Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.

Background Clusters of rare cylindroma or spiradenoma tumors are a recurrent clinical presentation, yet conventional genetic testing results in individuals with these tumors are frequently normal. Objective To determine if genetic mosaicism accounts for such cases. Methods A study of 6 cases from a series of 55 patients who met criteria for diagnostic gene testing for pathogenic CYLD variants over a 5-year period (2012-2017) was performed. A novel genetic assay was used to study DNA from peripheral blood leukocytes and, where possible, matched skin and tumor tissue. Results Two patients had mosaic pathogenic CYLD variants in both the blood and skin. One of these patients transmitted a pathogenic variant to her daughter, and we report the novel phenotype of a contiguous gene deletion syndrome involving CYLD. Two patients had recurrent pathogenic variants in skin tumors from a single cluster but none detectable in the blood. Limitations The remaining 2 patients had clinical features of mosaicism, but these cases were not solved with the assays used because of a lack of access of fresh tumor tissue. Conclusion Genetic mosaicism should be considered in patients presenting with clustered cylindromas, because this may inform genetic testing and counseling of these patients.

Aims Timothy syndrome (TS) is an extremely rare multisystem disorder characterized by marked QT prolongation, syndactyly, seizures, behavioural abnormalities, immunodeficiency, and hypoglycaemia. The aim of this study was to categorize the phenotypes and examine the outcomes of patients with TS. Methods and results All patients diagnosed with TS in the United Kingdom over a 24-year period were reviewed. Fifteen centres in the British Congenital Arrhythmia Group network were contacted to partake in the study. Six patients with TS were identified over a 24-year period (4 boys and 2 girls). Five out of the six patients were confirmed to have a CACNA1C mutation (p.Gly406Arg) and the other patient was diagnosed clinically. Early presentation with heart block, due to QT prolongation was frequently seen. Four are still alive, two of these have a pacemaker and two have undergone defibrillator implantation. Five out of six patients have had a documented cardiac arrest with three occurring under general anaesthesia. Two patients suffered a cardiac arrest while in hospital and resuscitation was unsuccessful, despite immediate access to a defibrillator. Surviving patients seem to have mild developmental delay and learning difficulties. Conclusion Timothy syndrome is a rare disorder with a high attrition rate if undiagnosed. Perioperative cardiac arrests are common and not always amenable to resuscitation. Longer-term survival is possible, however, patients invariably require pacemaker or defibrillator implantation.

This article provides an overview of selected genetic skin conditions where multiple inherited cutaneous tumours are a central feature. Skin tumours that arise from skin structures such as hair, sweat glands and sebaceous glands are called skin appendage tumours. These tumours are uncommon, but can have important implications for patient care. Certain appendageal tumours, particularly when multiple lesions are seen, may indicate an underlying genetic condition. These tumours may not display clinical features that allow a secure diagnosis to be made, necessitating biopsy and dermatopathological assessment. Coupled with robust clinical assessment, biopsy findings can guide genetic testing as, increasingly, the causative genes are known for these conditions. Here we review illustrative examples of appendageal tumours and relevant advances made in genetic discovery, and suggest when referral to a geneticist may need to be considered.

The Macmillan Cancer Family History Service in Teesside has provided genetic risk assessment for individuals with a personal or family history of cancer since 2004. We sought to examine the effect of risk assessment on patient management, with particular emphasis on referral for clinical screening and selection of families for tertiary genetics assessment. The degree of concordance between the initial risk assignment (using diagnoses reported by the family) and final risk assignment (using confirmed diagnoses) was no greater than 72.3 % in 1,363 breast cancer families; a similar effect was seen in 764 colorectal cancer families (77.3 %). Clinically important risk reassignment occurred at the three key stages in the risk assessment pathway. Overall, genetic risk was reassigned in almost 30 % of colorectal families and 20 % of breast cancer families, resulting in a change in screening recommendation and/or referral for tertiary genetic assessment. Careful, detailed family history assessment, with confirmation of reported diagnoses where it may affect risk assignment, is an important process for the point of view of patient management and resource allocation.

