European Journal of Human Genetics最新文献

Marfan syndrome (MFS) is a genetic disorder caused by an FBN1 variant and is diagnosed based on the revised Ghent criteria, which incorporate clinical manifestations and genetic testing. Up-to-date FBN1 variant interpretation is crucial for proper diagnosis and management of MFS; however, some FBN1 variants of uncertain significance (VUSs) remain inconclusive despite applying Clinical Genome Resource (ClinGen) FBN1-specific guideline. Recently, the ClinGen guidance for PP1/BS4 co-segregation and PP4 phenotype specificity criteria (new PP1/PP4 criteria) were released. Here, we performed reassessment of FBN1 VUSs using these new PP1/PP4 criteria. FBN1 VUSs collected from December 2015 to April 2024 were reassessed according to the ClinGen FBN1-specific guideline and new PP1/PP4 criteria. Medical records and previous studies were reviewed to evaluate the phenotype-specificity of evidence based on the revised Ghent criteria. Collectively, 927 patients with suspected MFS underwent FBN1 sequencing and 72 VUSs were detected. When applying the FBN1-specific guideline only, of 72 VUSs, 29 (40.3%) were reclassified as pathogenic variants (PVs) or likely PVs (LPVs). When additionally applying the new PP1/PP4 criteria, 16 (37.2%) of the remaining 43 VUSs were reclassified as LPVs. After reassessing FBN1 VUSs according to the new PP1/PP4 criteria, the rate of reclassification from VUS to PV/LPV significantly increased from 40.3% to 62.5%. The new PP1/PP4 criteria provide sufficient evidence for evaluating the pathogenicity of FBN1 variants detected in MFS patients fulfilling the revised Ghent criteria and will be helpful in clinical analysis.

DDX3X-related neurodevelopmental disorder is one of the most common monogenic causes of intellectual disability in females, with currently >1000 females diagnosed worldwide. In contrast, reports on affected males with DDX3X variants are scarce. The limited knowledge on this X-linked disorder in males hinders the interpretation of hemizygous DDX3X variants in clinical practice. In this study, we present a new cohort of 19 affected males (from 17 unrelated families) with (possibly) disease-causing DDX3X variants, for whom we collected clinical and molecular data. Additionally, we reviewed the existing literature on 13 males with DDX3X variants. The phenotype in males is diverse, including intellectual disability, speech/language delays, behavioural challenges and structural brain abnormalities. The vast majority of males have missense variants, including two recurrent variants (p.(Arg351Gln) and p.(Arg488Cys)). No truncating variants have been reported, consistent with the presumed embryonic lethality of complete loss-of-function of DDX3X in males. In our novel cohort, 6/17 variants are de novo in the affected male and 3/17 variants are de novo in the mother. This study provides significant insights in the genetic and phenotypic spectrum of males with DDX3X variants, by presenting the data of a combined cohort (n = 32) of novel and published individuals. Our data show that variants in DDX3X can cause an X-linked neurodevelopmental disorder in males, with unaffected or mildly affected carrier females. These findings will aid the interpretation of hemizygous missense variants in DDX3X and can guide clinical management and counselling, in particular with regard to recurrence risks in the respective families.

Mendelian randomization (MR) studies using diseases as exposures are increasingly prevalent although any observed associations do not necessarily imply effect of diseases. To illustrate this challenge, we conducted a systematic review of MR studies focusing on COVID-19 consequence. We hypothesized if outcome genome-wide association studies (GWAS) were conducted before COVID-19 pandemic in late 2019, any observed associations in these studies were unlikely to be driven by COVID-19. We systematically searched PubMed, EMBASE, and MEDLINE for all MR studies published between 1 January 2019 and 20 May 2023. Inclusion criteria included MR studies which used COVID-19 as the exposure and designed to assess COVID-19's impact on health outcomes. We extracted relevant information, such as result interpretation and relevance assumption assessment. This review was registered at PROSPERO (CRD42023421079). Amongst 57 included studies, 45 studies used outcome GWAS published prior to 2019 whilst the remaining studies likely used outcome GWAS containing data collected before 2019. Relevance assumption was assessed mainly by p values. A total of 35 studies showed an association of COVID-19 liability with health outcomes. Regardless of the results, 45 studies attributed these as evidence (or lack of evidence) of COVID-19 consequence. In MR studies using disease liability as exposure, relevance assumption should consider the prevalence of the disease in the outcome GWAS in the context of 2 sample Mendelian randomization study rather than p values/F-statistic alone. Even when these are verified, these studies likely suffered from pleiotropy, making corresponding interpretation as effect of disease challenging.

