Cathie Hilditch, Samuel Curtis, Samuel Cotton, Shannon LeBlanc, Sunita De Sousa
{"title":"涉及不变TAD边界的非渗透性Xq26.3重复:VGLL1区域作为x连锁肢巨人症的GPR101垂体增强因子的临床证据","authors":"Cathie Hilditch, Samuel Curtis, Samuel Cotton, Shannon LeBlanc, Sunita De Sousa","doi":"10.1007/s11102-025-01559-4","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>X-linked acrogigantism (X-LAG; OMIM: 300942) is a rare X-linked dominant, fully penetrant form of infancy-onset pituitary gigantism caused by Xq26.3 tandem duplications involving the GPR101 gene. All previously reported X-LAG-associated duplications disrupt the integrity of the resident topologically associating domain (TAD). This creates a neo-TAD, permitting ectopic chromatin interactions between GPR101 and centromeric pituitary enhancers postulated to lie between RBMX and VGLL1, and culminating in pituitary GPR101 misexpression and growth hormone excess. Conversely, none of the few previously reported cases of Xq26.3 duplications in unaffected individuals include the tissue-invariant TAD border that shields GPR101 from its centromeric enhancers. Preservation of this boundary has thus been considered synonymous with non-penetrance of X-LAG.</p><p><strong>Methods: </strong>We examined a series of four family members from the same kindred with an incidentally detected GPR101-containing Xq26.3 duplication involving the invariant TAD border.</p><p><strong>Results: </strong>Chromosome microarray demonstrated an interstitial chromosome Xq26.3 duplication: arr[GRCh37] Xq26.3(135,954,223 - 136,224,319)x2, including GPR101, the TAD invariant border and RBMX, but not VGLL1. None of the relatives with the Xq26.3 duplication exhibited evidence of growth hormone excess, making this the first unaffected family with a GPR101-containing Xq26.3 duplication involving the invariant TAD border. The predicted neo-TAD in this kindred excludes the VGLL1 region, which is present in all previously described X-LAG patients and absent in all previously described unaffected individuals with Xq26.3 duplications.</p><p><strong>Conclusion: </strong>Our clinical findings suggest that TAD border involvement is not sufficient for X-LAG to develop, and implicates the VGLL1 region as likely the sole pituitary enhancer responsible for GPR101 misexpression and the X-LAG phenotype. Pending corroborative studies, this new insight into X-LAG pathogenesis may guide interpretation of future Xq26.3 duplications and counselling of families in whom such duplications are found.</p>","PeriodicalId":20202,"journal":{"name":"Pituitary","volume":"28 4","pages":"85"},"PeriodicalIF":3.4000,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277222/pdf/","citationCount":"0","resultStr":"{\"title\":\"Non-penetrant Xq26.3 duplication involving the invariant TAD border: clinical evidence for the VGLL1 region as the GPR101 pituitary enhancer of X-linked acrogigantism.\",\"authors\":\"Cathie Hilditch, Samuel Curtis, Samuel Cotton, Shannon LeBlanc, Sunita De Sousa\",\"doi\":\"10.1007/s11102-025-01559-4\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>X-linked acrogigantism (X-LAG; OMIM: 300942) is a rare X-linked dominant, fully penetrant form of infancy-onset pituitary gigantism caused by Xq26.3 tandem duplications involving the GPR101 gene. All previously reported X-LAG-associated duplications disrupt the integrity of the resident topologically associating domain (TAD). This creates a neo-TAD, permitting ectopic chromatin interactions between GPR101 and centromeric pituitary enhancers postulated to lie between RBMX and VGLL1, and culminating in pituitary GPR101 misexpression and growth hormone excess. Conversely, none of the few previously reported cases of Xq26.3 duplications in unaffected individuals include the tissue-invariant TAD border that shields GPR101 from its centromeric enhancers. Preservation of this boundary has thus been considered synonymous with non-penetrance of X-LAG.</p><p><strong>Methods: </strong>We examined a series of four family members from the same kindred with an incidentally detected GPR101-containing Xq26.3 duplication involving the invariant TAD border.</p><p><strong>Results: </strong>Chromosome microarray demonstrated an interstitial chromosome Xq26.3 duplication: arr[GRCh37] Xq26.3(135,954,223 - 136,224,319)x2, including GPR101, the TAD invariant border and RBMX, but not VGLL1. None of the relatives with the Xq26.3 duplication exhibited evidence of growth hormone excess, making this the first unaffected family with a GPR101-containing Xq26.3 duplication involving the invariant TAD border. The predicted neo-TAD in this kindred excludes the VGLL1 region, which is present in all previously described X-LAG patients and absent in all previously described unaffected individuals with Xq26.3 duplications.