Journal of Medical Genetics最新文献

Whole-genome sequencing (WGS) for every UK newborn is hailed as a leap towards lifelong personalised medicine, yet policymakers have scarcely examined the informatics iceberg beneath the initiative: where, and at what cost, will millions of genomes be stored? This perspective contends that the research-era reflex of keeping raw reads and alignments in high-performance 'hot' cloud storage is incompatible with NHS budgets and net-zero targets. Drawing on the National Genomic Research Library's current practice (~80 GB per child), I estimate the UK government's 10-year rollout would accumulate more than 0.5 exabytes and incur ~£620 million in standard S3 fees-exceeding NICE's entire core budget over the same period-while driving up data-centre energy demand. By contrast, automatically migrating files to deep-archive tiers 3 months after newborn screening preserves future utility but cuts lifetime storage costs by 91% to about £18 per child and reduces operational power by an order of magnitude; 12-24 hour restore latencies remain clinically acceptable for episodic re-analysis. I argue that newborn sequencing is primarily a logistics challenge rather than a scientific one, and that a national 'screen-then-archive' policy, anchored by a retrieval service-level agreement, would safeguard public funds, support workforce expansion and honour NHS carbon commitments while allowing consent-based re-analysis at adolescence or adulthood. Embedding cold storage economics now will prevent the programme from sinking under an exabyte scale liability.

Background: Whole genome sequencing (WGS) has recently been introduced as a diagnostic test for patients with particular rare diseases in the National Health Service (NHS) in England. Little is known about the process of communicating results from WGS to families in practice.

Methods: We audio-recorded clinicians and parents discussing the results of WGS for their child's rare disease diagnosis as part of a larger mixed-methods evaluation of the implementation of the NHS Genomic Medicine Service during its early years.

Results: 10 consultations were audio-recorded across four NHS Trusts. Clinical indications for WGS were related to neurological and developmental disorders. Seven parents received a genetic diagnosis for their child's condition, two received a variant of uncertain significance, and one received a no primary finding result. One parent also received an incidental finding for their child. Challenges in discussing results included (1) explaining a diagnosis when the genotype was established before detailed phenotyping, (2) navigating follow-up for an adult-onset condition identified in childhood, (3) disclosing an unexpected diagnosis for a parent from trio testing and (4) conveying a diagnosis with an uncertain prognosis.

Conclusion: This study illustrates some of the issues that can arise from unexpected and uncertain information when returning results from broad-scope genomic testing for paediatric neurological and developmental disorders. Further study of actual interactions between clinicians and families discussing results from WGS across different specialities and conditions is needed to inform guidance on communication of results within this rapidly evolving area of medicine.

Background: Myotonic dystrophy type 1 (DM1) is a multisystem disorder with autosomal dominant inheritance, caused by the abnormal expansion of the CTG triplet in the DMPK gene. Biomarker discovery in DM1 is crucial for monitoring disease progression.

Methods: We performed RNA sequencing on blood, skin and muscle samples from the same patients to assess splicing events. Mis-splicing events were identified using the Mann-Whitney U rank-sum test, and per cent spliced in for exons was correlated with repeat expansion size using Spearman's correlation. We also examined the relationship between mis-splicing and disease severity through Fisher's exact test and correlation analyses.

Results: We identified 937, 384 and 1216 mis-splicing events in muscle, blood and skin, respectively. Of these, 52 exons in muscle and 10 in blood correlated with estimated progenitor allele length (false discovery rate (FDR) <0.1), but none in skin. Notably, nine exons in blood correlated with total muscle mis-splicing (FDR<0.05), suggesting their potential as biomarkers of severity.

Conclusion: This is the first study to identify splicing dysregulation in blood and skin in patients with DM1 and identify novel potential blood-based mis-splicing biomarkers for disease severity. The correlation between several blood exons and the muscle splicing dysregulation indicates that blood-based biomarkers can be valuable for assessing disease severity, monitoring disease progression and evaluating treatment efficacy. Larger sample sizes may be necessary to clarify the relationship between mis-splicing and disease severity.

