Journal of Medical Genetics最新文献

Background: Biallelic PLA2G6 mutations are associated with early onset autosomal recessive parkinsonism, exhibiting a broad spectrum of clinical heterogeneity.

Objective: To comprehensively characterise the clinical, imaging and genetic features of PLA2G6-related parkinsonism.

Methods: We report 14 new cases of PLA2G6-related parkinsonism in Southwest China and conduct a systematic literature review.

Results: Among the 14 patients in our cohort, 16 PLA2G6 variants were identified, including seven novel and nine previously reported variants. The mean age at symptom onset was 26.50±6.57 years. The most common initial presentation was parkinsonism (9/14, 64.3%), followed by gait disturbance (6/14, 42.9%) and psychiatric symptoms (1/14, 7.1%). A literature review identified 118 patients with PLA2G6-related parkinsonism, with a mean age at onset of 24.53±8.84 years. The most common initial clinical features included parkinsonism (61/117, 52.1%), cerebellar signs (46/85, 54.1%), cognitive impairment (65/92, 70.7%) and psychiatric symptoms (80/93, 86.0%). Subgroup analysis showed that the mean age at symptom onset was older in Chinese patients (26.65±7.08 years) compared with those of European ancestry (20.83±9.79 years) (p=0.016). Additionally, patients of European ancestry showed delayed parkinsonism 5.35±8.14 years after onset. Iron deposition was reported more frequently in patients of European ancestry (10/16, 62.5%) than that in Chinese patients (6/37, 16.2%) (p=0.0002).

Conclusion: Our study provides new insights on the diverse clinical spectrum of PLA2G6-related parkinsonism, encompassing parkinsonian features, psychiatric symptoms, cognitive impairment and early levodopa-induced motor complications.

Background: Positron emission tomography-CT (PET-CT) is widely used to diagnose cardiac sarcoidosis (CS). Emerging evidence suggests genetic arrhythmogenic cardiomyopathies (ACMs) may similarly present with episodes of myocardial inflammation resembling CS. We hypothesise a high rate of ACM diagnosis and associated pathogenic variants in patients with positive cardiac PET-CT scans referred for genetic testing. This study also seeks to delineate the role of PET-CT and anti-inflammatory therapy in ACM.

Methods: Patients at the UCLA Cardiovascular Genetics Clinic who underwent a cardiomyopathy gene panel were included. Genotypes were classified as genotype-positive (pathogenic or likely pathogenic variants), uncertain (variant of uncertain significance) or negative. Genes were grouped into ACM or non-ACM. PET-CT positivity was defined by cardiac fludeoxyglucose uptake without extracardiac involvement.

Results: Among 48 patients receiving PET-CT scans, 48% (23/48) were genotype-positive. Of 268 patients with pathogenic/likely pathogenic variants, 23 (8.6%) underwent PET-CT (11 ACM, 12 non-ACM). PET-CT positivity was observed in 27% (3/11) of ACM and 8% (1/12) of non-ACM cases. Two PET-CT-positive patients (FLNC, MYH7) received steroids with variable outcomes.

Conclusion: Receiving a PET-CT scan yielded a high genetic diagnostic yield (48%) in our clinic. Randomised controlled trials of immunosuppressive responsiveness and novel therapeutics are needed to address treatment gaps for ACM.

Purpose: Variants in the human SLC26A4 gene are a major cause of hereditary hearing loss. Many splice site variants have been identified, but their pathogenicity is not well understood.

Methods: In accordance with the guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology, we analysed the spectrum of SLC26A4 gene variants. We performed in silico analysis and in vitro splicing assays to evaluate novel or known variants of uncertain significance that may contribute to aberrant alternative splicing.

Results: In a cohort of 178 patients carrying SLC26A4 variants, selected from 202 hearing loss patients with or without inner ear malformations who underwent SLC26A4 gene testing, we identified a total of 50 variants. Among these, 10 intronic variants potentially affecting splicing collectively accounted for 54.8% of the total allele frequency of all identified variant types and were prioritised for messenger RNA (mRNA) splicing analysis. Further investigation demonstrated that four variants led to distinct types of aberrant splicing outcomes. Overall, the clinical significance of seven splice site variants was reclassified, representing at least 4.34% (14/323) of the variants within our cohort.

