Kolanczyk Mateusz, Krawitz Peter, Hecht Jochen, Hupalowska Anna, Miaczynska Marta, Marschner Katrin, Schlack Claire, Emmerich Denise, Kobus Karolina, Kornak Uwe, Robinson Peter N, Plecko Barbara, Grangl Gernot, Uhrig Sabine, Mundlos Stefan, Horn Denise
1] Institute for Medical Genetics and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany [2] Max Planck Institute for Molecular Genetics, Berlin, Germany.
Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Berlin, Germany.
Eur J Hum Genet. 2015 May;23(5):633-8. doi: 10.1038/ejhg.2014.109. Epub 2014 Jun 11.
Ritscher-Schinzel syndrome (RSS)/3C (cranio-cerebro-cardiac) syndrome (OMIM#220210) is a rare and clinically heterogeneous developmental disorder characterized by intellectual disability, cerebellar brain malformations, congenital heart defects, and craniofacial abnormalities. A recent study of a Canadian cohort identified homozygous sequence variants in the KIAA0196 gene, which encodes the WASH complex subunit strumpellin, as a cause for a form of RSS/3C syndrome. We have searched for genetic causes of a phenotype similar to RSS/3C syndrome in an Austrian family with two affected sons. To search for disease-causing variants, whole-exome sequencing (WES) was performed on samples from two affected male children and their parents. Before WES, CGH array comparative genomic hybridization was applied. Validation of WES and segregation studies was done using routine Sanger sequencing. Exome sequencing detected a missense variant (c.1670A>G; p.(Tyr557Cys)) in exon 15 of the CCDC22 gene, which maps to chromosome Xp11.23. Western blots of immortalized lymphoblastoid cell lines (LCLs) from the affected individual showed decreased expression of CCDC22 and an increased expression of WASH1 but a normal expression of strumpellin and FAM21 in the patients cells. We identified a variant in CCDC22 gene as the cause of an X-linked phenotype similar to RSS/3C syndrome in the family described here. A hypomorphic variant in CCDC22 was previously reported in association with a familial case of syndromic X-linked intellectual disability, which shows phenotypic overlap with RSS/3C syndrome. Thus, different inactivating variants affecting CCDC22 are associated with a phenotype similar to RSS/3C syndrome.
里彻-申策尔综合征（RSS）/3C（颅-脑-心）综合征（OMIM编号：220210）是一种罕见的、临床异质性发育障碍，其特征为智力残疾、小脑脑畸形、先天性心脏缺陷和颅面异常。最近一项对加拿大队列的研究确定，编码WASH复合物亚基斯特伦佩林的KIAA0196基因中的纯合序列变异是一种形式的RSS/3C综合征的病因。我们在一个有两个患病儿子的奥地利家庭中寻找与RSS/3C综合征相似表型的遗传病因。为了寻找致病变异，对两个患病男童及其父母的样本进行了全外显子组测序（WES）。在进行WES之前，应用了比较基因组杂交（CGH）阵列。使用常规桑格测序对WES和遗传分离研究进行验证。外显子组测序在CCDC22基因第15外显子中检测到一个错义变异（c.1670A>G；p.(Tyr557Cys)），该基因定位于Xp11.23染色体。来自患病个体的永生化淋巴母细胞系（LCLs）的蛋白质免疫印迹显示，患者细胞中CCDC22的表达降低，WASH1的表达增加，但斯特伦佩林和FAM21的表达正常。我们确定CCDC22基因中的一个变异是本文所述家庭中一种与RSS/3C综合征相似的X连锁表型的病因。先前报道CCDC22中的一个低表达变异与一例家族性综合征性X连锁智力残疾病例相关，该病例与RSS/3C综合征存在表型重叠。因此，影响CCDC22的不同失活变异与一种与RSS/3C综合征相似的表型相关。
