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...
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1227164/full |
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| author | Jenifer P. Suntharalingham Miho Ishida Antoinette Cameron-Pimblett Sinead M. McGlacken-Byrne Federica Buonocore Ignacio del Valle Gaganjit Kaur Madhan Tony Brooks Gerard S. Conway John C. Achermann |
| author_facet | Jenifer P. Suntharalingham Miho Ishida Antoinette Cameron-Pimblett Sinead M. McGlacken-Byrne Federica Buonocore Ignacio del Valle Gaganjit Kaur Madhan Tony Brooks Gerard S. Conway John C. Achermann |
| author_sort | Jenifer P. Suntharalingham |
| collection | DOAJ |
| description | 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<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. |
| first_indexed | 2024-03-11T23:12:01Z |
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| id | doaj.art-ee6eb85adb354a4193d7aee6c6ee8b19 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-03-11T23:12:01Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-ee6eb85adb354a4193d7aee6c6ee8b192023-09-21T08:32:34ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-09-011410.3389/fendo.2023.12271641227164Analysis of genetic variability in Turner syndrome linked to long-term clinical featuresJenifer P. Suntharalingham0Miho Ishida1Antoinette Cameron-Pimblett2Sinead M. McGlacken-Byrne3Federica Buonocore4Ignacio del Valle5Gaganjit Kaur Madhan6Tony Brooks7Gerard S. Conway8John C. Achermann9Genetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomGenetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomInstitute for Women’s Health, University College London, London, United KingdomGenetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomGenetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomGenetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomUCL Genomics, UCL Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomUCL Genomics, UCL Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomInstitute for Women’s Health, University College London, London, United KingdomGenetics & Genomic Medicine Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London, United KingdomBackgroundWomen 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<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.https://www.frontiersin.org/articles/10.3389/fendo.2023.1227164/fullTurner syndromeX chromosomemonosomydiabetes mellitushypothyroidismautoimmunity |
| spellingShingle | Jenifer P. Suntharalingham Miho Ishida Antoinette Cameron-Pimblett Sinead M. McGlacken-Byrne Federica Buonocore Ignacio del Valle Gaganjit Kaur Madhan Tony Brooks Gerard S. Conway John C. Achermann Analysis of genetic variability in Turner syndrome linked to long-term clinical features Frontiers in Endocrinology Turner syndrome X chromosome monosomy diabetes mellitus hypothyroidism autoimmunity |
| title | Analysis of genetic variability in Turner syndrome linked to long-term clinical features |
| title_full | Analysis of genetic variability in Turner syndrome linked to long-term clinical features |
| title_fullStr | Analysis of genetic variability in Turner syndrome linked to long-term clinical features |
| title_full_unstemmed | Analysis of genetic variability in Turner syndrome linked to long-term clinical features |
| title_short | Analysis of genetic variability in Turner syndrome linked to long-term clinical features |
| title_sort | analysis of genetic variability in turner syndrome linked to long term clinical features |
| topic | Turner syndrome X chromosome monosomy diabetes mellitus hypothyroidism autoimmunity |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1227164/full |
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