INTRODUCTION:Rapid advances in whole-exome sequencing (WES) have enabled large-scale detection of pathogenic variants. Although hundreds of genes are implicated in hearing loss, up to half of inherited cases remain unsolved, limiting eligibility for gene therapy trials that require genetic diagnosis. Biobanks and electronic medical records (EMRs) offer opportunities to integrate genomic and clinical data at scale and expand the spectrum of hearing loss genes. Despite clinical value, EMRs often lack key information such as inheritance patterns, posing challenges for accurate interpretation. METHODS:WES was performed on DNA samples from 1038 hearing-impaired patients enrolled in the Maccabi Research and Innovation Center Tipa Biobank. Clinical data were extracted from EMRs. Audiograms were available for all cases, although data on age of onset, family history and mode of inheritance were mostly unavailable. We applied a scalable bioinformatics analysis strategy for high-throughput annotation, filtering and prioritisation of WES variants across more than 1000 patients, designed to accommodate incomplete and heterogeneous clinical records. RESULTS:Using this approach, 15% of cases were solved or potentially solved through known or novel variants in established deafness genes. Homozygous variants in novel candidate genes were identified in 3% of cases. Functional characterisation was performed for promising candidate genes to validate their role in the ear. CONCLUSION:These findings demonstrate that WES can determine disease aetiology in large, genetically heterogeneous populations, even in the context of incomplete clinical data. This approach supports large-scale genetic screening and provides a framework for identifying patients who may benefit from emerging gene-based therapies.
BACKGROUND:Pathogenic missense variants in the MORC2 gene are associated with two distinct disorders: Charcot-Marie-Tooth disease type 2Z (CMT2Z) and the recently described DIGFAN (developmental delay, impaired growth, dysmorphic facies and axonal neuropathy) phenotype, which encompasses a broad range of clinical manifestations that vary significantly between individuals. METHODS:Clinical and imaging data from 16 patients were collected. Western blot analysis was performed on 10 identified variants in affected patients as well as on two novel variants without clinical data. Those missense variants were introduced into the wild-type vector transfected into HEK293T cells, and western blot analysis was performed to assess protein expression level. RESULTS:A total of 11 different missense variants in the MORC2 gene were identified in our cohort, including four novel variants. We demonstrate that early-onset MORC2-associated disorders segregate into two principal neurological phenotypes: a predominantly neuromuscular form and a central nervous system-predominant form. The p.Ser87Leu variant, which defines the neuromuscular cluster, was uniquely characterised by a significant reduction in MORC2 protein levels, distinguishing it mechanistically from other variants. Overall, western blot analysis revealed no statistically significant difference in protein expression levels between variants related to CMT2Z and DIGFAN cases. CONCLUSION:A comparison of our patients with previously reported cases revealed an intriguing trend suggesting a probable dependence of the leading clinical features on specific variants in the MORC2 gene. Further accumulation of patient data is required to determine whether this observation correlates with other specific variants.
BACKGROUND:The heterozygous variant c.628G>A (p.Glu210Lys) in UBTF (upstream binding transcription factor) causes childhood-onset neurodegeneration with brain atrophy (CONDBA) (OMIM # 600673), characterised by early normal or mildly delayed development followed by regression, with individuals frequently experiencing movement disorders. This study defines the natural history of this rare disorder and explores potential biomarkers in humans and mice. METHODS:Caregivers of individuals with CONDBA completed cross-sectional surveys detailing genetic, developmental and clinical features. Patients evaluated in a neurogenetics clinic underwent Brief Ataxia Rating Scale (BARS) assessments compared with remotely collected wrist and ankle accelerometry data. Neurofilament light chain (NFL) levels were assessed in the clinic cohort and in a Ubtf E210K knock-in mouse model. RESULTS:All 11 caregiver surveys reported onset of neurodevelopmental regression (median 3.5 years, range 0.5-5 years), at times following anaesthesia or illness and 82% developed ataxia. Motor activity data from five participants (median 11.8 years, range 8.1-12.5 years) had high test-retest reliability, correlated with ataxia severity as measured by the BARS, and showed declines across multiple measures over the study period. NFL was abnormally elevated in both humans and the mouse model. CONCLUSION:UBTF-related CONDBA presents with early normal or mildly delayed development followed by regression and progressive ataxia. Wearable accelerometers provide a reliable measure of disease severity, and elevated NFL may serve as a biomarker of neuronal injury in both humans and animal models.
