Journal of Medical Genetics最新文献

Background: Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) is characterised by aplasia of the uterus, cervix and upper part of the vagina. The genetic aetiology remains incompletely understood.

Methods: We performed gene-level and gene set-level burden analyses based on exome sequencing/genome sequencing data from 727 probands with MRKHS and 2504 female control individuals. Single-cell RNA sequencing (scRNA-seq) was performed on human and mouse embryonic metanephros at different developmental stages. Genetic and transcriptomic data were integrated to prioritise suboptimal genetic signals, identify relevant cell types and determine key developmental stages. Potential digenic inheritance was assessed and prioritised using coexpression patterns from scRNA-seq data.

Results: We identified known MRKHS genes (PAX8, BMP7, GREB1L) and novel candidates (PAN2, AGPAT2) with exome-wide significance. Enriched biological processes included cell apoptosis and mesenchymal-to-epithelial transition. In human embryos, MRKHS-associated genes were enriched in the uterine epithelium at eight gestational weeks (w8) and Wolffian duct epithelium at w11, supporting the biological relevance of burden signals. We detected 992 digenic combinations in MRKHS, with three achieving exome-wide significance (CPSF3L/CYP2A7, AICDA/NOS1, EVC2/KANK1).

Conclusion: Our study reveals both established and novel genetic contributors to MRKHS, links them to specific embryonic cell types and stages, and highlights potential digenic inheritance patterns. Integrating genetic burden and single-cell transcriptomic data provides new insights into the complex molecular mechanisms underlying MRKHS.

Background: Genetic testing for (likely) pathogenic variants (PVs) in BRCA1/BRCA2 has been performed in Manchester since 1996, with molecular methods/techniques and eligibility criteria changing over time. In 2004, UK National Institute for Health and Care Excellence guidelines determined a 20% detection threshold, which reduced to 10% in 2013. The Manchester score (MS) was developed in 2004 to assess the likelihood of detecting PVs at the 10%/20% threshold and was updated to include pathology adjustment (2009/17). Current testing algorithms for NHS England are now closer to 5%, although an MS of 15 (=10%) and CanRisk of 10% are still backstop indications. We provide an update of MS on testing of nearly 10 000 breast and/or ovarian cancer (BC/OC) cases.

Methods: MS using pathology adjustment was applied to cases of non-Jewish BC/OC cases undergoing full screening of BRCA1/2 with testing for CNVs.

Results: Overall, 6744 BC and 3291 OC cases were tested. For BC, 453 (6.7%) PVs were detected in BRCA1 and 456 (6.8%) in BRCA2 (combined 13.5%). Combined detection with MS=13-14, 15-19 and 20-24 was 52/821 (6.3%), 168/1440 (11.7%) and 193/877 (22.0%), respectively. The MS 15-19 (10%) threshold held true for all age groups and BC pathology types, except grade 1 (very low detection). For OC, detection rates were 273 (8.3%) and 193 (5.9%) for BRCA1 and BRCA2, respectively. Again, the 10%/20% threshold MS held true with MS=15-19=123/861 (14.3%) and 13-14=22/301 (7.3%). MS=11 gave a robust 5% threshold, although only 1/86 (1.2%) OC <30 years tested positive; this was 1/5 high-grade serous cancers. For sporadic OC >79 years, only 2/177 (1.1%) tested positive.

Conclusions: MS remains a robust algorithm for assessing likelihood of a BRCA1/BRCA2 PV for individuals with BC/OC.

Surveillance is increasingly considered an alternative to prophylactic total gastrectomy in asymptomatic carriers of CDH1 pathogenic variants. There are three main reasons for this paradigm shift: (1) decreasing penetrance estimates for signet ring cell gastric cancer based on large, unselected case series, (2) increasing evidence for the indolent nature of pT1a (intramucosal) lesions and (3) recent improvements in the performances of endoscopic surveillance. We report on 20 carriers undergoing long-term surveillance with an annual upper gastrointestinal gastroscopy per Cambridge protocol. There were 8 women and 12 men, with a median age of 42 years (range 19-70). Thirteen (65%) carriers had a family history of gastric cancer. Mean follow-up duration was 62 months (range 17-128). The total number of endoscopies was 95, with a mean and median of 4.75 and 4, respectively. Ten pT1a signet ring cell carcinoma foci were identified in six patients; nine through random and one through targeted biopsies. There were no atypias or mitoses. All patients pursued surveillance regardless of biopsies. None developed aggressive (>pT1a) cancer. The longest follow-up after a positive biopsy was 82 months. Survival for the whole cohort was 100%. In conclusion, annual expert endoscopic surveillance appears safe, and pT1a lesions should not be seen as a formal indication for PTG. We emphasise the importance of providing patients with balanced, individualised and up-to-date information.

Background: Achondroplasia is the most common form of disproportionate short stature and is associated with reduced life expectancy. It is not clear to what extent cardiovascular disease (CVD) is responsible for this. The primary aim of this systematic review was to identify the prevalence of CVD in individuals with achondroplasia.

Methods: A systematic review of the literature was conducted in accordance with PRISMA guidelines by two independent reviewers using two databases. There were no language or date restrictions. The search strategy consisted of the terms: "achondroplasia" AND "vascular" OR "cardiovascular" OR "metabolic". Quality assessment was undertaken using the Critical Appraisal Skills Programme checklists.

Results: In total, 300 articles which met the inclusion criteria were screened. Of these, 33 (11%) were included for analysis published between 1972 and 2023, encompassing >5000 individuals with achondroplasia. Techniques of cardiovascular assessment included measures of adiposity in 20 (61% of included studies), metabolic parameters in 9 (27%), blood pressure in 6 (18%), physical activity in 6 (18%) and morbidity and mortality secondary to CVD in 5 (15%). People with achondroplasia were found to be at increased risk of obesity, impaired glucose regulation and hypertension.

