Jeffery Fletcher

Multicystic Dysplastic Kidney and Variable Phenotype in a Family with a Novel Deletion Mutation of PAX2

The renal coloboma syndrome (OMIM 120330) is caused by mutations in the PAX2 gene. Typical findings in these patients include renal hypoplasia, renal insufficiency, vesicoureteric reflux, and optic disc coloboma. A family with a novel heterozygous 10-bp deletion in exon 2 of the PAX2 gene leading to a truncating mutation and variable phenotype across three generations is reported. The first presentation of multicystic dysplastic kidney in this syndrome is reported. The possibility that abnormal PAX2 protein in this case may cause a dominant negative effect also is discussed. The finding of multicystic dysplastic kidney in renal coloboma syndrome could suggest that PAX2 may play a role in early ureteric obstruction and subsequent renal maldevelopment.

Chronic allograft nephropathy

Chronic allograft nephropathy (CAN) is the leading cause of renal allograft loss in paediatric renal transplant recipients. CAN is the result of immunological and nonimmunological injury, including acute rejection episodes, hypoperfusion, ischaemia reperfusion, calcineurin toxicity, infection and recurrent disease. The development of CAN is often insidious and may be preceded by subclinical rejection in a well-functioning allograft. Classification of CAN is histological using the Banff classification of renal allograft pathology with classic findings of interstitial fibrosis, tubular atrophy, glomerulosclerosis, fibrointimal hyperplasia and arteriolar hyalinosis. Although improvement in immunosuppression has led to greater 1-year graft survival rates, chronic graft loss remains relatively unchanged and opportunistic infectious complications remain a problem. Protocol biopsy monitoring is not current practice in paediatric transplantation for CAN monitoring but may have a place if new treatment options become available. Newer immunosuppression regimens, closer monitoring of the renal allograft and management of subclinical rejection may lead to reduced immune injury leading to CAN in the paediatric population but must be weighed against the risk of increased immunosuppression and calcineurin inhibitor nephrotoxicity.

Prevalence of genetic renal disease in children

BackgroundGenetic etiology comprises a significant proportion of renal disease in childhood. Completion of the Human Genome Project and increased genetic testing has assisted with the increased recognition of a genetic basis to many renal disorders. Australia and New Zealand have a relatively stable but diverse population, with eight major pediatric nephrology referral centers, which allow ascertainment of disease frequency.MethodsTo determine prevalence, pediatric nephrologists at the eight centers in Australia and New Zealand were surveyed on their estimated number of patients with renal disease of genetic etiology over a 10-year period. Disease prevalence was calculated using combined national population data.ResultsThe overall prevalence of genetic kidney disease in children in Australia and New Zealand is 70.6 children per million age-representative population. Congenital anomalies of the kidney and urinary tract (CAKUT) and steroid-resistant nephrotic syndrome (SRNS) are the most frequent, with a prevalence of 16.3 and 10.7, respectively, per million children.ConclusionWe find a similar prevalence of genetic renal disorders in Australia and New Zealand to those reported in other countries. This is likely to be due to inclusion of children with all forms of renal disease rather than being limited to those with renal impairment.

Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders

Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment individualized to the patients phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.

Bilateral Wilms Tumor and Early Presentation in Pediatric Patients Is Associated with the Truncation of the Wilms Tumor 1 Protein

OBJECTIVES To investigate the frequency of constitutional Wilms tumor 1 gene (WT1) abnormalities in children with bilateral Wilms tumor (WT) and the age of tumor onset in patients with a mutation. STUDY DESIGN Eight patients with bilateral WT were studied. High-resolution melting and direct sequencing were used to screen for the WT1 gene. Western blotting was performed to determine whether the identified mutations were associated with expressed truncated WT1 protein. RESULTS The median age of tumor onset in patients with a mutation in the WT1 was lower (10 months) than in those without a mutation (39 months). Three novel heterozygous nonsense mutations were identified in exon 8 in peripheral blood from 3 individuals, whereas all 3 tumor tissues lacked the wild-type allele. All mutations led to a premature stop codon with truncation of the WT1 protein. In 1 patient, a truncated form of WT1 protein was identified, suggesting that development of the WT may have resulted from expression of an abnormal protein. Four distinct silent single-nucleotide polymorphisms (SNPs) were detected. All 3 patients with a pathogenic WT1 mutation had 2 synonymous SNPs, whereas only 1 of the remaining 5 patients had a single synonymous SNP (P < .05). CONCLUSIONS Bilateral WT are associated with early presentation in pediatric patients and a high frequency of WT1 nonsense mutations in exon 8. Silent SNPs may also be involved in the development of WT.

Utilising Exome Sequencing to Identify Nephronophthisis Mutations Within An Australian Clinical Cohort

and the only basis for predictions of Renal Replacement Therapy (RRT), but there are no systems for monitoring ambulatory CKD in Australia. We have developed a collaborative multidisciplinary platform called CKD.QLD, in which all public renal units in Queensland participate. It includes a registry to characterise CKD patients and their longitudinal course. Website: www.ckdqld.org. Cairns and Hinterland Hospital and Health Service

Exomic Approaches to Diagnosis Amongst Australians with Genetic Renal Diseases

and the only basis for predictions of Renal Replacement Therapy (RRT), but there are no systems for monitoring ambulatory CKD in Australia. We have developed a collaborative multidisciplinary platform called CKD.QLD, in which all public renal units in Queensland participate. It includes a registry to characterise CKD patients and their longitudinal course. Website: www.ckdqld.org. Cairns and Hinterland Hospital and Health Service