Biallelic variants in COL25A1 have been associated with isolated congenital cranial dysinnervation disorders (CCDDs) and arthrogryposis multiplex congenital (AMC) with or without CCDD. COL25A1 encodes collagen XXV that belongs to the subfamily of membrane-associated collagens with interrupted triple helices. COL25A1 contains four non-collagenous and three collagenous domains. Three alternatively spliced COL25A1 transcript variants are known. In mice, Col25a1 is required for intramuscular motor innervation and cranial motor neuron development. We report seven subjects with novel biallelic COL25A1 pathogenic variants, including three AMC-affected individuals, one of whom died in infancy, and four unrelated fetuses. We expand the associated phenotypic spectrum as fetuses showed lethal phenotypes including reduced or no movement, contractures, and hydrops in three and growth retardation and skeletal abnormalities in one. The molecular spectrum includes two microdeletions encompassing several 5' or 3' exons, two missense, one nonsense, one frameshift, and one variant affecting splicing. In fibroblasts of the subject who was compound heterozygous for the c.367G > C and c.1198G > T variants, we identified skipping of exon 3 in COL25A1 mRNAs due to the G-to-C change. These aberrantly spliced transcripts were subject to nonsense-mediated mRNA decay. Analysis of transcriptome sequencing data from primary human fibroblasts without COL25A1 pathogenic variants revealed novel COL25A1 exon-exon junctions and 13 not previously annotated alternatively spliced in-frame exons. We hypothesized that interindividual variation in the splicing of COL25A1 exons in different tissues may underlie the variable phenotypes in the affected individuals.

In practice, healthcare systems and insurers determine that there is "need" for genetic testing when there is potential for clinical utility. However, it is not currently known how the public understands the need for genetic testing and if this aligns with clinical utility. We recruited participants in Canada through a survey distributed through a market research company (Leger Opinion Panel). Participants who self-reported the need for genetic testing were then purposively sampled to complete a semi-structured virtual interview. We used an interpretive description approach and reflexive thematic analysis. We completed 19 interviews and found that participants' self-identified need for genetic testing was informed by their experiences with genetic information and the perceptions that genetic information is actionable (clinical utility) and has personal meaning (personal utility). Most participants would not be eligible for funded testing based on their personal and family history, however, they had unmet informational and psychological needs, indicating unmet need for genetic counseling. The public understanding of the need for genetic testing is complex and varied. Participants identified many benefits resulting from genetic testing which are not reflected in how need is operationalized in reimbursement decisions, however unmet expectations for testing contributed to medical distrust and dissatisfaction.

FLVCR2 is a highly conserved member of the major facilitator superfamily (MFS), the largest superfamily of solute carriers that are involved in the transport of small molecules across lipid bilayers. The loss of the murine ortholog Mfsd7c, an endothelial transporter in brain blood vessels, causes brain angiogenic growth deficiency and lethality. Recessive FLVCR2 variants cause proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome. This often-lethal condition features microcephaly, skeletal deformities, and severe cerebrovascular defects. Although a number of cases have been reported, very limited evidence of the pathogenicity of FLVCR2 variants is available. In this study, we thoroughly investigated a new fetal case of Fowler syndrome. Through exome sequencing, we identified two compound heterozygous FLVCR2 variants: the maternal c.1124+3_1124+6del and the paternal p.(Arg492Trp). The effects of the c.1124+3_1124+6del variant were investigated through a minigene assay, which showed impaired splicing of the exon 5 of FLVCR2. To characterize the impact of the p.(Arg492Trp) substitution, we performed protein modeling using Rosetta and DynaMut2, that showed a highly destabilizing effect. Then, based on the very recent evidence that choline is a major FLVCR2 ligand, we performed a radiolabeled-choline or ethanolamine transport assays in HEK 293 cells and found that the p.(Arg492Trp) variant causes a 50-60% reduction of FLVCR2 transport activity, resulting in a net activity of 25-30%. Our findings suggest that FLVCR2 deficiency may be sufficient to cause PVHH even in the absence of a complete loss of transport activity, possibly involving extragenetic factors in the pathophysiology of this complex condition.

