Hilditch Cathie, Curtis Samuel, Cotton Samuel, LeBlanc Shannon, De Sousa Sunita
Paediatric and Reproductive Genetics Unit, Women's and Children's Health Network, North Adelaide, South Australia.
Adelaide Medical School, The University of Adelaide, Adelaide, South Australia.
Pituitary. 2025 Jul 20;28(4):85. doi: 10.1007/s11102-025-01559-4.
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.
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.
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.
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.
X连锁肢端巨大症（X-LAG；OMIM：300942）是一种罕见的X连锁显性遗传病，是由涉及GPR101基因的Xq26.3串联重复导致的婴儿期起病的垂体巨人症的完全显性形式。所有先前报道的与X-LAG相关的重复都破坏了驻留拓扑相关结构域（TAD）的完整性。这产生了一个新的TAD，使得GPR101与假定位于RBMX和VGLL1之间的着丝粒垂体增强子之间发生异位染色质相互作用，最终导致垂体GPR101表达异常和生长激素过量。相反，先前报道的少数未受影响个体的Xq26.3重复病例中，没有一个包含保护GPR101免受其着丝粒增强子影响的组织不变性TAD边界。因此，保留这个边界被认为与X-LAG的非显性同义。
我们检查了来自同一家族的四名家庭成员，他们偶然检测到一个包含GPR101的Xq26.3重复，涉及不变性TAD边界。
染色体微阵列显示Xq26.3间质染色体重复：arr[GRCh37] Xq26.3(135,954,223 - 136,224,319)x2，包括GPR101、TAD不变边界和RBMX，但不包括VGLL1。所有具有Xq26.3重复的亲属均未表现出生长激素过量的证据，这使得该家族成为首个具有包含GPR101的Xq26.3重复且涉及不变性TAD边界的未受影响家族。该家族中预测的新TAD不包括VGLL1区域，该区域在所有先前描述的X-LAG患者中存在，而在所有先前描述的具有Xq26.3重复的未受影响个体中不存在。
我们的临床研究结果表明，TAD边界受累不足以导致X-LAG的发生，并表明VGLL1区域可能是导致GPR101表达异常和X-LAG表型的唯一垂体增强子。在进行确证性研究之前，这种对X-LAG发病机制的新见解可能会指导对未来Xq26.3重复的解读以及对发现此类重复的家族进行遗传咨询。