This document is written on behalf of the two professional bodies in the UK that represent genetic counsellors (the Association of Genetic Nurses and Counsellors (AGNC)) and clinical geneticists (the Clinical Genetics Society). The delivery of genomic medicine in the UK continues to evolve in response to technological advancements, increasing demand and national strategic priorities. This paper presents an updated framework describing the professional roles within specialist genomic services, refining responsibilities across key domains of clinical care, education, research and mainstreaming.Building on previous role descriptors, through focused workshops with specific expertise, we integrated national consultation, emerging service models and policy alignment. A new colour-coded matrix delineates role-specific scope of practice for different roles as described in the AGNC career structure.A key development is the formal inclusion of the genomic practitioner role, reflecting workforce diversification. Expanded emphasis is placed on mainstreaming genomic services and involvement in clinical and psychosocial research.This updated framework provides a structured and transparent tool for workforce planning, interprofessional collaboration and service development across genomic medicine. The framework remains aspirational and adaptable, acknowledging regional variability and anticipating future service developments.
BACKGROUND:BHLHE22 encodes a basic helix-loop-helix transcription factor expressed exclusively in the retina and central nervous system and functions as an important regulator of neuronal differentiation. However, BHLHE22 has not yet been associated with a Mendelian neurodevelopmental or neurological disorder. METHODS:15 individuals from 13 unrelated families carrying BHLHE22 variants identified by exome sequencing were collected through an international collaboration. RESULTS:De novo missense variants located in the highly conserved helix-loop-helix domain of the protein were found in six individuals, and one recurrent homozygous frameshift variant, NP_689627.1:p.Gly74AlafsTer18, was found in nine individuals. Frequent clinical features include absent or limited speech (10/13), delayed or impaired motor abilities (11/13), intellectual disability (ID; 9/12), partial or complete agenesis of the corpus callosum (12/15), involuntary movements and/or stereotypies (11/13) and abnormal muscle tone (13/13), depending on data availability. Two individuals developed spastic paraplegia, without ID or callosal anomalies. One individual had moderate developmental delay and ID but without callosal anomalies. CONCLUSION:Collectively, our data establish BHLHE22 as a previously unrecognized neurodevelopmental disease gene. Disruption of BHLHE22, through either dominant or recessive variants, results in a distinct syndrome characterised by abnormalities in brain development, cognition, tone and movement.
BACKGROUND:Preconception genetic screening is a key preventive strategy for identifying at-risk couples (ARCs) of inherited disorders and supporting informed reproductive decision-making. However, increasing population admixture and the widespread adoption of next-generation sequencing challenge the validity of ancestry-driven risk stratification. METHODS:A total of 107 739 individuals participated in the national screening programme, including 51 722 couples and 4295 individuals tested independently, representing 33 ethnic groups. Under the sequential testing strategy, all women underwent initial screening, whereas male partners were tested only when a pathogenic variant (PV) was identified in the female partner. Consequently, carrier-status results were available for 76 317 individuals. RESULTS:Among 76 317 individuals tested, 30 475 (39.9%) carried at least one PV. ARCs were identified in 1.15% of couples, reaching up to 10% in certain ethnic groups. Risk increased with shared ancestry, rising to 5.72% among same-ancestry couples versus 1.28% among mixed-ancestry couples (OR 4.69; 95% CI 3.70 to 6.01). Compared with ethnicity-based screening, the pan-ethnic targeted common variant (TCV) screening approach identified 11.9% more ARCs, with 26.8% of variants detected outside their historically associated populations. Postimplementation analyses also identified variants with limited yield, supporting periodic panel refinement. CONCLUSION:The TCV approach improves carrier and ARC detection compared with ethnicity-based approaches and represents a practical screening model for genetically diverse populations. These findings support consideration of the TCV approach as a practical screening strategy in genetically diverse populations, with continuous panel refinement, inclusive reference datasets and targeted outreach to high-risk communities essential to maximising its population impact.
