ESPN 51th Annual Meeting

ESPN 2018


 
Comprehensive genetic analysis of nephronophthisis-related ciliopathies (NPHP-RC) using next generation sequencing.
Nana Sakakibara 1 Naoya Morisada 2 Shinya Ishiko 1 Yuya Aoto 1 China Nagano 1 Junya Fujimura 1 Shogo Minamikawa 1 Tomohiko Yamamura 1 Kandai Nozu 1 Kazumoto Iijima 1

1- Department of Pediatrics, Kobe University Graduate School of Medicine
2- Department of Clinical Genetics, Hyogo Prefectural Kobe Children’s Hospital
 
Introduction:

Nephronophthisis(NPHP) is an autosomal-recessive kidney disease that is caused by abnormality of primary cilia. NPHP accompanied by extrarenal manifestations including intellectual disability, retinitis pigmentosa or hyperdactylia can be classified into disease entities such as Bardet-Biedl syndrome(BBS), Joubert syndrome(JBTS), Senior-Løken syndrome(SLNS) or Short-rib thoracic dysplasia(SRTD). The term nephronophthisis-related ciliopathies (NPHP-RC) is used to describe these clinical conditions. The clinical features often overlap in NPHP-RC patients and more than 70 NPHP-RC related genes are known; therefore, comprehensive genetic analysis using next generation sequencing (NGS) is useful for the definitive diagnosis of patients clinically suspected of having NPHP-RC. 

Material and methods:

From 2010 to 2017, we performed genetic analysis using NGS in 464 patients who have renal dysfunction without urinary abnormalities or known glomerulonephritis.

Results:

Mutations were detected in 26 patients. The gene mutations were as follows (number of patients): NPHP1(4), NPHP3(3), BBS2(2), MKKS(2), SDCCAG8(2), WDR19(2), WDR35(2), OFD1(1), BBS4(1), BBS10(1), BBS12(1), IFT140(1), TMEM67(1), TTC21B(1). Digenic mutations in CEP290 and AHI1 were also identified in one patient. Renal replacement therapy (RRT) was performed in 14 cases. The mean age at starting RRT was 5.4 years. Depending on the causative genes, the initiation time of RRT was different, for example, each patient with WDR19 mutations needed to start RRT before one year old. In these 26 cases, 17 cases were suspected to be NPHP-RC before the analysis. In other cases, some were clinically diagnosed with congenital anomalies of the kidney and urinary tract (CAKUT). Final diagnosis were as shown below (number of patients): BBS(8), NPHP(6), JBTS(2), SLSN(2), SRTD(2).

Conclusions:

A comprehensive genetic analysis using NGS is useful for patients who have renal dysfunction without urinary abnormalities accompanied by extrarenal manifestations including intellectual disability, retinitis pigmentosa or hyperdactylia. This is also important in genetic counseling for their families.