BACKGROUND AND OBJECTIVES: Steroid-resistant nephrotic syndrome overwhelmingly progresses to ESRD. More than 30 monogenic genes have been identified to cause steroid-resistant nephrotic syndrome. We previously detected causative mutations using targeted panel sequencing in 30% of patients with steroid-resistant nephrotic syndrome. Panel sequencing has a number of limitations when compared with whole exome sequencing. We employed whole exome sequencing to detect monogenic causes of steroid-resistant nephrotic syndrome in an international cohort of 300 families.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Three hundred thirty-five individuals with steroid-resistant nephrotic syndrome from 300 families were recruited from April of 1998 to June of 2016. Age of onset was restricted to <25 years of age. Exome data were evaluated for 33 known monogenic steroid-resistant nephrotic syndrome genes.

RESULTS: In 74 of 300 families (25%), we identified a causative mutation in one of 20 genes known to cause steroid-resistant nephrotic syndrome. In 11 families (3.7%), we detected a mutation in a gene that causes a phenocopy of steroid-resistant nephrotic syndrome. This is consistent with our previously published identification of mutations using a panel approach. We detected a causative mutation in a known steroid-resistant nephrotic syndrome gene in 38% of consanguineous families and in 13% of nonconsanguineous families, and 48% of children with congenital nephrotic syndrome. A total of 68 different mutations were detected in 20 of 33 steroid-resistant nephrotic syndrome genes. Fifteen of these mutations were novel.,,, andwere the most common genes in which we detected a mutation. In another 28% of families, we detected mutations in one or more candidate genes for steroid-resistant nephrotic syndrome.

CONCLUSIONS: Whole exome sequencing is a sensitive approach toward diagnosis of monogenic causes of steroid-resistant nephrotic syndrome. A molecular genetic diagnosis of steroid-resistant nephrotic syndrome may have important consequences for the management of treatment and kidney transplantation in steroid-resistant nephrotic syndrome.

Chronically increased echogenicity on renal ultrasound is a sensitive early finding of chronic kidney disease that can be detected before manifestation of other symptoms. Increased echogenicity, however, is not specific for a certain etiology of chronic kidney disease. Here, we performed whole exome sequencing in 79 consanguineous or familial cases of suspected nephronophthisis in order to determine the underlying molecular disease cause. In 50 cases, there was a causative mutation in a known monogenic disease gene. In 32 of these cases whole exome sequencing confirmed the diagnosis of a nephronophthisis-related ciliopathy. In 8 cases it revealed the diagnosis of a renal tubulopathy. The remaining 10 cases were identified as Alport syndrome (4), autosomal-recessive polycystic kidney disease (2), congenital anomalies of the kidney and urinary tract (3), and APECED syndrome (1). In 5 families, in whom mutations in known monogenic genes were excluded, we applied homozygosity mapping for variant filtering and identified 5 novel candidate genes (RBM48, FAM186B, PIAS1, INCENP, and RCOR1) for renal ciliopathies. Thus, whole exome sequencing allows the detection of the causative mutation in 2/3 of affected individuals, thereby presenting the etiologic diagnosis, and allows identification of novel candidate genes.Kidney International advance online publication, 21 October 2015; doi:10.1038/ki.2015.317.

DATA SOURCES: Medline, Embase, Cochrane Oral Health Group's Trials Register and the Cochrane Central Register of Controlled Trials (CENTRAL). Unpublished data were sought by searching ClinicalTrials.gov, the National Research Register and Pro-Quest Dissertation Abstracts and Thesis database. There were no language restrictions.

STUDY SELECTION: Randomised and controlled clinical trials (including split mouth) directly comparing self-etch and acid-etch primers including patients with full-arch, fixed and bonded orthodontic appliances (not banded) with follow-up periods of at least 12 months were included.

DATA EXTRACTION AND SYNTHESIS: Two authors abstracted data independently, with disagreements being resolved by a third. The Cochrane Risk of Bias tool was used to assess study quality. A random effects meta-analysis was undertaken.

RESULTS: Eleven studies were included in the qualitative summary with five studies contributing to a meta-analysis. These five studies (n =3444 brackets, 1721 acid-etch, 1723 self-etch) had relatively low statistical and clinical heterogeneity. Meta-analysis demonstrated a tendency for a higher risk of failure (odds ratio 1.35; 95% CI, 0.99-1.83; P 5 0.06) with self-etch primers. The use of self-etch techniques was also associated with a small but statistically significant time saving (weighted mean difference 23.2 seconds per bracket; 95% CI, 20.7-25.8; P \0.001). There was insufficient evidence to assess the effect of bonding modality on demineralisation rates.

CONCLUSIONS: There is weak evidence indicating higher odds of failure with self-etch primer than acid-etch over 12 months in orthodontic patients, and there is strong evidence that a self-etch primer is likely to result in modest time savings (eight minutes for full bonding) compared with acid-etch.