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).
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.
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%).
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.
Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for ...this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.
Correspondence to Dr Terri Patricia McVeigh, Cancer Genetics Unit, Royal Marsden Hospital NHS Foundation Trust, London, UK; terri.mcveigh@gmail.com MUTYH-associated polyposis (MAP) is an autosomal ...recessive condition caused by biallelic constitutional pathogenic variants in the MUTYH gene. Presently, criteria are reasonably broad, suggesting that such testing can be considered where the result would influence reproductive decision-making, if the carrier frequency of pathogenic variants in the associated gene is at least one in 70 (or if consanguinity is a consideration). Previous work has demonstrated that testing of partners of patients with MAP is cost-effective.13 However, ascertainment of heterozygous carriers of MUTYH variants is increasing, given associated growth in genetic testing using pan-cancer predisposition panels in patients with and without a MUTYH-related phenotype. Because of the relatively high carrier frequency of MUTYH variants in the general population, incidental detection of carrier status is not rare and represents a commonly encountered clinical challenge for genetics services, without a precedent in clinical guidelines to inform decision-making.14 Cascade testing is associated with significant workload, particularly in countries with large family sizes. Data collection was considered complete once at least one response (Microsoft form) was received from every relevant regional service (n=32).
Correspondence to Dr Terri Patricia McVeigh, Royal Marsden Hospital NHS Trust, London, UK; terri.mcveigh@gmail.com ; Dr Helen Hanson, Faculty of Health and Life Sciences, University of Exeter, St ...Luke's Campus, Exeter, UK; h.hanson@exeter.ac.uk The National Health Service (NHS) in the UK is a publicly funded entity, and decisions regarding allocation of scarce resources for provision of services, including related to genetic testing and cancer surveillance, are based on clinical and cost-effectiveness of proposed interventions, and are grounded by ethical considerations related to justice—allocation of resources based on clinical need; equity—fair provision of services across the population; beneficence and non-maleficence—provision of genetic testing/surveillance for clinical benefit, and minimisation of associated harm related to overinvestigation or overdiagnosis.1 NHS-funded cancer screening in the general population is guided by Wilson and Jungner criteria.2 These criteria, originally described in 1968, emphasise certain factors that should be considered in evaluating a screening test—related to the condition (natural history and severity), the test (sensitivity and specificity), the actionability of a positive finding (effective treatment), as well as acceptability and cost-effectiveness.2 Priority for cancer surveillance is typically given to those individuals at highest risk of disease—where numbers needed to screen or treat to prevent disease-associated mortality are low.3 NHS-funded constitutional (germline) genetic testing has traditionally been restricted, for the most part, to those individuals in whom the likelihood of identifying a causative clinically actionable constitutional pathogenic variant is at least 10%,4 although expansion of testing is already increasing as associated cost of testing falls and therapeutic implications expand.5 NHS-funded constitutional genetic testing is also focused, dependent on the patient phenotype, and limited to genes for which strong evidence regarding gene–disease association exists.6 7 Furthermore, analysis and reporting of variants are restricted to those associated with intermediate to high penetrance and where identification of the variant has clinical utility. The UK Cancer Genetics Group (UKCGG), a constituent group of the British Society of Genomic Medicine, has issued a response to the InSiGHT position statement,11 incorporating health priorities, opportunity cost and equity of access within the UK NHS, mindful that adoption of these recommendations may conflict with the aims of the authors of to standardise clinical management of carriers of this variant. Homozygous carriers with wide phenotypic variability have been reported, but data are scant, such that the exact risks in such individuals are unclear.10 Carrier frequency in individuals of other ancestries is much less frequent, and associated risk uncertain.10 In line with this, the InSiGHT group recommends predictive testing in first-degree relatives of probands of Ashkenazi Jewish heritage as well as colorectal cancer surveillance of identified carriers (heterozygous or homozygous) every 5 years starting from 45 to 50 years if of Ashkenazi Jewish heritage, but not in individuals of other ethnicities.10 Recommendations for enhanced screening are based on family history as well as genotype. Current British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland/UKCGG guidelines recommend that individuals at high familial colorectal cancer risk (>6-fold) have 5-yearly colonoscopy from age 40 years, and those at moderate colorectal cancer risk (approximately 2-fold to 6-fold risk), a one-off colonoscopy at age 55 years,14 before entry to the National Bowel Cancer Screening Programme (NBCSP), predicated on the impact of colonoscopy on the mitigation of cancer risk in these populations.
Our main objective was to identify baseline prognostic factors predictive of rapid disease progression in a large unselected clinical autosomal dominant polycystic kidney disease (ADPKD) cohort.
A ...cross-sectional analysis was performed in 618 consecutive ADPKD patients assessed and followed-up for over a decade. A total of 123 patients (19.9%) had reached kidney failure by the study date. Data were available for the following: baseline eGFR (n = 501), genotype (n = 549), baseline ultrasound mean kidney length (MKL, n = 424) and height-adjusted baseline MKL (HtMKL, n = 377). Rapid disease progression was defined as an annualized eGFR decline (∆eGFR) of >2.5 mL/min/year by linear regression over 5 years (n = 158). Patients were further divided into slow, rapid and very rapid ∆eGFR classes for analysis. Genotyped patients were classified into several categories: PKD1 (T, truncating; or NT, non-truncating), PKD2, other genes (non-PKD1 or -PKD2), no mutation detected or variants of uncertain significance.
