背景:Coffin-Lowry综合征(CLS)[OMIM#303600]是一种罕见的X连锁显性综合征。CLS是由RPS6KA3基因(OMIM*300,075)中的高度异质性功能丧失突变引起的。CLS的特点是智力残疾(ID),身材矮小,锥形手指,特征性的面部特征,和进行性骨骼变化。远端22q11.2微缺失综合征(OMIM#611867)是一种常染色体显性遗传和复发性基因组疾病。它主要包括三种类型[远端I型(D-E/F),II型(E-F),和III型(F-G)]并表现出可变的临床表型(轻度,中度,甚至正常):早产,出生前和/或出生后生长受限,发展滞后,ID,行为问题,心血管缺陷,骨骼异常,和畸形的面部特征。我们调查了一个具有ID的中国家系的遗传病因,身材矮小,数字异常,面部畸形,和月经紊乱。杂合RPS6KA3基因变异c.898C>T(p。R300X)在该家族性病例中被鉴定。两名具有远端22q11.2微缺失的女性CLS患者表现出更严重的临床表型。我们提供了这些中国女性CLS患者的临床特征。案例介绍:我们描述了一个有三名受影响女性的中国家庭(母亲,姐姐,和先证者)。母亲和姐姐有更严重的临床表型(中度面部畸形,更严重的认知障碍,和较短的身材)。常见的特征表型是ID,身材矮小,面部畸形,月经不调,和心血管疾病。从谱系收集外周血样品。全外显子组测序(WES)鉴定出一个杂合无义RPS6KA3基因变体c.898C>T(p。R300X)。通过Sanger测序验证。拷贝数变异测序(CNV-seq)显示,母亲和姐姐均携带CNVseq[hg19]del(22)(q11.22-q11.23)(22997582-23637176)×0.5。来自外周血样品的RNA用于测量mRNA(由RPS6KA3的外显子14表达)的相对定量。在母亲和姐姐的血液样本中,mRNA相对表达水平显着降低。在先证者的血液样本中,mRNA相对表达水平显着升高。X染色体失活(XCI)研究表明,先证者显示出极度偏斜的XCI,并且姐姐的XCI模式是随机的。结论:在此,我们报道了三名中国女性患者,患有杂合无义RPS6KA3基因变异c.898C>T。进行了进一步的遗传研究。据我们所知,具有这种变异的中国患者以前在文献中没有报道。三名女性患者的严重程度各不相同。这些中国女性CLS患者的临床特征可以扩大CLS的表型谱。我们帮助医生进一步了解基因型-表型相关性。
Background: Coffin-Lowry syndrome (CLS) [OMIM#303600] is a rare X-linked dominant syndrome. CLS is caused by highly heterogeneous loss-of-function mutations in the RPS6KA3 gene (OMIM*300,075). CLS is characterized by intellectual disability (ID), short stature, tapered fingers, characteristic facial features, and progressive skeletal changes. Distal 22q11.2 microdeletion syndrome (OMIM#611867) is an autosomal dominant and recurrent genomic disorder. It mainly includes three types [distal type I (D-E/F), type II (E-F), and type III (F-G)] and exhibits variable clinical phenotypes (mild, moderate, or even normal): preterm birth, pre- and/or postnatal growth restriction, development delay, ID, behavioral problems, cardiovascular defects, skeletal anomalies, and dysmorphic facial features. We investigated the genetic etiology of a Chinese pedigree with ID, short stature, digit abnormalities, facial dysmorphism, and menstrual disorder. A heterozygous RPS6KA3 gene variant c.898C>T (p.R300X) was identified in this familial case. Two female CLS patients with distal 22q11.2 microdeletion presented with more severe clinical phenotypes. We provided clinical characteristics of these Chinese female CLS patients. Case presentation: We described a Chinese family with three affected females (the mother, the elder sister, and the proband). The mother and the elder sister had more severe clinical phenotypes (moderate facial dysmorphism, more severe cognitive impairment, and shorter stature). The common characteristic phenotypes are ID, short stature, facial dysmorphism, irregular menstruation, and cardiovascular disorders. Peripheral blood samples were collected from the pedigree. Whole-exome sequencing (WES) identified a heterozygous nonsense RPS6KA3 gene variant c.898C>T (p.R300X). It was verified by Sanger sequencing. Copy number variation sequencing (CNV-seq) showed that both the mother and the elder sister carried a CNVseq [hg19] del (22) (q11.22-q11.23) (22997582-23637176)×0.5. RNA from peripheral blood samples was used for measuring the relative quantification of mRNA (expressed by exon 14 of RPS6KA3). The levels of mRNA relative expressions were significantly lower in the mother\'s and the elder sister\'s blood samples. The levels of mRNA relative expressions were significantly higher in the proband\'s blood sample. X-chromosome inactivation (XCI) studies demonstrated that the proband showed extremely skewed XCI, and the XCI pattern of the elder sister was random. Conclusion: Herein, we reported three Chinese female patients with a heterozygous nonsense RPS6KA3 gene variant c.898C>T. Further genetic studies were performed. To our knowledge, Chinese patients with this variant have not been previously reported in the literature. The three female patients presented with variable degrees of severity. The clinical characteristics of these Chinese female CLS patients could expand the phenotypic spectrum of CLS. We helped physicians to understand the genotype-phenotype correlation further.