Discussion: There is significant heterogeneity in the outcomes measured to assess CVD risk in people with achondroplasia. As a result, there remain significant gaps in the literature regarding the development of CVD in individuals with this condition. Longitudinal studies offering detailed cardiovascular phenotyping should be considered in people with achondroplasia to mitigate the risks of CVD-related morbidity and mortality.

Background: Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant gastric cancer associated with germline CDH1 mutations. Carriers of CDH1 mutations have a higher risk of developing gastric cancer at a younger age, highlighting the need for a phenotypic feature for early diagnosis and management.

Methods: We analysed 121 patients with gastric cancer who underwent genetic testing at the National Cancer Center in China. CDH1 mutation status was assessed using next-generation sequencing. Fisher's exact test and Mann-Whitney U test were performed to compare clinicopathological features between CDH1-mutated and non-mutated patient groups.

Results: Among 121 index cases, three CDH1 germline mutation carriers (2.5%) were identified. Mutation carriers were diagnosed at a significantly younger age compared with non-carriers (p<0.05). Notably, two patients in our cohort exhibited congenital tooth agenesis, a phenotypical feature rarely reported in patients with HDGC and previously undocumented in East Asian cohorts.

Conclusion: Congenital tooth agenesis represents a phenotypic manifestation associated with CDH1 germline mutations. Awareness of such features could enhance recognition of high-risk individuals and support genetic counselling and surveillance strategies. Further studies are needed to confirm these associations.

Background: Pathogenic variants in the protection of telomerase 1 (POT1) gene are associated with predisposition to a broad spectrum of malignancies, although the specific genotype-phenotype correlation has not yet been fully elucidated. To further characterise the phenotypic spectrum, we describe six families with germline POT1 variants and evaluate existing literature to highlight the possible association between variants in POT1, telomere dysregulation and predisposition to malignant central nervous system (CNS) tumours.

Methods: Genetic analyses were performed using an Illumina sequencing platform. All variants were examined by in silico analysis in Alamut as well as Rare Exome Variant Ensemble Learner (REVEL), and one variant was additionally examined by RNA analysis.Telomere length assessment was performed through RepeatDX Europe.

Results: We identified four missense and two frameshift POT1 germline variants: c.255G>C, p.(Lys85Asn), c.322G>A, p.(Gly108Arg), c.323G>A, p.(Gly108Glu), c.676C>T, p.(His226Tyr), c.707del, p.(Gly236Glufs*16) and c.709del, p.(Ser237Alafs*15). The variants c.255G>C and c.322G>A were observed in two patients with astrocytoma and c.676C>T in a patient with oligodendroglioma, corresponding to the most prevalent CNS tumour histopathology described in POT1 carriers in previous publications. Longer telomeres were found in probands with the CNS tumour phenotype.

Conclusion: Our findings support a possible association between pathogenic POT1 germline variants and increased risk of CNS tumours mainly oligodendroglioma, astrocytoma and glioblastoma. We highlight the potential importance of missense variants and telomeric measurement in tailoring of surveillance and advocate further studies to guide future personalised surveillance strategies.

Neuroendocrine tumours (NETs) are increasingly associated with Lynch syndrome (LS). In this autosomal dominant cancer predisposition syndrome, a somatic mutation in addition to a germline pathogenic variant is required for tumour development. We describe the case of a middle-aged female patient with LS with a known germline MLH1 mutation who was diagnosed with Cushing's syndrome. An ectopic adrenocorticotropic hormone (ACTH) producing carcinoid tumour of the lung with lymph node metastases was found and resected. Immunohistochemical analysis showed loss of MLH1/PMS2 expression, and genetic analysis confirmed a deletion of the entire MLH1 gene, acting as the second hit for tumour formation. This provides unequivocal evidence of the tumour's association with LS. Only 30 cases of NETs in LS have been described in the literature, most of them of gastrointestinal origin. We describe the first bronchopulmonary NET in a patient with LS, broadening the spectrum of LS tumours, and the first ACTH-producing tumour in LS.

Background: Parent/patient-reported (PRD) datasets provide ready access to phenotypic data for monogenic neurodevelopmental disorders, yet their concordance with clinical data is unclear.

Methods: In the GenROC study, 547 children (mean age 7.6 years, balanced sex ratio) had parallel parent-reported web questionnaires and clinician-reported (CRD) Human Phenotype Ontology proformas. We compared the two sources per participant by system, gene and gene group and overall for quantity, detail and similarity.

Results: 547 probands were analysed ranging in age from infancy to 16 years (mean 7.6) with similar gender distribution. PRD provided more terms for dental, gastroenterology, immunology and respiratory systems and for vision (p<0.001 for all) and to a lesser degree for cardiac (p=0.0012). CRD provides more detail than PRD for most gene subgroups, combined systems and for neurology (p<0.001). Similarity scores were low overall per participant (mean 0.38 for combined). Similarity scores were highest for cardiac (mean 0.74) and lowest for Ear/Nose/Throat(ENT) (mean 0.34). There was minimal difference in similarity scores across gene groups or between the top 10 genes-scaffold adaptor gene groups had the highest (mean 0.43) as did STXBP1 (mean 0.5) and CACNA1A (0.49). CRD is more similar to published syndrome phenotypes for syndromic genes.

Conclusions: Parents reported more common childhood phenotypes, such as asthma and dental issues, while clinicians provided clinical phenotype descriptors, such as brain morphology and seizure semiology. It is important to understand the differences when designing studies and using datasets to appreciate their strengths and limitations.