European Journal of Human Genetics最新文献

Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.

Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals.

Facioscapulohumeral muscular dystrophy (FSHD) is genetically associated with reduction of the D4Z4 macrosatellite array at 4q35 on a permissive 4qA haplotype, a configuration that enables the stable expression of the DUX4 transcription factor. Current diagnostic and mechanistic models, however, rely heavily on the incomplete GRCh38/hg38 reference and assume that D4Z4 repeats are predominantly confined to 4q35 and 10q26 loci. Here we present a systematic re-analysis of the configuration of D4Z4-like repeats in the human genome using the Telomere-to-Telomere human genome assembly (T2T-CHM13 v2.0/hs1) and complementary experimental validation. Using the terminal 4q35 repeat as a query, we annotated the full repertoire of D4Z4-like loci across the genome and characterized their structural completeness, flanking sequences, and coding potential. This survey uncovered clusters and isolated monomers on at least ten additional chromosomes, several of which harbor intact DUX4 open reading frames or polyadenylation signals. In silico PCR and assays on monochromosomal hybrid cell lines demonstrate that primer sets widely employed for DUX4 or DBE-T detection amplify multiple loci beyond 4q/10q. Together, these findings demonstrate that many signals historically attributed to the pathogenic 4q locus may in fact arise from paralogous arrays. Our study establishes the necessity of locus-resolved, repeat-aware approaches, combining long-read sequencing, methylation-aware profiling, and isoform-resolved transcriptomics, for accurate diagnostics and to define the molecular basis of FSHD.

Polygenic risk scores (PGS) have the potential to support enhanced, risk-based screening for breast cancer. Previous studies for many diseases found that genome-wide PGS (GW-PGS) outperform PGS derived by applying hard GWAS significance thresholds. To support future breast cancer risk predictions, we compared the predictive performance of two existing PGS (including PGS313, a leading hard-thresholding PGS) and five newly developed GW-PGS (applying different methods to recent GWAS). We evaluated the performance of PGS Z-scores and of predicted 5-year absolute breast cancer risks based on age alone or age and PGS, across three large cohorts from the UK (UK Biobank) and Australia (QSkin, Melbourne Collaborative Cohort Study). Performance was assessed using discrimination (AUC) and calibration metrics, with dedicated evaluations for European, South Asian and African genetic ancestry groups, different age groups and for UKB, by pre-baseline mammogram screening history. Z-scores from three GW-PGS (LDpred2, PRS-CS, PRS-CS₂₀₁₇) yielded improved discrimination over PGS313, especially in European and South Asian ancestry groups (AUC improvements 2-18%, p < 0.029). Incorporating PGS substantially improved absolute risk predictions compared to age-only models, with the strongest evidence in European-ancestry groups (AUC improvements 15-39%, p < 10⁻⁴) and similar trends in non-European groups. No PGS outperformed all others across all ancestry groups. Estimated relative risk for highest GW-PGS risk groups (e.g. top 5% LDpred2) was ~2.5-fold population-average risk, similar to previous estimates for individuals with pathogenic variants in ATM and CHEK2 genes. These findings support the potential of PGS for risk-based breast cancer screening, noting that current GW-PGS may not substantially improve breast cancer risk predictions compared to PGS313.

Cancer predisposition syndromes (CPSs), including genetic tumour risk syndromes (genturis), are a heterogeneous group of genetic disorders characterised by an increased risk of developing tumours compared to the general population. CPSs raise reproductive issues for affected individuals because of the risk of passing the disease-causing genetic alterations on to offspring. The demand for reproductive counselling is often unmet due to the lack of sufficient healthcare professionals with the specialised knowledge, experience and skill. Based on a comprehensive literature review of 851 publications and expert consensus (multidisciplinary medical experts and patient representatives), the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) developed a guideline providing 16 recommendations for reproductive counselling in CPSs. The central recommendation is to offer reproductive counselling proactively to all individuals with a CPS and their relevant family members, together with psychological support and in multidisciplinary collaborations. This guideline aims to standardize the offer of reproductive counselling for individuals with a CPS across Europe, empowers healthcare professionals for their specific tasks, and helps patients dealing with their own challenges.

