Ji Jianling, Lee Hane, Argiropoulos Bob, Dorrani Naghmeh, Mann John, Martinez-Agosto Julian A, Gomez-Ospina Natalia, Gallant Natalie, Bernstein Jonathan A, Hudgins Louanne, Slattery Leah, Isidor Bertrand, Le Caignec Cédric, David Albert, Obersztyn Ewa, Wiśniowiecka-Kowalnik Barbara, Fox Michelle, Deignan Joshua L, Vilain Eric, Hendricks Emily, Horton Harr Margaret, Noon Sarah E, Jackson Jessi R, Wilkens Alisha, Mirzaa Ghayda, Salamon Noriko, Abramson Jeff, Zackai Elaine H, Krantz Ian, Innes A Micheil, Nelson Stanley F, Grody Wayne W, Quintero-Rivera Fabiola
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California Los Angeles, CA, USA.
UCLA Clinical Genomics Center, Los Angeles, CA, USA.
Eur J Hum Genet. 2015 Nov;23(11):1473-81. doi: 10.1038/ejhg.2015.71. Epub 2015 May 6.
Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A ) is a highly conserved gene located in the Down syndrome critical region. It has an important role in early development and regulation of neuronal proliferation. Microdeletions of chromosome 21q22.12q22.3 that include DYRK1A (21q22.13) are rare and only a few pathogenic single-nucleotide variants (SNVs) in the DYRK1A gene have been described, so as of yet, the landscape of DYRK1A disruptions and their associated phenotype has not been fully explored. We have identified 14 individuals with de novo heterozygous variants of DYRK1A; five with microdeletions, three with small insertions or deletions (INDELs) and six with deleterious SNVs. The analysis of our cohort and comparison with published cases reveals that phenotypes are consistent among individuals with the 21q22.12q22.3 microdeletion and those with translocation, SNVs, or INDELs within DYRK1A. All individuals shared congenital microcephaly at birth, intellectual disability, developmental delay, severe speech impairment, short stature, and distinct facial features. The severity of the microcephaly varied from -2 SD to -5 SD. Seizures, structural brain abnormalities, eye defects, ataxia/broad-based gait, intrauterine growth restriction, minor skeletal abnormalities, and feeding difficulties were present in two-thirds of all affected individuals. Our study demonstrates that haploinsufficiency of DYRK1A results in a new recognizable syndrome, which should be considered in individuals with Angelman syndrome-like features and distinct facial features. Our report represents the largest cohort of individuals with DYRK1A disruptions to date, and is the first attempt to define consistent genotype-phenotype correlations among subjects with 21q22.13 microdeletions and DYRK1A SNVs or small INDELs.
双特异性酪氨酸（Y）磷酸化调节激酶1A（DYRK1A）是位于唐氏综合征关键区域的一个高度保守基因。它在早期发育和神经元增殖调控中起重要作用。包含DYRK1A（21q22.13）的21号染色体21q22.12q22.3微缺失很少见，且仅描述了少数DYRK1A基因中的致病性单核苷酸变异（SNV），因此，迄今为止，DYRK1A破坏及其相关表型的全貌尚未得到充分探索。我们鉴定出14例携带DYRK1A新生杂合变异的个体；5例为微缺失，3例为小插入或缺失（INDEL），6例为有害SNV。对我们队列的分析以及与已发表病例的比较表明，21q22.12q22.3微缺失个体以及DYRK1A内易位、SNV或INDEL个体的表型是一致的。所有个体出生时均有先天性小头畸形、智力残疾、发育迟缓、严重言语障碍、身材矮小和独特的面部特征。小头畸形的严重程度从-2标准差到-5标准差不等。三分之二的所有受影响个体存在癫痫发作、脑结构异常、眼部缺陷、共济失调/宽基步态、宫内生长受限、轻微骨骼异常和喂养困难。我们的研究表明，DYRK1A单倍剂量不足会导致一种新的可识别综合征，对于具有天使综合征样特征和独特面部特征的个体应考虑这种综合征。我们的报告代表了迄今为止最大的一组携带DYRK1A破坏的个体，并且是首次尝试在21q22.13微缺失以及DYRK1A SNV或小INDEL受试者中定义一致的基因型-表型相关性。
