Balkan Journal of Medical Genetics

THE ROLE OF NEXT GENERATION SEQUENCING IN THE DIFFERENTIAL DIAGNOSIS OF CAROLI’S SYNDROME
Smolović B, Muhović D, Hodžić A, Bergant G, Peterlin B
*Corresponding Author: Professor Borut Peterlin, M.D., Ph.D., Department of Gynecology and Obstetrics, Institute of Medical Genetics, Department of Gynecology and Obstetrics, University Medical Centre Ljubljana, Šlajmerjeva Street 4, Ljubljana, Slovenia. Tel./Fax: +386-(0)1-540-1137. E-mail: borut.peterlin@guest.arnes.si
page: 49

MATERIALS AND METHODS

In order to resolve the diagnostic dilemma (PSC or CD), we referred the patient for genetic diagnostics, where clinical exome sequencing (CES) using a TruSight One capture kit (Illumina, San Diego, CA, USA) was performed, followed by sequencing on an Illumina MiSeq platform. The bioinformatic analysis was performed according to GATK Best Practices workflow [14,15]. The strategy for exome data interpretation was primarily based on the combined disease and phenotype gene target definition approach we previously described [16]. Considering the observation of multiple renal cysts in the patient, bioinformatic analysis and interpretation of genes associated with polycystic kidney disease was performed (BICC1, HNF1B, LRP5, NOTCH2, PKD1, PKD2, PKHD1, REN, SEC63, VHL). Sequencing Results. Sequencing data analysis showed the presence of two pathogenic heterozygous variants in the PKHD1 gene: nonsense variant c.370C>T, corresponding to an amino acid change Arg124Ter and missense variant c.4870C>T corresponding to an amino acid change Arg1624Trp. Both identified variants are rare in the control population and in the 138,000 controls of the gnomAD project [17,18], its population frequency was estimated at 0.0016% for c.370C>T and 0.018% for c.4870C>T, respectively. Based on the anticipated effect, the c.370C>T variant likely affects function of the protein coded by the gene with this variant, whereas for c.4870C>T, it was predicted as pathogenic with two from the three pathogenicity prediction algorithms employed (Sift) [19,20], Polyphen2 [21,22], MutationTaster [23,24]. Both identified variants are featured in the ClinVar database as pathogenic (accession numbers: 167499; 188369) [25]. The reported variants in the PKHD1 gene present a likely cause for the clinical presentation of the patient. Based on recurrent cholangitis, cystic dilatation of the intrahepatic bile ducts associated with polycystic kidney disease, normal findings on extra hepatic bile ducts, presence of two pathogenic heterozygous variants in the PKHD1 gene, we concluded that the correct diagnosis in this case is CD.

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