Germline pathogenic variants in
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are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum ...management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype-phenotype correlations in a large cohort of
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mutation carriers.
A retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in
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(n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.
Tumour risks analysis provided novel penetrance estimates and genotype-phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the
p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising
missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in
and (paternally inherited)
mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband
mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for
mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).
Overall risks of clinically apparent tumours for
mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype-tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for
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mutation carriers.
pathogenic germline variants (PGVs) are identified in up to 10% of patients with paraganglioma and phaeochromocytoma and up to 30% with wild-type gastrointestinal stromal tumours. Most
PGV carriers ...present with an apparently sporadic tumour, but often the pathogenic variant has been inherited from parent who has the variant, but has not developed any clinical features. Studies of
PGV carriers suggest that lifetime penetrance for SDHA-associated tumours is low, particularly when identified outside the context of a family history. Current recommended surveillance for
PGV carriers follows an intensive protocol. With increasing implementation of tumour and germline large panel and whole-genome sequencing, it is likely more
PGV carriers will be identified in patients with tumours not strongly associated with
or outside the context of a strong family history. This creates a complex situation about what to recommend in clinical practice considering low penetrance for tumour development, surveillance burden and patient anxiety. An expert
working group was formed to discuss and consider this situation. This paper outlines the recommendations from this working group for testing and management of
PGV carriers in clinical practice.
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.
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By analyzing genome sequencing data for 33,924 families from a heterogeneous rare-disease cohort, Pagnamenta et al. identified 45 families where inversions likely explain the etiology. In six instances, RNA-seq helped support the respective diagnoses, and exemplar cases include complex SVs involving MECP2 where long-read sequencing data influenced the clinical interpretation.
Germline
gene pathogenic variants (pv) cause a very high lifetime risk of developing cancer, almost 100% for women and 75% for men. In the UK, annual MRI breast screening is recommended for female
pv ...carriers. The SIGNIFY study (Magnetic Resonance Imaging screening in Li Fraumeni syndrome: An exploratory whole body MRI) study reported outcomes of whole-body MRI (WB-MRI) in a cohort of 44
pv carriers and 44 matched population controls. The results supported the use of a baseline WB-MRI screen in all adult
pv carriers. Here we report the acceptability of WB-MRI screening and effects on psychosocial functioning and health-related quality of life in the short and medium terms.
Psychosocial and other assessments were carried out at study enrolment, immediately before MRI, before and after MRI results, and at 12, 26 and 52 weeks' follow-up.
WB-MRI was found to be acceptable with high levels of satisfaction and low levels of psychological morbidity throughout. Although their mean levels of cancer worry were not high, carriers had significantly more cancer worry at most time-points than controls. They also reported significantly more clinically significant intrusive and avoidant thoughts about cancer than controls at all time-points. There were no clinically significant adverse psychosocial outcomes in either carriers with a history of cancer or in those requiring further investigations.
WB-MRI screening can be implemented in
pv carriers without adverse psychosocial outcomes in the short and medium terms. A previous cancer diagnosis may predict a better psychosocial outcome. Some carriers seriously underestimate their risk of cancer. Carriers of pv should have access to a clinician to help them develop adaptive strategies to cope with cancer-related concerns and respond to clinically significant depression and/or anxiety.
Constitutional abnormalities at the imprinted 11p15 growth regulatory region cause syndromes characterized by disordered growth, some of which include a risk of Wilms tumor. We explored their ...possible contribution to nonsyndromic Wilms tumor and identified constitutional 11p15 abnormalities in genomic lymphocyte DNA from 13 of 437 individuals (3%) with sporadic Wilms tumor without features of growth disorders, including 12% of bilateral cases (P = 0.001) and in one familial Wilms tumor pedigree. No abnormality was detected in 220 controls (P = 0.006). Abnormalities identified included H19 DMR epimutations, uniparental disomy 11p15 and H19 DMR imprinting center mutations (one microinsertion and one microdeletion), thus identifying microinsertion as a new class of imprinting center mutation. Our data identify constitutional 11p15 defects as one of the most common known causes of Wilms tumor, provide mechanistic insights into imprinting disruption and reveal clinically important epigenotype-phenotype associations. The impact on clinical management dictates that constitutional 11p15 analysis should be considered in all individuals with Wilms tumor.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Craniofrontonasal syndrome (CFNS, MIM 304110) is an X-linked craniofacial disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Mutations have been ...identified in the EFNB1 gene that encodes a member of the ephrin-B family of transmembrane ligands for Eph receptor tyrosine kinases. Here, we describe two unrelated families, in both of which a mother and her son have proven mutations in EFNB1. The mothers have classical features of CFNS; although the sons have no major craniofacial features other than telecanthus, both had a congenital diaphragmatic hernia (CDH). Our cases represent the first in which CDH has been confirmed in males with mutations in EFNB1, highlighting an important role for signalling by ephrin-B1 in the development of the diaphragm.
As data at progressively granular spatial scales become available, the temptation is to target interventions to areas with higher malaria transmission – so-called hotspots – with the aim of reducing ...transmission in the wider community. This paper reviews literature to determine if hotspots are an intrinsic feature of malaria epidemiology and whether current evidence supports hotspot-targeted interventions. Hotspots are a consistent feature of malaria transmission at all endemicities. The smallest spatial unit capable of supporting transmission is the household, where peri-domestic transmission occurs. Whilst the value of focusing interventions to high-burden areas is evident, there is currently limited evidence that local-scale hotspots fuel transmission. As boundaries are often uncertain, there is no conclusive evidence that hotspot-targeted interventions accelerate malaria elimination.
•Hotspots are an intrinsic part of malaria transmission biology.•The size of hotspots depends on the spatial resolution of the input data with important implications for any resulting inference.•Where an infectious mosquito/human interacts with a susceptible human/mosquito determines the unit of transmission. The underlying transmission unit is currently unclear and may involve complex nested spatial scales.•Infections are more likely to be related when detected closely in space and time; advances in parasite genetic analysis are needed to allow the elucidation of transmission networks at local spatial scales and inform the optimum scale at which interventions need to be undertaken.•Evidence for impact on transmission as a result of hotspot-targeted strategies has been limited but is likely due to confounding factors and an incomplete understanding of spatial transmission dynamics.
Malaria infections occurring below the limit of detection of standard diagnostics are common in all endemic settings. However, key questions remain surrounding their contribution to sustaining ...transmission and whether they need to be detected and targeted to achieve malaria elimination. In this study we analyse a range of malaria datasets to quantify the density, detectability, course of infection and infectiousness of subpatent infections. Asymptomatically infected individuals have lower parasite densities on average in low transmission settings compared to individuals in higher transmission settings. In cohort studies, subpatent infections are found to be predictive of future periods of patent infection and in membrane feeding studies, individuals infected with subpatent asexual parasite densities are found to be approximately a third as infectious to mosquitoes as individuals with patent (asexual parasite) infection. These results indicate that subpatent infections contribute to the infectious reservoir, may be long lasting, and require more sensitive diagnostics to detect them in lower transmission settings.
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