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

Am J Hum Genet. 2019 Apr 4;104(4):731-737. doi: 10.1016/j.ajhg.2019.02.018. Epub 2019 Mar 21.


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.

Keywords: Joubert syndrome; SHH; bulbous ciliary tip; ciliary length; oral-facial-digital syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adolescent
  • Alleles
  • Cerebellum / abnormalities*
  • Child, Preschool
  • Cilia / genetics
  • Cilia / pathology*
  • Ciliopathies / diagnosis*
  • Ciliopathies / genetics*
  • Consanguinity
  • Cytoskeletal Proteins / genetics*
  • Exome
  • Eye Abnormalities / genetics*
  • Genes, Recessive
  • Homozygote
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Male
  • Mutation*
  • Nervous System Malformations / genetics
  • Orofaciodigital Syndromes / genetics
  • Phenotype
  • Retina / abnormalities*
  • Sequence Analysis, DNA
  • Signal Transduction
  • Turkey


  • Cytoskeletal Proteins
  • FAM149B1 protein, human

Supplementary concepts

  • Agenesis of Cerebellar Vermis