Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

Hee Gyung Kang, Hyun Kyung Lee, Yo Han Ahn, Je Gun Joung, Jaeyong Nam, Nayoung K.D. Kim, Jung Min Ko, Min Hyun Cho, Jae I. 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 I.L. Cheong

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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 ciliopathyrelated 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.

Original languageEnglish
Article numbere251
JournalExperimental and Molecular Medicine
Volume48
Issue number8
DOIs
Publication statusPublished - 2016 Aug 26

Fingerprint

Exome
Genetic Heterogeneity
Genes
Mutation
Liver
Screening
Ciliopathies
Inheritance Patterns
Korea
Chronic Kidney Failure

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Kang, Hee Gyung ; Lee, Hyun Kyung ; Ahn, Yo Han ; Joung, Je Gun ; Nam, Jaeyong ; Kim, Nayoung K.D. ; Ko, Jung Min ; Cho, Min Hyun ; Shin, Jae I. ; 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 I.L. / Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. In: Experimental and Molecular Medicine. 2016 ; Vol. 48, No. 8.
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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-L{\o}ken 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 ciliopathyrelated 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.",
author = "Kang, {Hee Gyung} and Lee, {Hyun Kyung} and Ahn, {Yo Han} and Joung, {Je Gun} and Jaeyong Nam and Kim, {Nayoung K.D.} and Ko, {Jung Min} and Cho, {Min Hyun} and Shin, {Jae I.} and Joon Kim and Park, {Hye Won} and Park, {Young Seo} and Ha, {Il Soo} and Chung, {Woo Yeong} and Lee, {Dae Yeol} and Kim, {Su Young} and Park, {Woong Yang} and Cheong, {Hae I.L.}",
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Kang, HG, Lee, HK, Ahn, YH, Joung, JG, Nam, J, Kim, NKD, Ko, JM, Cho, MH, Shin, JI, Kim, J, Park, HW, Park, YS, Ha, IS, Chung, WY, Lee, DY, Kim, SY, Park, WY & Cheong, HIL 2016, 'Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy', Experimental and Molecular Medicine, vol. 48, no. 8, e251. https://doi.org/10.1038/emm.2016.63

Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy. / Kang, Hee Gyung; Lee, Hyun Kyung; Ahn, Yo Han; Joung, Je Gun; Nam, Jaeyong; Kim, Nayoung K.D.; Ko, Jung Min; Cho, Min Hyun; Shin, Jae I.; 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 I.L.

In: Experimental and Molecular Medicine, Vol. 48, No. 8, e251, 26.08.2016.

Research output: Contribution to journalArticle

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T1 - Targeted exome sequencing resolves allelic and the genetic heterogeneity in the genetic diagnosis of nephronophthisis-related ciliopathy

AU - Kang, Hee Gyung

AU - Lee, Hyun Kyung

AU - Ahn, Yo Han

AU - Joung, Je Gun

AU - Nam, Jaeyong

AU - Kim, Nayoung K.D.

AU - Ko, Jung Min

AU - Cho, Min Hyun

AU - Shin, Jae I.

AU - Kim, Joon

AU - Park, Hye Won

AU - Park, Young Seo

AU - Ha, Il Soo

AU - Chung, Woo Yeong

AU - Lee, Dae Yeol

AU - Kim, Su Young

AU - Park, Woong Yang

AU - Cheong, Hae I.L.

PY - 2016/8/26

Y1 - 2016/8/26

N2 - 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 ciliopathyrelated 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.

AB - 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 ciliopathyrelated 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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