DM status. Study 4 Pilot array study of T2DM-associated SNP to assess if there was an over-represented in those with Impaired Glucose Tolerance or DM. Conclusions TS-associated DM was found to have a unique profile that has features of both T2DM and LADA such as genetic influences, insulin resistance and a degree of autoimmunity

Analysis of genetic variability in Turner syndrome linked to long-term clinical features

BackgroundWomen with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management.ObjectiveWe investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a “two-hit” hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated.MethodsWhole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA.ResultsStandard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, p&lt;0.02).ConclusionsWomen with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated

DataSheet_1_Analysis of genetic variability in Turner syndrome linked to long-term clinical features.pdf

BackgroundWomen with Turner syndrome (TS) (45,X and related karyotypes) have an increased prevalence of conditions such as diabetes mellitus, obesity, hypothyroidism, autoimmunity, hypertension, and congenital cardiovascular anomalies (CCA). Whilst the risk of developing these co-morbidities may be partly related to haploinsufficiency of key genes on the X chromosome, other mechanisms may be involved. Improving our understanding of underlying processes is important to develop personalized approaches to management.ObjectiveWe investigated whether: 1) global genetic variability differs in women with TS, which might contribute to co-morbidities; 2) common variants in X genes - on the background of haploinsufficiency - are associated with phenotype (a “two-hit” hypothesis); 3) the previously reported association of autosomal TIMP3 variants with CCA can be replicated.MethodsWhole exome sequencing was undertaken in leukocyte DNA from 134 adult women with TS and compared to 46,XX controls (n=23), 46,XX women with primary ovarian insufficiency (n=101), and 46,XY controls (n=11). 1) Variability in autosomal and X chromosome genes was analyzed for all individuals; 2) the relation between common X chromosome variants and the long-term phenotypes listed above was investigated in a subgroup of women with monosomy X; 3) TIMP3 variance was investigated in relation to CCA.ResultsStandard filtering identified 6,457,085 autosomal variants and 126,335 X chromosome variants for the entire cohort, whereas a somatic variant pipeline identified 16,223 autosomal and 477 X chromosome changes. 1) Overall exome variability of autosomal genes was similar in women with TS and control/comparison groups, whereas X chromosome variants were proportionate to the complement of X chromosome material; 2) when adjusted for multiple comparisons, no X chromosome gene/variants were strongly enriched in monosomy X women with key phenotypes compared to monosomy X women without these conditions, although several variants of interest emerged; 3) an association between TIMP3 22:32857305:C-T and CCA was found (CCA 13.6%; non-CCA 3.4%, pConclusionsWomen with TS do not have an excess of genetic variability in exome analysis. No obvious X-chromosome variants driving phenotype were found, but several possible genes/variants of interest emerged. A reported association between autosomal TIMP3 variance and congenital cardiac anomalies was replicated.</p