Whole exome sequencing identifies recessive PKHD1 mutations in a Chinese twin family with Caroli disease.
BACKGROUND
Mutations in PKHD1 cause autosomal recessive Caroli disease, which is a rare congenital disorder involving cystic dilatation of the intrahepatic bile ducts. However, the mutational spectrum of PKHD1 and the phenotype-genotype correlations have not yet been fully established.


METHODS
Whole exome sequencing (WES) was performed on one twin sample with Caroli disease from a Chinese family from Shandong province. Routine Sanger sequencing was used to validate the WES and to carry out segregation studies. We also described the PKHD1 mutation associated with the genotype-phenotype of this twin.


RESULTS
A combination of WES and Sanger sequencing revealed the genetic defect to be a novel compound heterozygous genotype in PKHD1, including the missense mutation c.2507 T>C, predicted to cause a valine to alanine substitution at codon 836 (c.2507T>C, p.Val836Ala), and the nonsense mutation c.2341C>T, which is predicted to result in an arginine to stop codon at codon 781 (c.2341C>T, p.Arg781*). This compound heterozygous genotype co-segregates with the Caroli disease-affected pedigree members, but is absent in 200 normal chromosomes.


CONCLUSIONS
Our findings indicate exome sequencing can be useful in the diagnosis of Caroli disease patients and associate a compound heterozygous genotype in PKHD1 with Caroli disease, which further increases our understanding of the mutation spectrum of PKHD1 in association with Caroli disease.
Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Xiwei
X
Hao
Genetic Laboratory, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Shiguo
S
Liu
Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Qian
Q
Dong
Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Hong
H
Zhang
Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Jing
J
Zhao
Pediatric Surgery, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.
Lin
L
Su
D019943:Amino Acid Substitution; D044466:Asian People; D016767:Caroli Disease; D002648:Child; D002681:China; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D059472:Exome; D005190:Family; D006579:Heterozygote; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D011956:Receptors, Cell Surface / Q000235:genetics*; D014427:Twins
D018389:Codon, Nonsense; C451750:PKHD1 protein, human; D011956:Receptors, Cell Surface