Journal of Medical Genetics最新文献

In the UK, most patients receive publicly funded medical care through the National Health Service (NHS), which funds tumour and/or germline testing for eligible patients with cancer to inform clinical management.Testing on tumour-derived DNA may identify putative heritable variants, with implications for the proband and their wider family, but is not a reliable substitute for germline genetic testing when hereditary cancer predisposition is suspected.The likelihood that a variant identified through tumour testing is of germline origin depends on multiple clinical and technical factors. Certain genotypes significantly influence a patient's cancer risk, and intervention in those carriers may facilitate cancer prevention or early detection, while other genotypes are associated with lower cancer risk, and associated intervention in such cases have limited clinical utility.We convened a national meeting of clinical cancer genetics and scientific leads to rationalise germline follow-up testing of variants identified through tumour-based testing. After contrasting potential approaches, implementation of an NHS-contextualised 'intermediate conservative' approach was agreed and refined by the authors, with the final pathway recirculated to the UK clinical and scientific community for consensus agreement and publication.We outline relevant patient, genetic and technical considerations informing likely origin of variants, a review of current relevant guidance and NHS laboratory practices and a workflow for laboratory and clinical teams to triage tumour-detected variants requiring onward germline follow-up. This approach aims to direct limited resources towards identifying germline variants associated with the greatest potential clinical impact, with a view to supporting more efficient and equitable delivery of genomic medicine in oncology.

Background: Facioscapulohumeral muscular dystrophy 1 (FSHD1) is one of the most common autosomal dominant neuromuscular diseases. Genetic diagnosis of FSHD1 remains a challenge because of the long length and repetitive nature of D4Z4 repeats. Long-read sequencing is an effective method for detecting FSHD1, but sequencing depth remains a limitation.

Methods: We developed a long-read library adaptive sampling (LRL-AS) method based on Oxford Nanopore Technologies (ONT) sequencing to comprehensively detect FSHD1. Two patients were sequenced by adaptive sampling, followed by analyses of D4Z4 repeat units (RUs), methylation and haplotype.

Results: Compared with whole-genome sequencing, our LRL-AS method shows significant improvements in both sequencing depth and read length. LRL-AS can identify D4Z4 RUs contraction with accuracy comparable to optical genome mapping in both 4q35 and 10q26 regions. We also calculated methylation levels in the double homeobox 4 (DUX4) gene region. With the benefit of higher sequencing depth, allele-specific methylation can be calculated with greater precision. We also observed that, at different sequencing depths, ONT sequencing data consistently provide stable calculations of methylation levels. More importantly, we demonstrated that data from adaptive sampling can be effectively used to construct the haplotype of the pathogenic allele using single-nucleotide polymorphisms.

Conclusion: Our LRL-AS method is a comprehensive approach for FSHD1 detection, improving the accuracy of D4Z4 RUs and methylation detection while enabling allele-specific haplotype construction. It holds promising potential for clinical application.

Background: Duplication of the pituitary gland (DPG)-plus syndrome is an extremely rare developmental malformation of unknown aetiology.

Methods: Two unreported patients of DPG-plus syndrome are described. Underlying genetic defects were explored, including chromosomal microarray (CMA), whole exome sequencing (WES) and mRNA analysis. A literature review was presented.

Results: Patient 1 had DPG, palatal cleft, bifid tongue, intraoral teratoma, lingual hamartoma and duplicated basilar artery and odontoid process. Patient 2 had DPG, epignathus teratoma, a nasal mass, choanal atresia, cleft palate, bifid tongue, abnormal basilar artery and fused upper cervical spine. CMA yielded normal results. WES of patient 1 disclosed a novel splice site PTCH2 variant, c.1590+1G>A, leading to exon 12 skipping and an in-frame deletion of 44 amino acids. WES of patient 2 revealed no candidate variants. A literature review of 51 cases showed mostly reported in childhood and female sex (80%). The leading anomalies identified included DPG (100%), cleft palate (68.6%), anomalous cervical spine (56.9%), hypothalamic mass/enlargement (58.8%), intraoral teratoma (58.8%), basilar arterial abnormalities (43.1%) and bifid/trifid tongue (23.5%). Non-craniofacial anomalies were found in <10% of cases. Late complications included precocious puberty, all in female patients, and hypogonadotropic hypogonadism in a few patients.

Conclusions: Two new cases of DPG-plus syndrome were reported, with rare findings of epignathus and choanal atresia. We propose that DPG-plus syndrome may result from a double hit in one of the genes involved in SHH signalling, arising from a germline pathogenic variant with mosaicism for a somatic pathogenic variant or digenic/oligogenic inheritance of the SHH signalling-related genes.

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.