BACKGROUND:The identification and reporting of actionable genotypes in the American College of Medical Genetics and Genomics (ACMG)-recommended secondary findings (SF) genes represent a key preventive strategy for hereditary diseases. Robust evidence quantifying their association with lifespan remains limited, particularly for non-coding regulatory variants, due to functional interpretation challenges. METHOD:Using data from the UK Biobank, we investigated associations between genetic variants and all-cause mortality in 490 086 participants with whole-genome sequencing. We systematically interpreted pathogenic or likely pathogenic coding variants in the 81 genes listed in the ACMG SF V.3.2. In parallel, we conducted saturation mutagenesis combined with a massively parallel reporter assay on the core promoters of these genes to generate a functional map of every potential variant, which we then used to interpret the functionally promoter variants in the cohort and evaluated their associations with mortality and disease incidence. RESULTS:Coding actionable genotypes were present in 3.40% of participants and were associated with increased all-cause mortality (HR in females, 1.42; 95% CI 1.34 to 1.52; HR in males, 1.31; 95% CI 1.24 to 1.39). All rare variants within the core promoter regions of these genes revealed no significant association with survival. Functionally promoter variants with downregulating activity of cancer genes were associated with elevated mortality risk (HR in females, 1.15; 95% CI 1.01 to 1.31; HR in males, 1.12; 95% CI 1.00 to 1.26). Furthermore, our findings provide clues that functional promoter variants may merit consideration when expanding actionable genotype lists. CONCLUSIONS:Our findings demonstrate that functionally verified promoter variants represent a previously unrecognised determinant of mortality risk, highlighting the potential value of looking beyond coding sequences in future studies.
BACKGROUND:Genomic testing will occasionally identify a highly actionable genetic variant or other finding that is not related to the reason for testing. Such incidental findings may be relevant to the patient undergoing testing or to their family members. METHODS:This guidance on managing incidental findings was developed by the British Society for Genetic Medicine to support clinicians requesting genomic tests and clinical scientists working in genomic laboratories within the National Health Service. RESULTS:Clinicians should include the possibility of incidental findings with a patient/parent(s) in discussions around genomic testing. Decisions regarding the reporting of a genetic variant unrelated to the referral reason will depend on clinical actionability, penetrance and the variant classification. Pathogenic variants may be reported if there is evidence of high penetrance and available treatment or surveillance that is likely to improve clinical outcome. Testing using large next generation sequencing gene panels and genome-wide array analysis increases the likelihood of revealing heterozygous carrier status for autosomal recessive disorders unrelated to the reason for testing. Reporting incidental heterozygous carrier status for autosomal recessive conditions is not recommended. CONCLUSION:This guidance provides a framework for the reporting of incidental findings with case examples and a cancer susceptibility gene list. Decision-making in accordance with guidelines will achieve greater consistency than case by case decisions. This guidance may be of use to healthcare professionals in other publicly funded healthcare systems with evolving genomic testing services.
BACKGROUND:Previous research identified an Ehlers-Danlos (EDS)-like phenotype in fragile X premutation (FXPC) women. This preliminary research examines associations between the presence of this connective tissue phenotype, FMR1 genotype and immune-mediated, autonomic-mediated and endocrine-mediated symptoms. METHODS:Women with FXPC (n=11; mean age=44 years, SD=9.9) were recruited from Greenwood Genetic Centre and southern Louisiana. Most participants were mothers or close female relatives of individuals with fragile X syndrome. Participants were assessed for hypermobile Ehlers-Danlos syndrome (hEDS) according to the 2017 criteria. They also underwent an active stand test and completed a health-related survey. RESULTS:Observed co-occurrence of this EDS-like phenotype in women with the premutation (n=5) was substantially higher than expected under statistical independence (one-sided OR 15.83, 95% CI 4.67 to 53.65, p=1.119 × 10-4]. Preliminary data also indicate that FXPC women with <90 FMR1 CGG repeats may be at higher risk of developing this phenotype compared with those with >90 repeats (p=0.016, Cohen's d=-1.928). FXPC women with the EDS-like phenotype also reported more immune-mediated symptoms (Benjamini-Hochberg (BH) adjusted p=0.032), a trend towards greater autonomic symptom burden (BH adjusted p=0.054), and had significantly higher supine/standing HR and BP during an active stand test compared with FXPC women without the connective tissue phenotype (p=0.003-0.034). CONCLUSIONS:Despite small sample numbers, the observed co-occurrence exceeded expectations under statistical independence and suggests a potential association warranting validation in larger cohorts.
