Abstract：
De novo variants in QRICH1 (Glutamine-rich protein 1) has recently been reported in 11 individuals with intellectual disability (ID). The function of QRICH1 is largely unknown but it is likely to play a key role in the unfolded response of endoplasmic reticulum stress through transcriptional control of proteostasis. In this study, we present 27 additional individuals and delineate the clinical and molecular spectrum of the individuals (n = 38) with QRICH1 variants. The main clinical features were mild to moderate developmental delay/ID (71%), nonspecific facial dysmorphism (92%) and hypotonia (39%). Additional findings included poor weight gain (29%), short stature (29%), autism spectrum disorder (29%), seizures (24%) and scoliosis (18%). Minor structural brain abnormalities were reported in 52% of the individuals with brain imaging. Truncating or splice variants were found in 28 individuals and 10 had missense variants. Four variants were inherited from mildly affected parents. This study confirms that heterozygous QRICH1 variants cause a neurodevelopmental disorder including short stature and expands the phenotypic spectrum to include poor weight gain, scoliosis, hypotonia, minor structural brain anomalies, and seizures. Inherited variants from mildly affected parents are reported for the first time, suggesting variable expressivity.
摘要：
QRICH1（富含谷氨酰胺的蛋白1）的从头变体最近在11个智力障碍（ID）的个体中被报道。QRICH1的功能在很大程度上是未知的，但它可能通过蛋白质停滞的转录控制在内质网应激的未折叠反应中起关键作用。在这项研究中,我们介绍了另外27例个体,并描述了QRICH1变异个体(n=38)的临床和分子谱.主要临床特征为轻度至中度发育迟缓/ID（71％），非特异性面部畸形（92％）和张力减退（39％）。其他发现包括体重增加不良（29％），身材矮小(29%)，自闭症谱系障碍（29%），癫痫发作（24%）和脊柱侧弯（18%）。在52％的具有脑成像的个体中报告了轻微的结构性脑异常。在28个个体中发现了截短或剪接变体，其中10个具有错义变体。四个变体遗传自轻度受影响的父母。这项研究证实，杂合QRICH1变异会导致神经发育障碍，包括身材矮小，并扩大表型范围，包括体重增加不良，脊柱侧弯,低张力,轻微的脑部结构异常,和癫痫发作。首次报道了轻度受影响父母的遗传变体，暗示可变的表现力。
