Journal of Medical Genetics最新文献

Background: MECOM encodes a developmental and haematopoietic transcription factor associated with a rare early-onset syndrome including bone marrow failure, skeletal and other congenital anomalies. Heterozygous de novo variants are the primary cause. We previously identified MECOM as a candidate gene for paediatric pulmonary arterial hypertension (PAH) using trio exome sequencing.

Methods: To test the role of MECOM in paediatric PAH and further define the clinical phenotype of MECOM-associated syndrome, we queried GeneMatcher and screened rare disease databases for individuals with predicted deleterious MECOM variants. We analysed the clinical spectrum of patients, performed protein modelling of genetic variants and assessed cardiopulmonary expression.

Results: We identified 15 individuals with MECOM variants, including 11 unrelated probands and 8 de novo variants. 11 individuals had severe or mild thrombocytopenia, 9 had skeletal issues, 8 had cardiac anomalies, 6 had PAH and 10 had additional conditions. Three were diagnosed in utero and died in the neonatal period. All missense variants map to the zinc finger 6 or zinc finger 8/9 region, a known hotspot for MECOM-associated syndrome. Protein modelling predicted that both regions are DNA-binding, and that the variants may interfere with binding to a VEGFR2/KDR enhancer. Data from LungMAP showed that MECOM is primarily expressed in pulmonary arterial endothelial cells.

Conclusion: Rare MECOM variants are associated with early-onset syndromic PAH. PAH monitoring should be considered for all individuals with rare MECOM variants. We speculate that the pathogenetic mechanism for PAH and cardiac defects may be impaired VEGFR2/KDR signalling.

Deleterious variants in the BRSK2 gene, which encodes a serine/threonine kinase crucial for neuronal polarisation and brain development, have recently been linked to the pathogenesis of autism spectrum disorder (ASD). However, comprehensive clinical descriptions of individuals with pathogenic BRSK2 variants remain limited, and the molecular and cellular consequences of these mutations are poorly understood. This case report provides a detailed clinical, cognitive and molecular characterisation of a male patient with ASD harbouring a de novo BRSK2 frameshift variant, who developed catatonia, developmental regression and cognitive decline during early adolescence. To assess the functional impact of the variant, induced pluripotent stem cells (iPSCs) and iPSC-derived neural organoids were generated from the patient. Molecular analyses revealed a significant reduction in BRSK2 transcript and protein levels. Sequencing of BRSK2 mRNA showed exclusive expression from the wild-type allele, consistent with degradation of the mutant transcript via nonsense-mediated decay. These findings broaden the mutational and phenotypic spectrum associated with BRSK2-related neurodevelopmental disorders and provide functional evidence supporting the pathogenicity of the identified variant. Furthermore, this report demonstrates the role of BRSK2 in complex neuropsychiatric features-such as catatonia and cognitive deterioration, which remain underreported in the existing literature-and emphasises the importance of longitudinal cognitive and behavioural monitoring in individuals with BRSK2 mutations.

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.

Purpose: Facial dysmorphism is a feature of many monogenic disorders and is important in diagnostics, variant interpretation and nosology. Nevertheless, comprehensively assessing the complex facial shape changes associated with specific syndromes remains challenging. Here, we present three-dimensional (3D) morphometric approaches to overcome these limitations, using Cri-du-Chat syndrome (CdCS) as a model.

Methods: We analysed 3D facial images from 24 participants with CdCS, 4540 unaffected controls and five participants with rare 5p15.33-15.32 deletions, incorporating two methods to account for age- and sex-related facial variation. We quantified phenotypic variation within and between groups and explored genotype-phenotype correlations in CdCS.

Results: We identified changes in the characteristic facial features of CdCS with age and found that facial shape in CdCS differed from controls in highly consistent directions, but with varying magnitudes of effect. 5p15.33-15.32 heterozygotes had non-specific dysmorphic features that were objectively different from those in CdCS, delineating multiple critical regions for facial dysmorphism on chromosome 5p.

Conclusion: This work explores 3D facial morphometry to complement the standard clinical assessment of facial dysmorphism. It provides insights into the genetic basis of facial shape in CdCS and highlights the potential of 3D morphometric techniques to facilitate clinical diagnostics, variant interpretation and delineation of syndrome nosology.

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.