European Journal of Human Genetics最新文献

Renal cell carcinoma (RCC) arises sporadically or in a hereditary context, with inherited cases accounting for less than 10%, depending on the genes analyzed. Next-generation sequencing has enabled the use of multigene panels (MGP) to characterize RCC linked to hereditary syndromes. The current French guidelines of the national reference network for hereditary renal cancers (PREDIR) recommend genetic testing for patients meeting specific clinical criteria. This study evaluates the diagnostic yield and the relevance of current criteria, the utility of MGP testing, and the added value of tumor analyses. We retrospectively analyzed 2057 RCC patients who underwent germline MGP testing across three French hospital laboratories. Tumor analysis results from 140 patients were also evaluated. The overall rate of germline pathogenic/likely pathogenic variants was 3.5%, with 39% in syndromic cases and 1.2% in apparently sporadic cases. Tumor analyses identified somatic pathogenic variants in 56.3% of cases. Our data support that the likelihood of identifying a germline PV is low in patients with sporadic single clear cell RCC, and that the clinical utility of testing all patients with other sporadic subtypes appears limited. This suggests a need to revise current testing criteria in patients with sporadic single RCC, for example, by lowering the age threshold for genetic testing from 45 to 40 years in clear cell RCC, and to 50 years in other subtypes. We also suggest incorporating tumor analyses to distinguish hereditary RCC from sporadic cases driven by tumor-specific pathogenic variants.

We recently identified de novo missense variants affecting the small GTPase ARF3 as the cause of a disorder characterized by developmental delay/intellectual disability, microcephaly, brain atrophy, epilepsy and minor skeletal defects. In vitro and in vivo analyses documented impaired Golgi integrity, vesicle trafficking, and brain and body axes development. Here, we report clinical features of five additional patients and the functional characterization of three novel ARF3 variants. Cell-based assays corroborate a deleterious, variant-specific effect on protein stability, GTP binding and Golgi morphology. Zebrafish models confirm the dominant behavior of the tested variants and their variable impact on development. ARF3 mutants significantly affected Golgi integrity in vivo as well as brain size, recapitulating patients' microcephaly. These findings expand the ARF3-related Golgipathy mutational spectrum, strengthen previous observations linking variants with dominant negative behavior to a markedly severe phenotype, and underscore the specific vulnerability of the nervous system to ARF and Golgi dysfunction.

The experiences and outcomes for women identified with a BRCA1/2 pathogenic variant during young adulthood are qualitatively described but not well quantified. This study investigated the impact of BRCA1/2 status on women's reproduction, intimate partner relationships, and sexual functioning. Australian women aged 18-40 years who had predictive BRCA1/2 testing, received either a positive or negative result, and had no personal cancer history, completed an online survey that used a case-control design. Outcome measures included childbearing, use of reproductive technologies, relationship status, and sexual functioning. 579 women participated (62.0% with a BRCA1/2 PV; 38.0% without a BRCA1/2 PV). More women with a BRCA1/2 PV had children compared to those who did not (49.0% c.f., 40.5%; p = 0.045). BRCA1/2 status did not predict whether women were partnered at survey completion (Odds Ratio 1.20; 95% CI 0.80, 1.78) or their sexual functioning over the previous month (β-coefficient -0.08; 95% CI -1.15, 0.98). Women with a BRCA1/2 PV were more likely to have children after genetic testing (OR 1.83: 95% CI 1.05, 3.21) and were more likely to have a greater number of children after genetic testing (β-coefficient 0.41; 95% CI 0.10, 0.73) compared to women without a BRCA1/2 PV, after adjustment for confounders. Receiving a positive predictive BRCA1/2 result is associated with an increased likelihood of childbearing and having a greater number of children compared to receiving a negative predictive BRCA1/2 result. These findings contribute to the evidence base to inform long-term follow-up for women after predictive BRCA1/2 testing.

Mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) are a group of proteins encoded by nuclear DNA that play a crucial role in mitochondrial protein synthesis. Mitochondrial diseases caused by mt-aaRS variants are phenotypically heterogenous but often present with significant neurological features such as childhood-onset encephalopathy and seizures. As such, these conditions are a diagnostic challenge. We present an approach that systematically quantifies phenotypic similarity of individuals with an mt-aaRS variant to published cases, to aid variant interpretation, in RD-Connect-a large Europe-wide rare disease cohort. Across 98 individuals with a mt-aaRS gene of interest, we prioritised 38 individuals with 63 variants following bioinformatic and manual analyses. We additionally reviewed Exomiser prioritisation using a pre-defined gene list for neurological disorders within the RD-Connect Genome-Phenome Analysis Platform (GPAP). We were able to generate likely diagnoses in 11 individuals and VUS findings in 13 individuals, following careful phenotype similarity analysis using a phenotype-genotype dataset generated from 234 published individuals. Four of these 24 individuals did not have an Exomiser-ranked gene variant in the GPAP. Therefore, this approach, using individual-level curated phenotype-genotype data to support variant interpretation, can highlight potentially significant variants that may not be captured by current pipelines. This workflow can be replicated in other heterogeneous rare diseases to support clinical practice.

Gastric cancer (GC) is a leading cause of cancer-related deaths worldwide. While most cases result from the cumulative risk of common genetic variants, a smaller proportion shows a monogenic etiology. We used germline exome sequencing data to assess the gene-based burden of loss-of-function pathogenic variants (LoF-PVs) in 471 early-onset GC cases as well as 666 GC cases from the UK Biobank (UKB), aiming to identify monogenic GC forms. In both datasets, LoF-PVs in CDH1 and ATM were enriched among GC cases. Beyond GC, ATM LoF-PVs were also enriched in UKB participants with pancreatic, oesophageal, breast, prostate, and lung cancer, though the effect size was notably high in GC. As an established disease gene for pancreatic, breast, ovarian, and prostate cancer, ATM should also be considered for genetic testing when monogenic GC is suspected. This is especially important for families in which other tumours associated with ATM PVs occur alongside GC.