European Journal of Human Genetics最新文献

KIF1A-Associated Neurological Disorder (KAND) is a rare, progressive neurodegenerative condition caused by variants in the KIF1A gene, which encodes a kinesin-3 motor protein essential for anterograde axonal transport of synaptic vesicles, dense core vesicles, and organelles in neurons. KAND comprises a broad spectrum of overlapping neurological phenotypes, including hereditary spastic paraplegia, intellectual disability, peripheral neuropathy, optic nerve atrophy, epilepsy, and progressive motor decline. Pathogenic variants in KIF1A disrupt the balance of intracellular transport and neuronal signalling through diverse mechanisms, manifesting with highly variable disease onset, severity, and clinical progression. Although advances in genomic testing have improved diagnosis, reported KAND cases remain concentrated in developed countries, highlighting ongoing global inequities in access to diagnosis and care. At present, no cure exists for KAND; treatment is limited to symptom management. A deeper understanding of KIF1A function, supported by the development of robust cellular and animal models, is critical for therapeutic development. This review summarises the clinical and molecular features of KAND and highlights current and emerging strategies aimed at slowing disease progression or correcting its underlying causes. We emphasise the urgent need for targeted treatment strategies addressing the heterogeneity of KAND.

Li-Fraumeni syndrome (LFS) is an inherited condition associated with high multi-organ cancer risks from birth. Young adults (YAs; 18-39 years) with LFS experience psychosocial challenges that may negatively affect health-related quality of life (HRQOL). This study aimed to describe a specific psychosocial challenge, concerns about the consequences of LFS (CC-LFS), and investigate relationships among CC-LFS and HRQOL among YAs. An online survey assessed CC-LFS and HRQOL among YAs with LFS enrolled in a National Cancer Institute study. Regression analyses examined relationships between CC-LFS and HRQOL scores, adjusted for age, cancer, and history of mental health challenges. Of 37 total respondents (78% female; M_age = 31 years), 51% had a cancer history. Many reported past mental health challenges, including emotional problems (70%), depression/anxiety disorders (68%), and suicidal ideation (43%). Mean scores for mental (M = 65.8), physical (M = 67.5), and general (M = 63.9) HRQOL were lower than in the general population. Higher CC-LFS scores (M = 31/50, SD = 7.2) were associated with lower scores for each HRQOL domain. Adjusting for covariates, higher CC-LFS scores were associated with lower physical HRQOL (β = -0.491, 95% CI -0.76, -0.22, p < 0.001) and general HRQOL (β = -0.466, 95% CI -0.77, -0.16, p = 0.004), but not mental HRQOL (p = 0.102). CC-LFS accounted for significant proportions of unique variance in general (R²_adj = 17.7%, p = 0.004) and physical HRQOL (R²_adj = 20.4%, p < 0.001). Findings suggest YAs with LFS may experience substantial concerns, mental health challenges, and diminished HRQOL. Concerns about LFS consequences appear to be a psychosocial risk factor that clinicians and researchers might address through targeted interventions to improve YAs' psychosocial health.

The inherited arrhythmia syndrome, Brugada Syndrome (BrS), is a leading cause of autopsy negative sudden death: the sudden arrhythmic death syndrome. Historically, BrS was believed to exhibit a Mendelian (autosomal dominant) mode of inheritance, caused by rare variants in SCN5A, the gene coding for the alpha subunit of the main cardiac sodium voltage channel. Challenges to this paradigm have arisen. For example, the majority of BrS cases do not exhibit rare variants in SCN5A. Moreover, genotype-phenotype mismatch in families has been observed. These findings suggest a more complex genetic architecture underpinning BrS. Subsequent large genomic studies of international patient cohorts have shown an unexpectedly high contribution of common genetic variation to its phenotypic development and severity. This has led to an alternative disease hypothesis whereby BrS develops as result of accumulated genetic and environmental risk surpassing a 'disease threshold' - the higher the accumulated risk, the more severe the clinical phenotype. Whilst expansion of standard clinical genetic testing to include an assessment of common variation might assist with diagnosis and phenotypic severity prediction in BrS, its incorporation into clinical practice presents inherent challenges which require careful consideration.

Language in clinical genetics is never neutral. The terms used to describe genetic concepts, like mutation or variant, sporadic or hereditary, patient or counselee not only shape scientific discourse but also profoundly affect how individuals understand their risks, experience counselling, and make decisions. Terminology carries ethical weight, influencing perceptions of identity, stigma, and inclusion. Precision and empathy in language are therefore central to ethical and effective care. We propose the use of consistent terminology in communication that integrates three ethical responsibilities, promoting inclusivity through careful terminology, fostering psychosocial awareness by recognising that words can evoke fear or stigma, or offer reassurance and communicative clarity. This can be achieved by standardising professional terminology (e.g., variant, sporadic/hereditary) while co-constructing meaning with counselees. We recommend avoiding ambiguous labels like positive or negative, using precise qualifiers for variants and harmonising language across professional disciplines. Communication itself can be a clinical intervention, as careful paraphrasing and clarification both enhance understanding and provide emotional support. As genetic testing becomes increasingly mainstream in oncology, empathetic, precise, and patient-centred communication is essential. By fostering clarity and reducing stigma, language can support informed decision-making, trust, and ultimately, the ethical integration of genetics into everyday healthcare.