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

• Published in: Experimental & molecular medicine 2016-08, Vol.48 (8), p.e251-e251
• Main Authors: 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 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
• Format: Article
• Language: English
• Subjects: 45; 45/47; 631/208/212/2301; Adolescent; Alleles; Biomedical and Life Sciences; Biomedicine; Child; Child, Preschool; Ciliopathies - diagnosis; Ciliopathies - genetics; Exome; Female; Genetic Heterogeneity; Humans; Infant; Kidney Diseases, Cystic - diagnosis; Kidney Diseases, Cystic - genetics; Male; Medical Biochemistry; Molecular Medicine; Mutation; Original; original-article; Sequence Analysis, DNA - methods; Stem Cells
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/emm.2016.63

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. Kidney disease: Step-wise gene testing yields diagnoses A two-step testing strategy can help reveal the genes responsible for a childhood kidney disease. A team led by Woong-Yang Park from the Samsung Genome Institute, Seoul, and Hae Il Cheong from Seoul National University tested a step-wise diagnostic approach on 55 Korean patients with nephronophthisis-related ciliopathy, a recessive disease marked by chronic renal failure during childhood and adolescence. First, the researchers used classical “Sanger” sequencing on five genes linked to the kidney disease; this offered a diagnosis in 12 of the patients. In the remaining subjects, they applied targeted “exome” sequencing of 34 candidate genes, and detected disease-causing mutations in another seven patients, for a total diagnostic success rate of 34%. This two-step approach, the authors argue, offers a cost-effective way to definitively diagnose this frequent genetic cause of kidney failure in children.