Conclusion: By using the standard classification of SLC26A4 variants, our results were able to interpret novel or uncertain SLC26A4 gene variants in a pathogenic or benign variant direction. This approach facilitates more refined genetic counselling for patients carrying SLC26A4 gene variants.

Temple syndrome is an imprinting disorder resulting from abnormal genomic or epigenomic aberrations of chromosome 14 including maternal uniparental disomy (matUPD), paternal deletion of 14q32, or aberrant methylation of the imprinting control regions at 14q32. Understanding the underlying molecular mechanism is essential to understanding the recurrence risk and physical effects. Currently, diagnosis requires the detection of aberrant methylation and copy number loss via methylation-sensitive assays such as methylation-specific multiplex ligation-dependent probe amplification, and short tandem repeat analysis to detect matUPD and the presence of epimutation. Therefore, a one-step approach that can detect aberrant methylation and underlying genetic mechanisms would be of high clinical value. Here we use nanopore sequencing to delineate the molecular diagnosis of a case with Temple syndrome. We demonstrate the application of nanopore sequencing to detect aberrant methylation and underlying genetic mechanisms simultaneously in this case, thus providing a proof of concept for a one-step approach for molecular diagnosis of this disorder.

RNU4-2 encodes U4 small nuclear RNA (snRNA), a non-coding RNA forming the spliceosome complex via the U4/U6 snRNA duplex. RNU4-2 heterozygous variants cause ReNU syndrome, which is characterised by intellectual disability, developmental delay, epilepsy, short stature and distinctive dysmorphic features. ReNU syndrome accounts for 0.4-0.5% of all cases of developmental delay, and RNU4-2 variants are located in the T-loop or stem III region of U4 snRNA, of which approximately 80% are the n.64_65insT variant in the T-loop. We identified four Japanese patients (4.3%) with novel and recurrent RNU4-2 variants from 93 individuals of developmental delay with negative results from exome sequencing. Genotype-phenotype correlations were observed in the present case series and a literature review. T-loop variants manifested severe developmental delay with more than 70% of cases being non-verbal. Stem III region variants resulted in milder developmental delay with fluent speech and nearly normal gross motor development milestones. In addition, we report a patient demonstrating intractable epilepsy with neurological regression harbouring a novel de novo heterozygous RNU4-2 variant (n.66A>G). This report expands the phenotypic spectrum of ReNU syndrome and suggests the presence of phenotypic variability related to variant location.

The aim of this document is to provide an updated statement from the Canadian College of Medical Geneticists (CCMG) regarding the current state and some future considerations on the collection, distribution, and storage of genomic information within electronic health records (EHRs), including which aspects of genomic data might warrant special attention. The original version of this document was written by the CCMG Ethics and Public Policy committee in 2010 based on data collected via an online survey of the CCMG membership at the time. It is updated here to reflect the current state of healthcare in 2024, where EHRs are almost ubiquitously used, and genomic medicine has expanded in its breadth and scope. The document was circulated to the general membership for review and feedback and has been approved by the CCMG Board of Directors.

Biallelic variants in NUP107 cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with syndromic SRNS have microcephaly, developmental delay or intellectual disability and short stature. Simplified gyration is observed in some individuals. We report on a 2-year-old girl with novel biallelic NUP107 variants, c.2606G>T; p.(Gly869Val) and c.1576+1G>A, proteinuria and a severe neurodevelopmental disorder with microcephaly, developmental delay, early-onset seizures, sensorineural hearing loss and brain structural anomalies, including simplified gyral pattern and hypoplasia of the corpus callosum, pons, brainstem and cerebellum. NUP107 is part of the NUP107-160 complex, which, together with other proteins termed nucleoporins, forms the nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport and other cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced NUP107 mRNAs with a frameshift and premature stop codon leading to non-sense-mediated mRNA decay, reduced levels of NUP107 transcripts, reduced NUP107 and NUP133 proteins, and a reduced NPC number. In addition, an abnormal nucleolar morphology was found in patient-derived cells. Our functional data support the conclusion that the NUP107 variants underlie the patient's phenotype, thereby broadening the clinical spectrum associated with NUP107 variants to include abnormal brain development.