Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a child with a novel Joubert and oral-facial-digital overlap syndrome

Cold Spring Harb Mol Case Stud. 2017 Jul 5;3(4):a001321. doi: 10.1101/mcs.a001321. Print 2017 Jul.


Disruption of normal ciliary function results in a range of diseases collectively referred to as ciliopathies. Here we report a child with a phenotype that overlapped with Joubert, oral-facial-digital, and Pallister-Hall syndromes including brain, limb, and craniofacial anomalies. We performed exome-sequence analysis on a proband and both parents, filtered for putative causative variants, and Sanger-verified variants of interest. Identified variants in CLUAP1 were functionally analyzed in a Xenopus system to determine their effect on ciliary function. Two variants in CLUAP1 were identified through exome-sequence analysis, Chr16:g.3558407T>G, c.338T>G, p.(Met113Arg) and Chr16:g.3570011C>T, c.688C>T, p.(Arg230Ter). These variants were rare in the Exome Aggregation Consortium (ExAC) data set of 65,000 individuals (one and two occurrences, respectively). Transfection of mutant CLUAP1 constructs into Xenopus embryos showed reduced protein levels p.(Arg230Ter) and reduced intraflagellar transport p.(Met113Arg). The genetic data show that these variants are present in an affected child, are rare in the population, and result in reduced, but not absent, intraflagellar transport. We conclude that biallelic mutations in CLUAP1 resulted in this novel ciliopathy syndrome in the proband.

Keywords: 2–3 toe syndactyly; abnormality of the eyebrow; accessory oral frenulum; broad nasal tip; central hypotonia; cutaneous finger syndactyly; depressed nasal bridge; dysgenesis of the cerebellar vermis; high, narrow palate; hypertelorism; incomplete cleft of the upper lip; mixed hearing impairment; patent foramen ovale; postaxial hand polydactyly; preaxial foot polydactyly; prominent epicanthal folds; rhizomelic arm shortening; sparse scalp hair; thick anterior alveolar ridges; underdeveloped supraorbital ridges.

Publication types

  • Case Reports

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Adult
  • Animals
  • Antigens, Neoplasm / genetics*
  • Antigens, Neoplasm / metabolism
  • Carrier Proteins / genetics
  • Cerebellum / abnormalities*
  • Child
  • Craniofacial Abnormalities / genetics
  • Exome
  • Eye Abnormalities / genetics*
  • Female
  • Flagella / genetics
  • Heterozygote
  • Humans
  • Kidney Diseases, Cystic / genetics*
  • Male
  • Orofaciodigital Syndromes / genetics*
  • Pallister-Hall Syndrome / genetics
  • Phenotype
  • Polydactyly / genetics
  • Retina / abnormalities*
  • Whole Exome Sequencing
  • Xenopus / genetics


  • Antigens, Neoplasm
  • CLUAP1 protein, human
  • Carrier Proteins

Supplementary concepts

  • Agenesis of Cerebellar Vermis
  • Oral-facial-digital syndrome, type 2