Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy.
- Author:
Hee Gyung KANG
1
;
Hyun Kyung LEE
;
Yo Han AHN
;
Je Gun JOUNG
;
Jaeyong NAM
;
Nayoung K D KIM
;
Jung Min KO
;
Min Hyun CHO
;
Jae Il SHIN
;
Joon KIM
;
Hye Won PARK
;
Young Seo PARK
;
Il Soo HA
;
Woo Yeong CHUNG
;
Dae Yeol LEE
;
Su Young KIM
;
Woong Yang PARK
;
Hae Il CHEONG
Author Information
- Publication Type:Original Article
- MeSH: Adolescent; Diagnosis*; Exome*; Genetic Heterogeneity*; Humans; Kidney Failure, Chronic; Korea; Liver; Mass Screening; Wills
- From:Experimental & Molecular Medicine 2016;48(8):e251-
- CountryRepublic of Korea
- Language:English
- Abstract: Nephronophthisis-related ciliopathy (NPHP-RC) is a common genetic cause of end-stage renal failure during childhood and adolescence and exhibits an autosomal recessive pattern of inheritance. Genetic diagnosis is quite limited owing to genetic heterogeneity in NPHP-RC. We designed a novel approach involving the step-wise screening of Sanger sequencing and targeted exome sequencing for the genetic diagnosis of 55 patients with NPHP-RC. First, five NPHP-RC genes were analyzed by Sanger sequencing in phenotypically classified patients. Known pathogenic mutations were identified in 12 patients (21.8%); homozygous deletions of NPHP1 in 4 juvenile nephronophthisis patients, IQCB1/NPHP5 mutations in 3 Senior–Løken syndrome patients, a CEP290/NPHP6 mutation in 1 Joubert syndrome patient, and TMEM67/MKS3 mutations in 4 Joubert syndrome patients with liver involvement. In the remaining undiagnosed patients, we applied targeted exome sequencing of 34 ciliopathy-related genes to detect known pathogenic mutations in 7 (16.3%) of 43 patients. Another 18 likely damaging heterozygous variants were identified in 13 NPHP-RC genes in 18 patients. In this study, we report a variety of pathogenic and candidate mutations identified in 55 patients with NPHP-RC in Korea using a step-wise application of two genetic tests. These results support the clinical utility of targeted exome sequencing to resolve the issue of allelic and genetic heterogeneity in NPHP-RC.