BACKGROUND:Mammalian target of rapamycin (mTOR) inhibitors are effective treatments for tumours and epilepsy in tuberous sclerosis complex (TSC). This study aimed to determine the effects of the mTOR inhibitor everolimus and a placebo on neuropsychological functioning in TSC. METHODS:Individuals with TSC aged 16-60 years and intelligence quotient >60 who scored ≤5th percentile in one or more of 10 memory or executive function variables from the Brain Injury Rehabilitation Trust Memory and Information Processing Battery, the Cambridge Neuropsychological Test Automated Battery and the Test of Everyday Attention were randomised 2:1 to 24 weeks everolimus or placebo and retested at baseline and 4, 12, 24 and 36 weeks. The primary outcome was the proportion of responders, defined as improvement by ≥1 SD in at least one variable. RESULTS:38 participants were randomised, of whom 23 in the everolimus arm and 12 in the placebo arm completed all primary endpoint assessments and were included in outcome analyses. Effect sizes for individual neuropsychological variables were small to medium (Cohen's d=0-0.465), but 20 of 23 (87%, 95% CI 67.9 to 95.5) in the everolimus arm and 9 of 12 (75%, 95% CI 46.8 to 91.1) in the placebo arm were responders. Adverse events were reported in 22/25 (88%) of those randomised to everolimus versus 8/13 (61.5%) for placebo. DISCUSSION:The large proportions of responders in both trial arms may reflect unexpectedly large familiarity, practice or placebo effects in TSC, psychometric issues with parallel test forms and how a response was defined. Our findings may inform the design of future trials of neuropsychological functioning in TSC and similar conditions. TRIAL REGISTRATION NUMBER:ISRCTN09739757 and NCT01954693.
PURPOSE:CACNA1C variants have been identified in cardiac arrhythmias and developmental disorders (DD). Here, we aimed to explore the association between CACNA1C and epilepsy and the mechanism underlying phenotypic heterogeneity. METHODS:Trio-based whole-exome sequencing was performed in patients with focal epilepsy. Genes with recurrently identified variants were selected for further studies. RESULTS:Three de novo CACNA1C variants were identified in three patients with focal epilepsy. All variants presented no minor allele frequency in the Genome Aggregation Database, which was significantly lower than that of benign variants in the ClinVar database. The three de novo variants were evaluated as pathogenic or likely pathogenic variants according to the updated American College of Medical Genetics and Genomics (ACMG) classification. Two patients experienced infrequent seizures and became seizure free. The other patient had refractory epilepsy with DD and arrhythmia. Previously, 138 CACNA1C variants were reported to be associated with arrhythmias, of which 39 were classified as pathogenic or likely pathogenic; 30 variants were associated with DD, 19 of which were classified as pathogenic or likely pathogenic according to the updated ACMG classification. Further analysis indicated that null variants were more common in DD than in epilepsy (p=1.39×10-3) and arrhythmias (p=6.31×10-7). The epilepsy-associated variants were predominantly located in the voltage sensor region (p=9.03×10-3), whereas the arrhythmia-associated variants were mostly located in the linker region (p=2.13×10-4). There was a greater percentage of de novo variants in patients with epilepsy and DD than in those with arrhythmias (p=6.02×10-3; p=2.47×10-2). CONCLUSION:CACNA1C is potentially a candidate causative gene of focal epilepsy. The genotype-phenotype correlation of CACNA1C helps explain phenotypic heterogeneity.
