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Compound heterozygous alterations in intraflagellar transport protein CLUAP1 in a
child with a novel Joubert and oral-facial-digital overlap syndrome
#MMPMID28679688
Johnston JJ
; Lee C
; Wentzensen IM
; Parisi MA
; Crenshaw MM
; Sapp JC
; Gross JM
; Wallingford JB
; Biesecker LG
Cold Spring Harb Mol Case Stud
2017[Jul]; 3
(4
): ? PMID28679688
show ga
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.
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