Journal of Medical Genetics最新文献

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.

Background: 5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in PDGFRB. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes.

Material and methods: The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place.

Results: As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use.

Conclusion: The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.

Background: Diagnosis of a hereditary cancer syndrome may impact family planning, particularly in reproductive age individuals. Factors influencing reproductive decision-making are understudied in individuals with germline CDH1 pathogenic or likely pathogenic (P/LP) variants.

Methods: We characterised reproductive decision-making and perinatal outcomes in 121 individuals aged 18-49 with hereditary diffuse gastric and lobular breast cancer syndrome due to a germline CDH1 P/LP variant.

Results: Half of individuals (50%, 60/121) reported their CDH1 diagnosis impacted family planning. Psychosocial and economic barriers to reproduction were encountered by 47% (56/119) of patients. Additionally, 12% (15/121) of individuals delayed pregnancy to prioritise personal cancer risk management with either endoscopic surveillance, prophylactic total gastrectomy (PTG) or mastectomy. Women were more likely to experience guilt about passing their CDH1 variant to offspring compared with men. Perinatal and fetal outcomes were investigated in six women who gave birth at a median time of 24 months (IQR 20-44) after PTG. Maternal micronutrient deficiencies were not uncommon in pregnant women after PTG despite compliance with a bariatric, prenatal multivitamin. Majority of women who became pregnant after PTG reported worsening post-gastrectomy syndromes. Most infants (90%, 9/10) born after PTG were full-term and no fetal complications were reported.

Conclusion: Reproductive decision-making is complex in individuals with germline CDH1 variants, who often encounter psychosocial and physical challenges during family planning and pregnancy. However, successful pregnancy is possible after PTG with the guidance of a multidisciplinary team including maternal fetal medicine specialists and a registered dietitian.

Trial registration number: NCT03030404.

Background: Molecular genetic diagnoses are critical to prevention and treatment of inherited polyposis and colorectal cancer. 19 genes responsible for these conditions are known, but many severely affected patients and families remain unsolved. Cryptic intronic variants that alter splicing of these genes and incomplete characterisation of recessive predisposition contribute to these diagnostic gaps.

Methods: Adaptive sampling long-read DNA sequencing targeted to 19 colon cancer genes, paired with direct long-read RNA whole-transcriptome sequencing, was undertaken for four patients referred for deficiency of mismatch repair proteins and/or familial polyposis, for whom multigene panel testing yielded negative or uncertain germline results.

Results: Genetic diagnoses were obtained for all four patients. Each patient carried a cryptic intronic germline variant in a different colon cancer gene. The variants abrogated splicing by various mechanisms, all leading to loss of gene function. Patient 1 was heterozygous for intronic insertion into MSH2 of an Alu element, leading to extension of transcription into the affected intron and a stop. Patient 2 was heterozygous for deep intronic insertion into APC of a Long Interspersed Nuclear Element (LINE), creating a pseudoexon and a stop. Patient 3 was compound heterozygous at MLH3, including a cryptic intronic substitution leading to exon skipping and a stop. Patient 4 was compound heterozygous at MUTYH, including a deep intronic deletion yielding an extremely short intron and transcriptional loss of an exon encoding a critical protein domain.

Conclusion: Paired long-read DNA and RNA sequencing can enhance diagnostic yield through detection of cryptic intronic variants that impact cancer predisposition.

Li-Fraumeni syndrome (LFS) is a high-risk hereditary cancer predisposition syndrome affecting 1 in 5000 individuals. Current standard of care in adults includes annual whole-body MRI (WB-MRI) and MRI brain (MRB) surveillance to enable early cancer detection. We performed a retrospective single-centre study of adults with TP53 pathogenic germline variants or proven somatic mosaicism undergoing annual WB-MRI surveillance between January 2012 and January 2024, and MRB surveillance between August 2017 and January 2024. 325 WB-MRI scans were performed in 75 individuals. 17 cancers were diagnosed in 16 individuals. Nine out of 17 cancers were WB-MRI detected (7/9 had stage 1/2 disease). Benign incidental findings were identified in 89/325 (27.4%) of WB-MRI scans, prompting 53 additional investigations. As a stand-alone surveillance tool, WB-MRI demonstrated a pan-cohort specificity of 95.5%, negative predictive value of 97.4% and sensitivity of 42.9%. 32 individuals underwent 53 MRB scans detecting one cancer. We report the findings from the longest and largest single-centre experience of WB-MRI surveillance for cancer early detection in adults with LFS, demonstrating a high and acceptable level of cancer exclusion but modest sensitivity with WB-MRI prompting a significant number of additional investigations.