Comprehensive genomic testing in routine cancer care pathways has created the need to interpret the consequences of somatic (acquired) genomic variants beyond the currently well-characterised driver variants in cancer gene hotspots. While several guidelines have been published to determine the oncogenicity of somatic cancer gene variants, they lack a comprehensive and flexible approach that encompasses all available lines of evidence. Individual UK laboratories have developed local approaches to standardise somatic variant interpretation, often based on different sets of published guidelines, but a comprehensive national standardised framework is lacking. The absence of standardisation in approaches to somatic variant interpretation highlights a significant gap in the field of genomic medicine within the UK healthcare system. Key stakeholders from across the UK cancer genomics diagnostic community formed the UK Somatic Variant Interpretation Group (SVIG-UK) in September 2018 to develop a consensus approach for interpretation of somatic variants identified through genomic testing in patients with solid tumours and haematological malignancies. SVIG-UK scientists conducted a review of existing somatic variant interpretation classification systems and although they mostly agreed on evidence sources for variant interpretation, differences were identified in how the evidence should be used, weighted and combined. The SVIG-UK team subsequently developed a single, standardised UK-wide approach to somatic variant interpretation which encompassed both solid tumour and haematological cancer genomic testing. This framework was shared with stakeholders across the UK alongside variants for preliminary testing. Outcomes were then reviewed and following engagement sessions across the community, the variant interpretation recommendations were updated and ratified by the UK Association of Clinical Genomics Sciences. We present herein the SVIG-UK framework and recommendations, which provide a standardised, comprehensive and flexible approach for classifying the oncogenicity of somatic variants in cancer genes.

Despite the identification of many genes involved in developmental eye phenotypes, a large percentage of families lack genetic diagnoses, suggesting novel mechanisms remain to be discovered. Large deletions of 16p11.2, 3p14 or 19p13.11 regions involving transcription factors MAZ, FOXP1 and SIN3B, correspondingly, along with other genes, have been previously reported in individuals with neurodevelopmental and variable other features, including ocular coloboma and/or microphthalmia; recently, intragenic variants in FOXP1 and SIN3B have also been shown to cause neurodevelopmental phenotypes, with developmental eye defects reported in a small number of individuals with FOXP1 variants. Through exome sequencing analysis we identified novel splicing variants in MAZ and SIN3B, and a recurrent nonsense allele in FOXP1 in unrelated families affected with colobomatous microphthalmia, all with predicted loss-of-function effects; additionally, we report two new families with coloboma and 16p11.2 genomic deletions including MAZ, one de novo and another inherited from an affected parent. These findings provide further support for a role for FOXP1 in structural eye phenotypes, expanding its spectrum to include colobomatous microphthalmia, and suggest a role for MAZ and SIN3B in human eye development and disease.

Li-Fraumeni syndrome and Birt-Hogg-Dubé syndrome are distinct cancer predisposition syndromes caused by germline pathogenic variants (GPVs) in TP53 and FLCN, respectively. Multilocus inherited neoplasia alleles syndrome (MINAS) describes the co-occurrence of GPVs in two or more cancer predisposition genes. We present a unique case of a boy aged 16 years with multiple, very early onset atypical cutaneous fibrous histiocytomas (ACFHs), diagnosed with MINAS due to de novo TP53 and paternally inherited FLCN GPVs. This case is the first reported association of ACFH with germline TP53 and FLCN pathogenic variants. This paper highlights the importance of considering MINAS in patients with unusual tumour presentations. We discuss the clinical, histopathological and genetic findings, emphasising the need for comprehensive genetic testing and personalised surveillance in such cases.

Purpose and scope: The aim of this position statement is to provide recommendations aimed at Canadian reproductive care clinicians and genetics professionals regarding the use of reproductive carrier screening for autosomal recessive and X-linked recessive conditions.

