Bi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.

TitleBi-allelic Mutations in FAM149B1 Cause Abnormal Primary Cilium and a Range of Ciliopathy Phenotypes in Humans.
Publication TypeJournal Article
Year of Publication2019
AuthorsShaheen, R, Jiang, N, Alzahrani, F, Ewida, N, Al-Sheddi, T, Alobeid, E, Musaev, D, Stanley, V, Hashem, M, Ibrahim, N, Abdulwahab, F, Alshenqiti, A, Sonmez, FMujgan, Saqati, N, Alzaidan, H, Al-Qattan, MM, Al-Mohanna, F, Gleeson, JG, Alkuraya, FS
JournalAm J Hum Genet
Volume104
Issue4
Pagination731-737
Date Published2019 Apr 04
ISSN1537-6605
Abstract

Ciliopathies are clinical disorders of the primary cilium with widely recognized phenotypic and genetic heterogeneity. In two Arab consanguineous families, we mapped a ciliopathy phenotype that most closely matches Joubert syndrome (hypotonia, developmental delay, typical facies, oculomotor apraxia, polydactyly, and subtle posterior fossa abnormalities) to a single locus in which a founder homozygous truncating variant in FAM149B1 was identified by exome sequencing. We subsequently identified a third Arab consanguineous multiplex family in which the phenotype of Joubert syndrome/oral-facial-digital syndrome (OFD VI) was found to co-segregate with the same founder variant in FAM149B1. Independently, autozygosity mapping and exome sequencing in a consanguineous Turkish family with Joubert syndrome highlighted a different homozygous truncating variant in the same gene. FAM149B1 encodes a protein of unknown function. Mutant fibroblasts were found to have normal ciliogenesis potential. However, distinct cilia-related abnormalities were observed in these cells: abnormal accumulation IFT complex at the distal tips of the cilia, which assumed bulbous appearance, increased length of the primary cilium, and dysregulated SHH signaling. We conclude that FAM149B1 is required for normal ciliary biology and that its deficiency results in a range of ciliopathy phenotypes in humans along the spectrum of Joubert syndrome.

DOI10.1016/j.ajhg.2019.02.018
Alternate JournalAm. J. Hum. Genet.
PubMed ID30905400
PubMed Central IDPMC6451727
Grant ListR01 NS048453 / NS / NINDS NIH HHS / United States
U54 HG006504 / HG / NHGRI NIH HHS / United States