A PKD1-T genotype had the strongest influence on the probability of reduced baseline kidney function by age. A multivariate logistic regression model identified PKD1-T genotype and HtMKL (>9.5 cm/m) as independent predictors for rapid disease progression. The combination of both factors increased the positive predictive value for rapid disease progression over age 40 years and of reaching kidney failure by age 60 years to 100%. Exploratory analysis in a subgroup with available total kidney volumes showed higher positive predictive value (100% vs 80%) and negative predictive value (42% vs 33%) in predicting rapid disease progression compared with the Mayo Imaging Classification (1C-E).
Real-world longitudinal data confirm the importance of genotype and kidney length as independent variables determining ∆eGFR. Individuals with the highest risk of rapid disease progression can be positively selected for treatment based on this combination.
Accurate classification of variants in cancer susceptibility genes (CSGs) is key for correct estimation of cancer risk and management of patients. Consistency in the weighting assigned to individual ...elements of evidence has been much improved by the American College of Medical Genetics (ACMG) 2015 framework for variant classification, UK Association for Clinical Genomic Science (UK-ACGS) Best Practice Guidelines and subsequent Cancer Variant Interpretation Group UK (CanVIG-UK) consensus specification for CSGs. However, considerable inconsistency persists regarding practice in the combination of evidence elements. CanVIG-UK is a national subspecialist multidisciplinary network for cancer susceptibility genomic variant interpretation, comprising clinical scientist and clinical geneticist representation from each of the 25 diagnostic laboratories/clinical genetic units across the UK and Republic of Ireland. Here, we summarise the aggregated evidence elements and combinations possible within different variant classification schemata currently employed for CSGs (ACMG, UK-ACGS, CanVIG-UK and ClinGen gene-specific guidance for PTEN, TP53 and CDH1). We present consensus recommendations from CanVIG-UK regarding (1) consistent scoring for combinations of evidence elements using a validated numerical ‘exponent score’ (2) new combinations of evidence elements constituting likely pathogenic’ and ‘pathogenic’ classification categories, (3) which evidence elements can and cannot be used in combination for specific variant types and (4) classification of variants for which there are evidence elements for both pathogenicity and benignity.
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.
Hereditary Breast and Ovarian Cancer (HBOC) is a genetic condition associated with increased risk of cancers. The past decade has brought about significant changes to hereditary breast and ovarian ...cancer (HBOC) diagnostic testing with new treatments, testing methods and strategies, and evolving information on genetic associations. These best practice guidelines have been produced to assist clinical laboratories in effectively addressing the complexities of HBOC testing, while taking into account advancements since the last guidelines were published in 2007. These guidelines summarise cancer risk data from recent studies for the most commonly tested high and moderate risk HBOC genes for laboratories to refer to as a guide. Furthermore, recommendations are provided for somatic and germline testing services with regards to clinical referral, laboratory analyses, variant interpretation, and reporting. The guidelines present recommendations where 'must' is assigned to advocate that the recommendation is essential; and 'should' is assigned to advocate that the recommendation is highly advised but may not be universally applicable. Recommendations are presented in the form of shaded italicised statements throughout the document, and in the form of a table in supplementary materials (Table S4). Finally, for the purposes of encouraging standardisation and aiding implementation of recommendations, example report wording covering the essential points to be included is provided for the most common HBOC referral and reporting scenarios. These guidelines are aimed primarily at genomic scientists working in diagnostic testing laboratories.
Biallelic PKD1 variants, including hypomorphic variants, can cause very early onset polycystic kidney disease (VEO-PKD). A family with unexplained recurrent VEO-PKD and neonatal demise in one ...dizygotic twin was referred for clinical testing. Further individuals with the putative hypomorphic PKD1 variant, p.(Ile3167Phe), were identified from the UK 100,000 genomes project (100 K), UK Biobank (UKBB), and a review of the literature. We identified a likely pathogenic PKD1 missense paternal variant and the putative hypomorphic PKD1 variant from the unaffected mother in the deceased twin but only the paternal PKD1 variant in the surviving dizygotic twin. Analysis of 100 K cases identified a second family with two siblings with similar biallelic inheritance who presented at birth with VEO-PKD and reached kidney failure in their teens unlike other affected relatives. Finally, a survey of 618 UKBB cases confirmed that adult patients monoallelic for PKD1 p.(Ile3167Phe) had normal kidney function. Our data reveals that p.(Ile3167Phe) is the second most common PKD1 hypomorphic variant identified and is neutral in heterozygosity but is associated with VEO-PKD when inherited in trans with a pathogenic PKD1 variant. Care should be taken to ensure that it is not automatically filtered from sequence data for VEO cases.
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