Journal of Medical Genetics最新文献

BRIP1 (OMIM: 605882), associated with hereditary ovarian cancer, has recently been described in association with central nervous system (CNS) tumours. Institutional germline database review identified 43 families with BRIP1 pathogenic germline variants (PGVs); 7 families (16.3%) reported 8 CNS tumours. Somatic database review identified 1143 individuals with CNS tumours who underwent somatic sequencing, of whom 7 had BRIP1 pathogenic variants (PVs) (0.6%); 1 of 2 germline-tested individuals had a BRIP1 PGV. Though BRIP1 PVs are rare in CNS tumours, a substantial proportion of BRIP1 carriers have a positive family history. Obtaining and documenting the clinical and pathological characteristics of reported CNS tumours in BRIP1 individuals and families is key to exploring a possible association.

The 22q11.2 deletion syndrome (22q11.2DS) results from a heterozygous deletion at chromosomal locus 22q11.2 and is associated with multisystem symptoms, including cardiovascular, psychiatric and palatal manifestations. Although congenital cardiovascular aberrations are frequent in patients with 22q11.DS, exact prevalence figures remain unclear. Literature was searched in August 2022 and updated in May 2024 using the databases PubMed, Web of Science and Cochrane library to retrieve studies in English and German focusing only on studies involving 22q11.2DS. Prevalence data for cardiovascular aberrations were arcsine transformed and summarised by random-effects models using Meta-XL. Evidence quality was assessed via the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. The systematic searches identified 4338 studies, of which 7 were included for the meta-analysis of prevalence using random-effects models and sensitivity analyses. The pooled prevalence for heart defects (mean; 95% CI) was found to be elevated for tetralogy of Fallot (20%; 0.17 to 0.23), ventricular septal defect (14%; 0.12 to 0.16), pulmonary atresia with ventricular septal defect (9%; 0.06; 0.12), interrupted aortic arch (10%; 0.06 to 0.15), truncus arteriosus communis (9%; 0.07 to 0.12) and atrial septal defect (3%; 0.01 to 0.04). The risk of bias of the included studies was low to moderate. This study, to our knowledge, represents the first systematic review and meta-analysis of prevalences for congenital cardiovascular aberrations in individuals with 22q11.2DS. The high frequencies observed underline the need for cardiovascular screening in patients with 22q11.2DS and genetic screening for 22q11.2DS in congenital heart disease.

Purpose: Williams-Beuren syndrome (WBS) is a well-known neurodevelopmental disorder caused by a copy-number loss at the 7q11.23 locus. Although the 1.5-1.8 Mb recurrent deletion carries several genes of interest, no single gene has been identified in which pathogenic variants cause a neurodevelopmental phenotype. At this locus, GTF2I, encoding the general transcription factor II-I, has been considered as the main candidate gene for the cognitive and behavioural phenotype of WBS, based on clinical observations of cases with atypical 7q.11.23 deletions and functional studies in humans and mice.

Methods: Individuals with a neurodevelopmental disorder were identified through a multicentre collaboration using GeneMatcher and the ERN-ITHACA network. They remained undiagnosed following genome/exome sequencing. Clinical evaluations were performed in each participating centre.

Results: We identified seven unrelated individuals with de novo variants in GTF2I (two non-sense, two splice-site, one missense, one indel and one intragenic deletion). We also identified one individual with a WBS phenotype and low GTF2I expression identified by RNA sequencing. All eight individuals presented with global developmental delay and facial dysmorphic features, with speech delay and/or autistic features in seven cases. The effect of the two splice-site variants was confirmed by RNA sequencing.

Conclusion: Pathogenic heterozygous GTF2I variants cause a neurodevelopmental disorder characterised by global developmental delay with facial dysmorphic features, partly resembling the phenotype observed in individuals affected with WBS.

Background: Improving the precision and accuracy of variant classification in clinical genetic testing requires further specification and stratification of the American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) criteria. While the ClinGen Bayesian framework enables quantitative evidence calibration for selected criteria, standardised tools to optimise evidence thresholds and refine ACMG/AMP criteria remain underdeveloped.

Methods: To address this need, we developed BayesQuantify, an R package that provides a unified tool for quantifying evidence strength for the ACMG/AMP criteria based on the Bayesian framework. BayesQuantify accepts a variant classification file as input and automatically calculates the odds of pathogenicity for each evidence strength, incorporating a user-provided prior probability of pathogenicity. Through bootstrapping, BayesQuantify generates thresholds by aligning the 95% lower bound of positive likelihood ratio/local positive likelihood ratio with the odds of pathogenicity for different evidence strengths. Three independent datasets derived from ClinVar, HGMD and gnomAD were used to evaluate the utility of BayesQuantify.

Results: BayesQuantify supports the calibration of both categorical and continuous ACMG/AMP evidence. Specifically, we replicated the PP3/BP4 thresholds for four computational tools recommended by ClinGen. Our analysis also indicated that the PM2 criterion can reach 'supporting,' or 'moderate,' evidence, varying by prior probability. Importantly, we established thresholds for supporting, moderate and strong evidence for in-silico tools, thereby expanding the application of PP3/BP4 criteria for missense variants in the PTEN gene.

Conclusion: BayesQuantify is a user-friendly tool that enhances the flexibility and reproducibility of ACMG/AMP criteria refinement, thus improving the accuracy and consistency of variant classification. The package is freely available at https://github.com/liusihan/BayesQuantify.

