Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran.
Arch Iran Med. 2021 May 1;24(5):364-373. doi: 10.34172/aim.2021.53.
Neurodevelopmental and intellectual impairments are extremely heterogeneous disorders caused by a diverse variety of genes involved in different molecular pathways and networks. Genetic alterations in cilia, highly-conserved organelles with sensorineural and signal transduction roles can compromise their proper functions and lead to so-called "ciliopathies" featuring intellectual disability (ID) or neurodevelopmental disorders as frequent clinical manifestations. Here, we report several Iranian families affected with ID and other ciliopathy-associated features carrying known and novel variants in two ciliary genes; and .
Whole exome and Targeted exome sequencing were carried out on affected individuals. Lymphoblastoid cell lines (LCLs) derived from the members of affected families were established for two families carrying mutations. RNA and protein expression studies were carried out on these cells using qPCR and Western blot, respectively.
A novel homozygous variant; NM_025114.3:c.7341_7344dupACTT p.(Ser2449Thrfs8) and four previously reported homozygous variants; NM_025114.3:c.322C>T p.(Arg108), NM_025114.3:c.4393C>T p.(Arg1465*), NM_025114.3:c.5668G>T p.(Gly1890*) and NM_025114.3:c.1666dupA p.(Ile556Asnfs20) were identified in . In two other families, two novel homozygous variants; NM_014704:c.2356_2357insTT p.(Cys786Phefs11) and NM_014704:c.1901_1902insT p.(Leu634Phefs*33) were identified in , another ciliary gene. qPCR and Western blot analyses showed significantly lower levels of CEP104 transcripts and protein in patients compared to heterozygous or normal family members.
We emphasize on the clinical variability and pleiotropic phenotypes due to variants of these genes. In conclusion, our findings support the pivotal role of these genes resulting in cognitive and neurodevelopmental features.
神经发育和智力障碍是由多种不同分子途径和网络中的基因引起的极其异质的疾病。纤毛的遗传改变，这些高度保守的细胞器具有感觉神经和信号转导作用，可能会损害它们的正常功能，并导致所谓的“纤毛病”，其特征是智力残疾 (ID) 或神经发育障碍作为常见的临床表现。在这里，我们报告了几个伊朗家庭，这些家庭受到两种纤毛基因的影响; 和. 已知和新的变异体，患有 ID 和其他纤毛病相关特征。
对受影响个体进行全外显子和靶向外显子测序。从受影响家庭的成员中建立了两个家庭携带 突变的淋巴母细胞系 (LCL)。使用 qPCR 和 Western blot 分别对这些细胞进行 RNA 和蛋白质表达研究。
一个新的纯合变异体; NM_025114.3:c.7341_7344dupACTT p.(Ser2449Thrfs8)和四个先前报道的纯合变异体; NM_025114.3:c.322C>T p.(Arg108)，NM_025114.3:c.4393C>T p.(Arg1465*)，NM_025114.3:c.5668G>T p.(Gly1890*)和 NM_025114.3:c.1666dupA p.(Ile556Asnfs20)在. 中被鉴定出来。在另外两个家庭中，两个新的纯合变异体; NM_014704:c.2356_2357insTT p.(Cys786Phefs11)和 NM_014704:c.1901_1902insT p.(Leu634Phefs*33)在另一个纤毛基因 中被鉴定出来。qPCR 和 Western blot 分析表明，与杂合子或正常家庭成员相比，患者的 CEP104 转录本和蛋白水平明显降低。
我们强调由于这些基因的变异导致的临床变异性和多效表型。总之，我们的发现支持这些基因在认知和神经发育特征中的关键作用。
