Nevado Julián, Rosenfeld Jill A, Mena Rocío, Palomares-Bralo María, Vallespín Elena, Ángeles Mori María, Tenorio Jair A, Gripp Karen W, Denenberg Elizabeth, Del Campo Miguel, Plaja Alberto, Martín-Arenas Rubén, Santos-Simarro Fernando, Armengol Lluis, Gowans Gordon, Orera María, Sanchez-Hombre M Carmen, Corbacho-Fernández Esther, Fernández-Jaén Alberto, Haldeman-Englert Chad, Saitta Sulagna, Dubbs Holly, Bénédicte Duban B, Li Xia, Devaney Lani, Dinulos Mary Beth, Vallee Stephanie, Crespo M Carmen, Fernández Blanca, Fernández-Montaño Victoria E, Rueda-Arenas Inmaculada, de Torres María Luisa, Ellison Jay W, Raskin Salmo, Venegas-Vega Carlos A, Fernández-Ramírez Fernando, Delicado Alicia, García-Miñaúr Sixto, Lapunzina Pablo
Section of Functional and Structural Genomics Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrid, Spain.
CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain.
Eur J Hum Genet. 2015 Dec;23(12):1615-26. doi: 10.1038/ejhg.2015.51. Epub 2015 Apr 8.
Array comparative genomic hybridization (aCGH) is a powerful genetic tool that has enabled the identification of novel imbalances in individuals with intellectual disability (ID), autistic disorders and congenital malformations. Here we report a 'genotype first' approach using aCGH on 13 unrelated patients with 19p13.3 submicroscopic rearrangement (11 deletions and 2 duplications) and review cases in the literature and in public databases. Shared phenotypic features suggest that these patients represent an interstitial microdeletion/microduplication syndrome at 19p13.3. Common features consist of abnormal head circumference in most patients (macrocephaly with the deletions and microcephaly with the duplications), ID with developmental delay (DD), hypotonia, speech delay and common dysmorphic features. The phenotype is associated with at least a ~0.113 Mb critical region harboring three strong candidate genes probably associated with DD, ID, speech delay and other dysmorphic features: MAP2K2, ZBTB7A and PIAS4, an E3 ubiquitin ligase involved in the ubiquitin signaling pathways, which we hypothesize for the first time to be associated with head size in humans.
阵列比较基因组杂交（aCGH）是一种强大的遗传学工具，它能够识别患有智力残疾（ID）、自闭症谱系障碍和先天性畸形的个体中的新型失衡情况。在此，我们报告一种“基因型优先”的方法，对13名患有19p13.3亚微观重排（11例缺失和2例重复）的无关患者进行aCGH检测，并回顾文献和公共数据库中的病例。共同的表型特征表明，这些患者代表了19p13.3处的一种间质性微缺失/微重复综合征。常见特征包括大多数患者头围异常（缺失者为巨头畸形，重复者为小头畸形）、伴有发育迟缓（DD）的ID、肌张力减退、语言发育迟缓以及常见的畸形特征。该表型与至少一个约0.113 Mb的关键区域相关，该区域包含三个可能与DD、ID、语言发育迟缓和其他畸形特征相关的强候选基因：MAP2K2、ZBTB7A和PIAS4，PIAS4是一种参与泛素信号通路的E3泛素连接酶，我们首次推测其与人类头部大小有关。