Methods of statement development: A multidisciplinary expert group was assembled to review the existing literature on reproductive carrier screening for autosomal recessive and X-linked recessive conditions and make recommendations relevant to the Canadian context. The statement was circulated for comment to the membership of the Canadian College of Medical Geneticists (CCMG) and Canadian Association of Genetic Counsellors (CAGC), and multiple family physician reviewers. Feedback from these groups was incorporated, and the final position statement was approved by the CCMG Board of Directors on 5 December 2024 and the CAGC Board of Directors on 14 April 2025.

Results and conclusions: Routinely offered pan-ethnic reproductive carrier screening via a provincial or territorial programme is recommended for a limited panel of relatively common and severe childhood onset genetic conditions, based on Canadian experience with ethnicity-based testing: cystic fibrosis, fragile X syndrome, spinal muscular atrophy, haemoglobinopathies and founder mutations for Tay-Sachs disease, Canavan disease and familial dysautonomia. Provincial/territorial programmes must be developed to provide oversight, ensure appropriate resourcing and manage education and roll-out. Maintaining regional ethnicity-based screening programmes is also recommended, where relevant. Publicly funded population-level expanded carrier screening is not recommended at this time.

Background: Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders. NF1 is caused by dominant loss-of-function pathogenic variants (PVs) of the tumour-suppressor gene NF1, which encodes neurofibromin, a negative regulator of rat sarcoma proteins. NF1 is an autosomal dominant disorder with complete penetrance, but a highly variable expression. Identification of genotype-phenotype correlations is challenging because of the wide clinical variability, the progressive nature of the disorder and the extreme diversity of the mutation spectrum. Only a few NF1 point variants have been associated with a specific phenotype in NF1 patients.

Methods: We investigated a large, well-phenotyped NF1 cohort.

Results: We report analyses of genotype-phenotype correlations in 112 NF1 patients with specific NF1 point variants: p.Arg1809 missense variants were associated with a mild form of NF1 (n=24), while a more severe phenotype was associated with codons 844-848 (n=27), p.Arg1276 (n=25) and p.Lys1423 (n=35) missense variants. We describe a new correlation for p.Arg1204 missense variants (n=11), with no neurofibroma observed in patients. Functional studies will be critical for drawing conclusions on the potential hypomorphic or dominant-negative effects of these variants.

Conclusion: The current data confirms several genotype-phenotype correlations in NF1, which may be relevant to the management and surveillance of NF1 patients with specific NF1 PVs.

Background: Heterozygous PURA (Purine-rich element-binding protein A) variants cause PURA syndrome, a neurodevelopmental disorder characterised by hypotonia, seizures and intellectual disability. Previous studies have focused on the effect of the PURA variant in the cytoplasmic location, but nuclear mislocalisation remains to be explored.

Methods: We identified a de novo heterozygous frameshift variant (c.442del, p.L148Wfs*77) via trio whole-exome sequencing in one child suspected of PURA syndrome due to intellectual disability. Functional analyses included structural modelling, subcellular localisation assays, RNA-seq, CUT&Tag and DNA unwinding assays.

Results: The variant disrupts PURA repeats II-III, causing aberrant nuclear mislocalisation. RNA-seq revealed 688 differentially expressed genes enriched in neurodevelopmental pathways. CUT&Tag analysis revealed that PURA and Pol II exhibit enhanced binding at transcription start sites in cells expressing the variant, indicating dysregulated transcriptional engagement. Despite retained nucleic acid binding, the variant impaired DNA unwinding partly due to disrupted repeat III-mediated homodimerisation.

Conclusions: Nuclear mislocalisation of the PURA variant dysregulates transcriptional balance and impairs DNA unwinding, linking PURA's structural integrity to neurodevelopmental deficits. This highlights PURA's dual roles in cytoplasmic RNA regulation and nuclear transcription, providing mechanistic insights into PURA syndrome pathogenesis.

Rare variants in GRIA3, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.