Identification of the gene defect underlying ICF2 syndrome

鉴定 ICF2 综合征背后的基因缺陷

• 批准号: 8080912
• 负责人: SILVERE M VAN DER MAAREL
• 金额: $ 13.14万
• 依托单位: LEIDEN UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-03 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080912
• 关键词: 20q; Agammaglobulinemia; B-Lymphocytes; Birth; Bone Marrow; Bone Marrow Transplantation; Candidate Disease Gene; Cell Culture Techniques; Cells; Chromosomes; Codon Nucleotides; Computer software; Congenital Abnormality; DNA; DNA Methylation; DNA Methyltransferase; DNA Methyltransferase 3B; DNA Modification Methylases; DNA Sequence; DNMT3B gene; Data; Databases; Defect; Diagnosis; Disease; Exons; Genes; Genetic; Genetic Counseling; Genome; Genotype; Human; Human Genome; Immune; Intervention; Introns; Life Expectancy; Long-Term Effects; Maps; Methods; Molecular; Mutation; Online Mendelian Inheritance In Man; Patients; Phytohemagglutinins; Play; Recurrence; Reporting; Respiratory Tract Infections; Role; Sequence Determination; Single Nucleotide Polymorphism; Syndrome; Testing; Variant; base; clinical phenotype; disease diagnosis; exome; gastrointestinal infection; gene function; genetic linkage; genetic linkage analysis; genome-wide; immunodeficiency-centromeric instability-facial anomalies syndrome; improved; postnatal; prenatal; public health relevance

DESCRIPTION (provided by applicant): Patients with ICF (Immunodeficiency, Centromeric instability, and Facial anomalies) syndrome suffer from recurrent and often fatal respiratory and gastrointestinal infections due to agammaglobulinemia with B cells as well as a variety of congenital malformations. In approximately half of the patients mutations in the DNA methyltransferase 3B (DNMT3B) gene have been identified as the underlying cause of ICF syndrome (ICF1), while in the remainder of patients the gene defect is unknown. These ICF2 patients without DNMT3B defect show a clinical phenotype identical to ICF1 patients. All patients with ICF, both ICF1 and ICF2, suffer from agammaglobulinemia with B cells. Upon phytohaemagglutinin stimulation, multiradiate chromosomes can be identified in all ICF patients. In addition, specific DNA repeats show pronounced hypomethylation. Both observations are considered molecular hallmarks for ICF syndrome. Since all ICF2 patients show alpha-satellite repeat hypomethylation, which distinguishes them from ICF1 patients, the involvement of a second disease locus (gene defect) in ICF2 syndrome is expected. This is further substantiated by the identification of three ICF2 cases in which the DNMT3B gene is excluded by genetic studies. The central premise of this application is to identify the gene defect and primary pathogenic mechanism underlying ICF2 syndrome. First, using the method of homozygosity mapping, candidate loci that show homozygosity by descent in five consanguineous ICF2 patients will be identified. Additional ICF2 cases are available to aid the mapping study. Second, by sequence determination of the whole human exome in two consanguineous ICF2 patients using the Illumina/Solexa Genome Analyzer, all homozygous DNA variants in these patients in all regions of homozygosity will be identified. Candidate genes carrying homozygous DNA variants will be prioritized for their causal involvement in ICF2 based on the absence of the identified sequence variants in SNP databases, gene function and codon change. Finally, by direct sequencing of all exons and exon-intron boundaries of the prioritized candidate genes in the remaining patients in combination with expression studies of the candidate genes in cell cultures of ICF2 patients, the gene defect underlying ICF2 syndrome will be identified. PUBLIC HEALTH RELEVANCE: The central premise of this application is to identify the gene defect in ICF2 syndrome, a primary immune deficiency. This will increase our understanding of the molecular mechanism underlying ICF2 syndrome, and may provide new clues for therapy. Additionally, it will improve prenatal and postnatal diagnosis of the disease and facilitate genetic counseling.

描述（由申请人提供）：ICF（免疫缺陷、着丝粒不稳定和面部异常）综合征患者因 B 细胞无丙种球蛋白血症以及各种先天畸形而遭受反复且通常致命的呼吸道和胃肠道感染。大约一半的患者 DNA 甲基转移酶 3B (DNMT3B) 基因突变已被确定为 ICF 综合征 (ICF1) 的根本原因，而其余患者的基因缺陷尚不清楚。这些没有 DNMT3B 缺陷的 ICF2 患者表现出与 ICF1 患者相同的临床表型。所有 ICF 患者（ICF1 和 ICF2）均患有 B 细胞无丙种球蛋白血症。在植物血凝素刺激下，可以在所有 ICF 患者中鉴定出多辐射染色体。此外，特定的 DNA 重复序列显示出明显的低甲基化。这两个观察结果都被认为是 ICF 综合征的分子标志。由于所有 ICF2 患者都表现出α-卫星重复低甲基化，这将他们与 ICF1 患者区分开来，因此预计 ICF2 综合征中会涉及第二个疾病位点（基因缺陷）。三个 ICF2 病例的鉴定进一步证实了这一点，其中 DNMT3B 基因被遗传学研究排除。该应用的中心前提是确定 ICF2 综合征的基因缺陷和主要致病机制。首先，使用纯合性作图方法，将鉴定在五名近亲ICF2患者中显示血统纯合性的候选基因座。其他 ICF2 案例可用于帮助映射研究。其次，通过使用 Illumina/Solexa 基因组分析仪对两名近亲 ICF2 患者的整个人类外显子组进行序列测定，将鉴定这些患者的所有纯合性区域中的所有纯合 DNA 变异。基于 SNP 数据库中不存在已识别的序列变异、基因功能和密码子变化，携带纯合 DNA 变异的候选基因将因其与 ICF2 的因果关系而被优先考虑。最后，通过对剩余患者中优先候选基因的所有外显子和外显子-内含子边界进行直接测序，结合ICF2患者细胞培养物中候选基因的表达研究，将鉴定ICF2综合征背后的基因缺陷。 公众健康相关性：本申请的核心前提是确定 ICF2 综合征（一种原发性免疫缺陷）中的基因缺陷。这将增加我们对ICF2综合征分子机制的理解，并可能为治疗提供新的线索。此外，它将改善该疾病的产前和产后诊断并促进遗传咨询。

项目成果

Immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome, due to ZBTB24 mutations, presenting with large cerebral cyst.

• DOI: 10.1002/ajmg.a.35486
• 发表时间: 2012-08
• 期刊: AMERICAN JOURNAL OF MEDICAL GENETICS PART A
• 影响因子: 2
• 作者: Cerbone, Manuela;Wang, Jun;Van der Maarel, Silvere M.;D'Amico, Alessandra;D'Agostino, Antonio;Romano, Alfonso;Brunetti-Pierri, Nicola
• 通讯作者: Brunetti-Pierri, Nicola

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

• DOI: 10.1038/ncomms8870
• 发表时间: 2015-07-28
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Thijssen PE;Ito Y;Grillo G;Wang J;Velasco G;Nitta H;Unoki M;Yoshihara M;Suyama M;Sun Y;Lemmers RJ;de Greef JC;Gennery A;Picco P;Kloeckener-Gruissem B;Güngör T;Reisli I;Picard C;Kebaili K;Roquelaure B;Iwai T;Kondo I;Kubota T;van Ostaijen-Ten Dam MM;van Tol MJ;Weemaes C;Francastel C;van der Maarel SM;Sasaki H
• 通讯作者: Sasaki H