Mutations in Fibrillin 1 (FBN1) are associated with Marfan syndrome and in some instances with the MASS phenotype (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal features, and striae). Potential confusion over diagnosis and management in patients with borderline features has been addressed through the revised Ghent nosology, which emphasizes the importance of aortic root dilatation and ectopia lentis as features of Marfan syndrome. The overlapping and more common mitral valve prolapse syndrome is precluded by ectopia lentis or aortic dilatation. Among these clinically related conditions, there is no compelling evidence that genotype predicts phenotype, with the exception of neonatal Marfan syndrome, mutations in which cluster within FBN1 exons 24−32. Recent reports also link two very different phenotypes to changes in FBN1. Heterozygous mutations in transforming growth factor β-binding protein-like domain 5 (TB5) can cause acromicric or geleophysic dysplasias—and mutations in the TB4 domain, which contains an integrin binding RGD loop, have been found in congenital scleroderma/stiff skin syndrome. We report on a variant in an evolutionarily conserved residue that stabilizes the integrin binding fragment of FBN1, associated with juvenile idiopathic arthritis, mitral valve prolapse or apparently normal phenotype in different family members. © 2013 Wiley Periodicals, Inc.

A 37-year-old man was referred to the nephrology department for further management. He had documented proteinuria for over 20 years, quantified as 700 mg 24 h−1 approximately 10 years ago in the context of preserved renal function (serum creatinine <1 mg per 100 ml). One year previously, following an ultrasound scan of his kidneys, which showed bilateral cystic changes, he was labeled as having ‘polycystic kidney disease’. His up-to-date biochemistry confirmed preserved renal function (creatinine 1.11 mg per 100 ml, estimated glomerular filtration rate 78.3 ml min−1 1.73 m−2), but modest proteinuria was now documented (urine protein 2 g 24 h−1). Additional imaging of his renal tract was performed. An intravenous urogram examination confirmed bilateral renal enlargement (right kidney 15 cm, left kidney 15.5 cm), but contrast was promptly excreted with no evidence of obstruction (Figure 1). A magnetic resonance image of the kidneys using gadolinium revealed ‘multiple parapelvic cysts’ that did not communicate with the collecting system (Figure 2).Figure 2A magnetic resonance image of the kidneys with contrast showing normal collecting system with prominent parapelvic cysts.View Large Image Figure ViewerDownload (PPT) The observation of multiple parapelvic cysts in the workup of a patient with kidney disease strongly suggested Fabry disease in the differential diagnosis (Kidney Int 2004; 66: 978–982). He confirmed a history of acroparesthesia, temperature intolerance, and fatigue dating back to childhood. His family history revealed a maternal grandfather dying of ‘nephritis at the age of 40 years’. Clinical examination revealed typical angiokeratomas on his scrotum. α-Galactosidase assay confirmed diagnosis of Fabry disease, showing α-galactosidase level of 0.45 μmol l−1 h−1 (normal range 2–20). Mutation analysis of the X-chromosome gene GLA in the patient has since detected a G-to-A substitution affecting the last nucleotide in exon 3 (c.547G>A), which is predicted to disrupt splicing, and his mother has been confirmed as being heterozygous for this change. We conclude that in the presence of parapelvic kidney cysts, diagnosis of Fabry disease should be considered.

The Teesside project took the underlying principle of the Kenilworth model–that people with a family history of cancer should be ‘triaged’ and signposted to appropriate clinical services–and applied it to a whole clinical cancer network in which inequity was the major driver for change. Unlike the Kenilworth model, the Department of Health/Macmillan Cancer Support-funded pilot project in Teesside embedded genetic risk assessment at secondary care level. The project took a ‘bottom up’ approach that engaged a wide variety of stakeholder groups and identified key challenges that formed the basis of a clear strategic plan. A number of specialist cancer nurses across the network had independently developed risk assessment roles over preceding years: these roles needed to be redefined prior to the creation of a small team of genetic risk assessment practitioners (‘GRAPs’). This innovation challenged existing nursing roles on a local and national level. In turn, however, we were able to introduce a simple, single network-wide referral pathway, reducing workload on both primary care and tumour-specific services; to adopt a standardised genetic risk assessment pathway; and to incorporate risk assessment as a key step in the decision to enrol an individual in a clinical screening programme. Collaborative audit proved to be a useful way of engaging stakeholders and holding their attention throughout the three-year project, proving the value of the project in their terms, and embedding the changes we had made. The keys to success in this project were inclusiveness, transparency and clear strategic management.