The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, however, no studies have examined genetic diagnostic yield for childhood apraxia of speech (CAS) and dysarthria in a clinical setting. Here, we used a clinically accredited genomics pipeline to investigate genetic diagnostic yield and variables predictive of a genetic diagnosis in a tertiary hospital speech clinic. A cohort of 153 children (range 2;7-16;5 years, 42 female) ascertained for motor speech disorder were assessed by a clinical geneticist and speech pathologist and underwent chromosomal microarray, Fragile X and exome sequencing. Odds ratios identified predictors of genetic diagnosis. 44/153 (29%, 15 female) had pathogenic variants (30 de novo), encompassing monogenic conditions (n = 35) and copy number variants (n = 9) across 38 distinct disorders. Delayed walking, fine and gross motor disorder, receptive language impairment and/or cognitive impairment, and dysmorphism were associated with a genetic diagnosis. The presence of CAS and dysarthria was more commonly associated with a genetic diagnosis than CAS alone. Autism spectrum disorder was less commonly associated with a genetic diagnosis. No child had a Fragile X diagnosis. The clinical genetic diagnostic yield for motor speech disorders is comparable to epilepsy and cerebral palsy, conditions where genetic testing is routine in most centres, unlike for motor speech disorders. Children with motor speech disorder with co-occurring motor, language and/or learning deficits, should be prioritised for genomic testing.

The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene-drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being "potentially beneficial". Genotyping prior to treatment can be considered on an individual patient basis.

The expansion of genomics provides opportunity to screen individuals beyond clinical indication yet the classification of genomic variants and implications for health outcomes in this context is still emerging. We investigated this further by analysing clinically relevant variants and expected clinical implications in a population with no reported medical conditions. Whole genomes from 9637 healthy unrelated research-consented participants in Singapore were analysed focusing on 1619 genes associated with severe paediatric disease. Association between causative variants and expected phenotype was assessed in correlation with participant characteristics and medical history where available. After considering protein impact, mode of inheritance and participant demographics for 110 variants, further analysis was performed for 44 variants occurring in 150 participants to understand clinical implications. Most carried variants associated with a mild phenotype (cystinuria), late onset (Fabry disease) or a potentially missed phenotype (Hajdu-Cheney syndrome). However, nine participants had variants associated with severe paediatric disease predicted to be symptomatic, such as limb-girdle muscular dystrophy and spastic paraplegia. Despite a cohort selected for absence of pre-existing health conditions, individuals were identified carrying variants associated with severe paediatric conditions. Further work is required to examine for subtle clinical symptoms or alternate genetic suppression mechanisms. This study revealed the challenge of predicting clinical outcomes from genotype-derived screening and emphasises the importance of expanding phenotype characterisation which is highly relevant in population and reproductive screening settings. Trial registration: NCT02791152.

Rapid genomic sequencing (rGS) is increasingly used in neonatal and paediatric intensive care units (ICUs) to inform diagnosis and guide management of critically ill infants and children. Although rGS has a high diagnostic yield and potential to influence treatment and care planning decisions, little is known about how families experience rGS in the ICU and the emotional and contextual factors influencing their testing-related decisions. We conducted semi-structured interviews with twenty-three parents of infants who consented to rGS in an ICU at two tertiary hospitals in Toronto, Ontario, Canada; all interviews took place in close proximity to the decision to pursue rGS. Parents' experiences with rGS and the related genetics consultation demonstrated a complex interplay of emotional, pragmatic, relational, and temporal 'sense-making' to grasp what was happening. Overall, parents felt overwhelmed in the ICU. Some de-prioritized genetic testing compared to other aspects of care while others reflected negatively or ambivalently on rGS or felt that it was implicitly expected that they pursue it. We conclude that an rGS approach tailored to the ICU setting is needed. Consideration should be given to distributing complex decisions (such as those relating to primary vs. secondary findings) across multiple briefer visits, and alleviating decisional burden by reframing rGS as one of the many shared decisions made with families in this setting.