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KMID : 0620920160480080003
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Experimental & Molecular Medicine
2016 Volume.48 No. 8 p.3 ~ p.3
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Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy
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Kang Hee-Gyung
Lee Hyun-Kyung
Ahn Yo-Han
Joung Je-Gun
Nam Jae-yong
Kim Na-Young
Ko Jung-Min
Cho Min-Hyun
Shin Jae-Il
Kim Joon
Park Hye-Won
Park Young-Seo
Ha Il-Soo
Chung Woo-Yeong
Lee Dae-Yeol
Kim Su-Young
Park Woong-Yang
Cheong Hae-Il
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Abstract
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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.
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KEYWORD
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