European Journal of Human Genetics最新文献

Limb-girdle muscular dystrophy type R3 (LGMDR3) is caused by pathogenic SGCA variants and typically presents as progressive muscle weakness with limited cardiac manifestations. We investigated five consanguineous families with substantial left ventricular dysfunction, arrhythmias, and life-threatening ventricular tachyarrhythmias. Cardiac assessments, including echocardiography, Holter monitoring, and cardiac magnetic resonance imaging, revealed a spectrum of findings from mild asymptomatic dysfunction to severe dilated cardiomyopathy and malignant arrhythmia requiring implantable cardioverter-defibrillators. Initial evaluation with exome sequencing showed no conclusive results until a genotype-phenotype correlation reanalysis pinpointed a single homozygous synonymous SGCA variant shared by all affected individuals. Despite being distant from canonical splice sites, this variant disrupted normal mRNA splicing, leading to aberrant transcripts and a presumably nonfunctional or structurally altered α-sarcoglycan protein. This study broadens the recognized clinical spectrum of LGMDR3 by revealing significant cardiac involvement and exemplifies how a splice-disrupting synonymous variant, initially classified as likely benign, can underlie a severe cardiac phenotype and merit reclassification. Our findings highlight the importance of integrating genotype-phenotype correlation with functional studies to improve diagnostic accuracy, particularly in underrepresented populations.

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.