Molecular bases of the clinically heterogenous Oculo-Auriculo-Vertebral Spectrum or Craniofacial Microsomia remain largely unknown. Although genetic diagnosis is established in less than 10% of the patients, variants in the FOXI3 gene are the most recurrent genetic cause. We studied a large family with 6 affected individuals on 4 generations showing an autosomal dominant transmission of Oculo-Auriculo-Vertebral Spectrum with incomplete penetrance. The genome sequencing strategy allowed the identification of a new likely pathogenic missense variant located within the Nuclear Localization Signal of FOXI3 and affecting its subcellular localization. Moreover, we described 3 additional rare FOXI3 variants identified in 3 other patients from a cohort of 251 patients with Oculo-Auriculo-Vertebral Spectrum. These variants were classified as Variants of Unknown Significance. In conclusion, this study confirms FOXI3 implication in the Oculo-Auriculo-Vertebral Spectrum and the importance of Nuclear Localization Signal integrity. Genotype-phenotype correlations and putative modifier haplotype are discussed.

The Genetic Counselling Outcome Scale-24 (GCOS-24) measures empowerment reliably in the context of genetic services, but its potential utility is constrained by some of its features. Using Rasch Measurement Theory, the GCOS-16 was developed: eight items were removed and the Likert scale collapsed from seven response options to three. The GCOS-16 has improved performance, and potential for usefulness beyond its original design i.e., identifying/triaging patients who may benefit most, and comparing genetic counseling (GC) to non-GC interventions. In this study, using the GCOS-24 data collected from a psychiatric GC clinic, we aimed to use a statistical method to determine the minimal clinically important difference (MCID) of the GCOS-16, and to examine whether the GCOS-16, or any individual items or subdomains could be used to identify patients who would most benefit from GC. The GCOS-24 data (24-items, 7-point Likert scale) from 307 charts were transformed into the GCOS-16 scoring (16 items, 3-point Likert scale). The GCOS-16 scores increased from pre- to post-GC (p < 0.001, d = 0.935), and the MCID was determined to be an increase of 2.5 points. There were significant differences between pre- to post-GC for all items and subdomains except for item #6. Patients receiving in-person GC were more likely to meet the MCID than those receiving service by telephone or telehealth (p < 0.001). Our data demonstrate that the GCOS-16 is sensitive to change in empowerment without ceiling effects - this could be used to triage patients for GC, and to compare GC to non-GC interventions.

As the discovery of new genes causing inherited retinal disease (IRD) has plateaued, we look to other factors which could be used to maximize diagnostic yield. We analyzed whole-exome sequencing (WES) data from 506 IRD probands, focusing on the interplay between diagnostic yield, age of symptom onset or diagnosis, family history, and initial clinical diagnosis. The cohort's overall diagnostic yield was 49.2%. Diagnostic yield was negatively correlated with the age of symptom onset and positively correlated with the number of affected family members. Diseases with distinctive clinical presentations such as Bietti crystalline dystrophy (BCD) or Leber congenital amaurosis (LCA) were more reliably diagnosed than more common and heterogeneous diseases like retinitis pigmentosa (RP) and cone-rod dystrophy (CRD). Recurrent genes and variants in this Chinese-majority cohort resemble those found in Chinese cohort studies but differ from populations of European descent, with implications for the design and prioritization of gene therapies. These insights may help optimize the diagnostic utility of genetic testing for IRDs, enhance the delivery of genetic counseling for patients, and guide the development of more inclusive targeted therapies.