CEP104 and CEP290 ; Genes with Ciliary Functions Cause Intellectual Disability in Multiple Families

• Published in: Archives of Iranian medicine Vol. 24; no. 5; pp. 364 - 373
• Main Authors: Khoshbakht, Shahrouz, Beheshtian, Maryam, Fattahi, Zohreh, Bazazzadegan, Niloofar, Parsimehr, Elham, Fadaee, Mahsa, Vazehan, Raheleh, Faraji Zonooz, Mehrshid, Abolhassani, Ayda, Makvand, Mina, Kariminejad, Ariana, Celik, Arzu, Kahrizi, Kimia, Najmabadi, Hossein
• Format: Journal Article
• Language: English
• Published: Iran Academy of Medical Sciences of I.R. Iran 01.05.2021
• Subjects: Antigens, Neoplasm; Cell Cycle Proteins - genetics; Cytoskeletal Proteins - genetics; Developmental disabilities; Exome; Families & family life; Humans; Intellectual disabilities; Intellectual Disability - genetics; Iran; Mutation; Neurodevelopmental disorders; Neurological disorders; Pedigree; Signal transduction; Whole Exome Sequencing; Iran; Ciliopathies; CEP104; Intellectual disability; Neurodevelopmental disorders; CEP290
• ISSN: 1029-2977; 1735-3947
• 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.(Ser2449Thrfs*8) 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.(Ile556Asnfs*20) were identified in . In two other families, two novel homozygous variants; NM_014704:c.2356_2357insTT p.(Cys786Phefs*11) 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.