Jouret Guillaume, Egloff Matthieu, Landais Emilie, Tassy Olivier, Giuliano Fabienne, Karmous-Benailly Houda, Coutton Charles, Satre Véronique, Devillard Françoise, Dieterich Klaus, Vieville Gaëlle, Kuentz Paul, le Caignec Cédric, Beneteau Claire, Isidor Bertrand, Nizon Mathilde, Callier Patrick, Marquet Valentine, Bieth Eric, Lévy Jonathan, Tabet Anne-Claude, Lyonnet Stanislas, Baujat Geneviève, Rio Marlène, Cartault François, Scheidecker Sophie, Gouronc Aurélie, Schalk Audrey, Jacquin Clémence, Spodenkiewicz Marta, Angélini Chloé, Pennamen Perrine, Rooryck Caroline, Doco-Fenzy Martine, Poirsier Céline
Department of Genetics, Reims University Hospital, Reims, France.
National Center of Genetics (NCG), Laboratoire national de santé (LNS), Dudelange, Luxembourg.
Am J Med Genet A. 2023 Jan;191(1):52-63. doi: 10.1002/ajmg.a.62983. Epub 2022 Oct 5.
A small but growing body of scientific literature is emerging about clinical findings in patients with 19p13.3 microdeletion or duplication. Recently, a proximal 19p13.3 microduplication syndrome was described, associated with growth delay, microcephaly, psychomotor delay and dysmorphic features. The aim of our study was to better characterize the syndrome associated with duplications in the proximal 19p13.3 region (prox 19p13.3 dup), and to propose a comprehensive analysis of the underlying genomic mechanism. We report the largest cohort of patients with prox 19p13.3 dup through a collaborative study. We collected 24 new patients with terminal or interstitial 19p13.3 duplication characterized by array-based Comparative Genomic Hybridization (aCGH). We performed mapping, phenotype-genotype correlations analysis, critical region delineation and explored three-dimensional chromatin interactions by analyzing Topologically Associating Domains (TADs). We define a new 377 kb critical region (CR 1) in chr19: 3,116,922-3,494,377, GRCh37, different from the previously described critical region (CR 2). The new 377 kb CR 1 includes a TAD boundary and two enhancers whose common target is PIAS4. We hypothesize that duplications of CR 1 are responsible for tridimensional structural abnormalities by TAD disruption and misregulation of genes essentials for the control of head circumference during development, by breaking down the interactions between enhancers and the corresponding targeted gene.
关于19p13.3微缺失或微重复患者的临床发现，正在出现一小部分但数量不断增加的科学文献。最近，一种近端19p13.3微重复综合征被描述出来，其与生长发育迟缓、小头畸形、精神运动发育迟缓及畸形特征有关。我们研究的目的是更好地描述与近端19p13.3区域（prox 19p13.3 dup）重复相关的综合征，并对潜在的基因组机制进行全面分析。我们通过一项合作研究报告了最大规模的prox 19p13.3 dup患者队列。我们收集了24例以基于阵列的比较基因组杂交（aCGH）为特征的末端或间质19p13.3重复的新患者。我们进行了定位、表型-基因型相关性分析、关键区域划定，并通过分析拓扑相关结构域（TADs）探索三维染色质相互作用。我们在chr19: 3,116,922-3,494,377，GRCh37中定义了一个新的377 kb关键区域（CR 1），与先前描述的关键区域（CR 2）不同。新的377 kb CR 1包括一个TAD边界和两个共同靶标为PIAS4的增强子。我们推测CR 1的重复通过TAD破坏以及发育过程中控制头围的关键基因的调控异常，打破增强子与相应靶基因之间的相互作用，从而导致三维结构异常。