Background: Routine genetic testing for germline pathogenic variants (GPVs) in cancer susceptibility genes (CSGs) in individuals with suspected hereditary cancer risk, and subsequent cascade testing in close relatives, has led to a significantly increased number of individuals identified to be at increased lifetime cancer risk in the UK. These individuals have differing clinical needs over their lifetime to implement cancer surveillance and discuss risk-reducing interventions, to advise on risk to close relatives and counsel on reproductive options. Regional clinical genetics services across the UK have implemented a range of clinical pathways to manage this patient cohort, with differences in practice across centres. Our aim was to provide consensus guidelines on best practice for recontact and follow-up for individuals with GPVs in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51C, RAD51D and mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) to ensure appropriate lifelong clinical management.

Methods: The UK Cancer Genetics Group convened a virtual consensus meeting involving key stakeholders. Consensus for best practice guidance was achieved through premeeting surveys, structured discussions and in-meeting polling.

Results: We identified variability in the extent of active recontact and follow-up for individuals with a GPV in CSGs across the UK. The availability of resources was a key determinant of the level of follow-up currently provided. We achieved consensus on best practice guidelines on key time points for recontact for those with a GPV in a CSG, processes for referral to specialist services and follow-up, the preferred method for recontact and the content of information given during recontact.

Conclusion: The consensus meeting broadly supported recontact and follow-up for most individuals with a GPV in a CSG. The consensus achieved by the multidisciplinary and expert group of healthcare professionals gives clear guidance on the long-term management of this patient cohort at increased lifetime risk of cancer and highlights the additional resources that would be required to effectively deliver this.

A structural aberration (SA) with secondary implications (SASIs) involving a cancer susceptibility gene is identified on chromosome microarray in approximately 0.6% tests performed on index cases. Identifying a SASI involving a high actionability cancer susceptibility gene (HA-CSG) has important genetic counselling and management implications for the individual and families. In 2019, a UK working group published recommendations for laboratories reporting SASIs involving HA-CSG. This study aims to evaluate whether these recommendations are reflected in the current UK practice. Data from a total of 63 cases of SASIs involving HA-CSGs from nine UK genetics centres were included for audit. The results have shown that 92% of microarray reports have the HA-CSG clearly named on the report, with 70% of reports having the anticipated increased risk of cancer stated. 73% of patients were appropriately managed for the associated cancer risk. For SAs where management was not given as per recommended guidelines, the identified variants were all within-gene duplications, which may represent the uncertainty around their potential to disrupt gene function and their association with true increased cancer susceptibility. This study demonstrates the practical implications of identifying a SA involving a HA-CSG and suggests room for improvement in clinical practice in reporting and management.

Background: Mitochondrial diseases are a group of rare, chronic disorders with a significant disease burden; however, there is limited knowledge about their effects on the health-related quality of life (HRQoL) of patients and their carers. This study estimates HRQoL among adult patients with mitochondrial diseases and their carers, using the Assessment of Quality-of-Life 8D (AQoL-8D), a validated instrument for measuring health utilities.

Methods: Ninety-nine adult patients and 24 carers were recruited to the Economic and Psychosocial Impacts of Caring for Families Affected by Mitochondrial Disease (EPIC-MITO) Study, based in New South Wales, Australia.

Results: Adult patients exhibited significantly lower utility values (0.52) compared with age-adjusted and gender-adjusted population norms (0.80; p<0.001). Regression analysis shows that mental health disorders, sleep disorders, financial stress and female gender were associated with reduced HRQoL. Carers also demonstrated AQoL-8D utility values (0.70) significantly below age-adjusted and gender-adjusted population norms (0.81; p=0.01) reflecting the broader burden of mitochondrial diseases on families.

Conclusion: With increasing use of genetic testing and genomic sequencing, as well as hope for gene therapies, health utility values will be necessary for economic evaluations of new interventions for mitochondrial disease. This paper shows the substantial impact on HRQoL of mitochondrial disease measured through utilities. The utility values from this paper can inform future economic evaluations for interventions for patients with mitochondrial disease. Further, the paper demonstrated that mitochondrial disease not only reduces the HRQoL of patients but also impacts the HRQoL of carers.

Background: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare and severe blistering skin disorder caused by loss-of-function mutations in the type VII collagen gene (COL7A1). The COL7A1 c.6527insC mutation is curiously prevalent among individuals with RDEB and is found worldwide in Europe and the Americas. Previous research has suggested the possibility of a Sephardic Jewish origin of the mutation; however, individuals with RDEB are not known to have predominant Jewish ancestry.

Methods: In this study, a global cohort of individuals with RDEB with the c.6527insC founder mutation from Spain, France, Argentina, Chile, Colombia and the USA were investigated by autosomal genotyping, pairwise identical-by-descent matching and a local ancestry analysis. Age estimation analysis was performed to determine when Jewish founders introduced the c.6527insC mutation into Iberian and Native American populations (~900 CE and 1492 CE, respectively).

Results: Sephardic ancestry was identified at the haplotype spanning the c.6527insC mutation in 85% of the individuals, despite mixed ancestry elsewhere in the genome and no known recent Sephardic ancestry. Identical-by-descent matching between this RDEB subpopulation and a known crypto-Jewish community in Belmonte, Portugal was also ascertained, providing support for crypto-Jewish ancestry in this RDEB subpopulation.

Conclusion: The identification of this unique RDEB subpopulation unified by the single most prevalent c.6527insC mutation holds great potential to facilitate promising new RDEB therapies using CRISPR Cas 9 gene and base editing. The identification of a single guide RNA allowing efficient and safe editing of this variant would represent a unique drug to treat a large cohort of patients with the same founder mutation.