</p><p><strong>Conclusion: </strong>Our clinical findings suggest that TAD border involvement is not sufficient for X-LAG to develop, and implicates the VGLL1 region as likely the sole pituitary enhancer responsible for GPR101 misexpression and the X-LAG phenotype. Pending corroborative studies, this new insight into X-LAG pathogenesis may guide interpretation of future Xq26.3 duplications and counselling of families in whom such duplications are found.</p>\",\"PeriodicalId\":20202,\"journal\":{\"name\":\"Pituitary\",\"volume\":\"28 4\",\"pages\":\"85\"},\"PeriodicalIF\":3.4000,\"publicationDate\":\"2025-07-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277222/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Pituitary\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s11102-025-01559-4\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pituitary","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s11102-025-01559-4","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Non-penetrant Xq26.3 duplication involving the invariant TAD border: clinical evidence for the VGLL1 region as the GPR101 pituitary enhancer of X-linked acrogigantism.
Introduction: X-linked acrogigantism (X-LAG; OMIM: 300942) is a rare X-linked dominant, fully penetrant form of infancy-onset pituitary gigantism caused by Xq26.3 tandem duplications involving the GPR101 gene. All previously reported X-LAG-associated duplications disrupt the integrity of the resident topologically associating domain (TAD). This creates a neo-TAD, permitting ectopic chromatin interactions between GPR101 and centromeric pituitary enhancers postulated to lie between RBMX and VGLL1, and culminating in pituitary GPR101 misexpression and growth hormone excess. Conversely, none of the few previously reported cases of Xq26.3 duplications in unaffected individuals include the tissue-invariant TAD border that shields GPR101 from its centromeric enhancers. Preservation of this boundary has thus been considered synonymous with non-penetrance of X-LAG.
Methods: We examined a series of four family members from the same kindred with an incidentally detected GPR101-containing Xq26.3 duplication involving the invariant TAD border.
Results: Chromosome microarray demonstrated an interstitial chromosome Xq26.3 duplication: arr[GRCh37] Xq26.3(135,954,223 - 136,224,319)x2, including GPR101, the TAD invariant border and RBMX, but not VGLL1. None of the relatives with the Xq26.3 duplication exhibited evidence of growth hormone excess, making this the first unaffected family with a GPR101-containing Xq26.3 duplication involving the invariant TAD border. The predicted neo-TAD in this kindred excludes the VGLL1 region, which is present in all previously described X-LAG patients and absent in all previously described unaffected individuals with Xq26.3 duplications.
Conclusion: Our clinical findings suggest that TAD border involvement is not sufficient for X-LAG to develop, and implicates the VGLL1 region as likely the sole pituitary enhancer responsible for GPR101 misexpression and the X-LAG phenotype. Pending corroborative studies, this new insight into X-LAG pathogenesis may guide interpretation of future Xq26.3 duplications and counselling of families in whom such duplications are found.
期刊介绍:
Pituitary is an international publication devoted to basic and clinical aspects of the pituitary gland. It is designed to publish original, high quality research in both basic and pituitary function as well as clinical pituitary disease.
The journal considers:
Biology of Pituitary Tumors
Mechanisms of Pituitary Hormone Secretion
Regulation of Pituitary Function
Prospective Clinical Studies of Pituitary Disease
Critical Basic and Clinical Reviews
Pituitary is directed at basic investigators, physiologists, clinical adult and pediatric endocrinologists, neurosurgeons and reproductive endocrinologists interested in the broad field of the pituitary and its disorders. The Editorial Board has been drawn from international experts in basic and clinical endocrinology. The journal offers a rapid turnaround time for review of manuscripts, and the high standard of the journal is maintained by a selective peer-review process which aims to publish only the highest quality manuscripts. Pituitary will foster the publication of creative scholarship as it pertains to the pituitary and will provide a forum for basic scientists and clinicians to publish their high quality pituitary-related work.