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Advances in technology have led to a massive expansion in the capacity for genomic analysis, with a commensurate fall in costs. The clinical indications for genomic testing have evolved markedly; the volume of clinical sequencing has increased dramatically; and the range of clinical professionals involved in the process has broadened. There is general acceptance that our early dichotomous paradigms of variants being pathogenic–high risk and benign–no risk are overly simplistic. There is increasing recognition that the clinical interpretation of genomic data requires significant expertise in disease–gene-variant associations specific to each disease area. Inaccurate interpretation can lead to clinical mismanagement, inconsistent information within families and misdirection of resources. It is for this reason that ‘national subspecialist multidisciplinary meetings’ (MDMs) for genomic interpretation have been articulated as key for the new NHS Genomic Medicine Service, of which Cancer Variant Interpretation Group UK (CanVIG-UK) is an early exemplar. CanVIG-UK was established in 2017 and now has >100 UK members, including at least one clinical diagnostic scientist and one clinical cancer geneticist from each of the 25 regional molecular genetics laboratories of the UK and Ireland. Through CanVIG-UK, we have established national consensus around variant interpretation for cancer susceptibility genes via monthly national teleconferenced MDMs and collaborative data sharing using a secure online portal. We describe here the activities of CanVIG-UK, including exemplar outputs and feedback from the membership.

Purpose To investigate the prevalence of biallelic PKD1 and PKD2 variants underlying very early onset (VEO) polycystic kidney disease (PKD) in a large international pediatric cohort referred for clinical indications over a 10-year period (2010–2020). Methods All samples were tested by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) of PKD1 and PKD2 genes and/or a next-generation sequencing panel of 15 additional cystic genes including PKHD1 and HNF1B. Two patients underwent exome or genome sequencing. Results Likely causative PKD1 or PKD2 variants were detected in 30 infants with PKD-VEO, 16 of whom presented in utero. Twenty-one of 30 (70%) had two variants with biallelic in trans inheritance confirmed in 16/21, 1 infant had biallelic PKD2 variants, and 2 infants had digenic PKD1/PKD2 variants. There was no known family history of ADPKD in 13 families (43%) and a de novo pathogenic variant was confirmed in 6 families (23%). Conclusion We report a high prevalence of hypomorphic PKD1 variants and likely biallelic disease in infants presenting with PKD-VEO with major implications for reproductive counseling. The diagnostic interpretation and reporting of these variants however remains challenging using current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) and Association of Clinical Genetic Science (ACGS) variant classification guidelines in PKD-VEO and other diseases affected by similar variants with incomplete penetrance.

available at http://www.ncbi.nlm.nih.gov/pubmed/25340609 Editorial Comment: This is a retrospective review of a large experience using genetic testing in the setting of autosomal dominant polycystic kidney disease (ADPKD). The main focus was to identify optimal use for screening of family members who wished to donate a kidney to a relative with ADPKD. In potential relative donors who are younger (this article uses 40 years as a cutoff) clinical evidence of ADPKD may not be present in those who may have genetic abnormalitities (in the PKD1 or PKD2 gene), suggesting that they may actually have the disease. This article is a must read for urologists who participate in the performance of living donor nephrectomy. In most cases genetic testing facilitates donation where it would otherwise be considered too risky. Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/25808278 Editorial Comment: Historically the use of deceased donor kidneys with acute kidney injury (AKI) has been limited due to concerns regarding the recoverability of renal function after transplantation. There have been a few studies supporting their use but the series tend to be small, with limited followup. The authors describe their experience with 162 cases using deceased donor kidneys with AKI, defined as terminal creatinine greater than 2.0 mg/dl. Levels of graft survival and renal function were comparable to those in a nonAKI group at 1 year. This result was seen in expanded criteria donor kidneys as well. More patients in the AKI group had delayed graft function. There were no differences in chronic changes on biopsy at 12 months between AKI and nonAKI kidneys. Gene expression studies showed increased expression of an inflammatory profile at 1 month but normal- ization by 4 months. Overall the article suggests that using AKI kidneys can result in outcomes similar to those with nonAKI kidneys at 1 year, although delayed graft function is more likely in renal units with AKI. Use of these kidneys can help offset the current shortage of donor organs.