BACKGROUND:Cancer Variant Interpretation Group UK (CanVIG-UK) was established in 2017 in response to the publication of the 2015 American College of Medical Genetics/Association for Molecular Pathology (ACMG/AMP) v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: (1) creation of a national multidisciplinary professional network and regular forum, (2) delivery of training and education, (3) establishment of a consensus approach to the fundamentals of variant interpretation in CSGs, (4) development and ratification of gene-specific frameworks for variant interpretation for CSGs, (5) development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community and (6) facilitation of UK contribution to international variant interpretation endeavours. METHODS:A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. RESULTS:The utility of the CanVIG-UK consensus recommendations for variant interpretation in CSGs was highly rated, with 89/145 (61.4%) of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128 (96.9%) rating it as extremely/very useful. The usage frequency and perceived utility reported for the gene-specific guidance by survey respondents were similar. CONCLUSION:Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.
BACKGROUND:Bartter syndrome (BS) is a salt-losing renal tubulopathy classically characterised by hypokalaemic metabolic alkalosis and hyperreninaemic hyperaldosteronism. METHODS:We investigated the genetic cause of a Bartter-like phenotype in an adolescent patient with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalaemia, significantly elevated urine chloride, failure to thrive, and a salt-losing tubulopathy. Additionally, the patient presented with hypergammaglobulinaemia, abnormal cerebral white matter signal changes, skin autoinflammation, and mild intellectual disability. RESULTS:No pathogenic variants were detected in known BS-related genes, and all recessive BS genes were outside regions of homozygosity (ROH) in this patient from a consanguineous family. Instead, exome sequencing and homozygosity mapping identified a homozygous splicing variant, c.2702-2A>G, in the epidermal growth factor receptor (EGFR) gene within an ~28 Mb ROH on chromosome 7p. RNA-Seq and RT-PCR analysis of the patient's RNA confirmed the pathogenicity of this variant, demonstrating aberrant splicing resulting in an in-frame retention of 27 nucleotides from intron 22 of EGFR. Immunofluorescence analysis of the proband's skin revealed a reduced EGFR protein level, rather than a complete absence, supporting a hypomorphic effect and likely explaining compatibility with survival into adolescence. Whereas previously reported EGFR variants have been associated with severe neonatal epithelial inflammation, bowel disease, and early mortality, our findings demonstrate that a hypomorphic variant can be compatible with survival into the second decade of life. CONCLUSION:These findings support an association between a syndromic Bartter-like salt-losing tubulopathy with epithelial autoinflammation and a homozygous splice-altering EGFR pathogenic variant, thereby expanding the phenotypic spectrum of EGFR-associated disorders.
BACKGROUND:Tetralogy of Fallot (TOF) is the most common cyanotic form of congenital heart disease (CHD). The myocyte enhancer factor 2C (MEF2C) transcription factor is a crucial regulator of cardiac development, and variants in the coding region of this gene are a known cause of CHD. However, a significant gap exists in understanding the role of non-coding regulatory variants, specifically those within the MEF2C promoter. This study seeks to fill this gap by investigating whether such promoter variants contribute to TOF pathogenesis and providing functional evidence for their impact. METHODS:Targeted sequencing of the MEF2C promoter was performed in 305 TOF patients and 306 controls. Identified rare variants were functionally characterised using dual-luciferase reporter assays in AC16 cardiomyocytes. Bioinformatic predictions and electrophoretic mobility shift assays (EMSA) were applied to assess the impact on transcription factor binding. RESULTS:Five variants (g.24599 G>A, g.24918 T>G, g.25270 T>A (rs904793941), g.25701 C>A and g.25769 T>C (rs886060871)) were identified exclusively in TOF patients. Four of the five variants significantly reduced transcriptional activity at a conservative threshold of p<0.01, with reductions ranging from 56.5% to 87.8% of wild-type. Bioinformatic analysis and EMSA confirmed that these variants alter key transcription factor binding sites (eg, for ETS1, GATA3, NFATC2) and disrupt DNA-protein interactions. CONCLUSION:This study provides the first functional evidence that MEF2C promoter variants are associated with TOF and affect transcriptional regulation, offering new insights into the potential genetic mechanisms of TOF.
Background Neurodevelopmental disorders are one of the most prevalent reasons for genetic testing in childhood. Despite the identification of over 1950 associated genes, many proposed candidate genes lack convincing gene-disease validity. The gene PREP encodes the broadly expressed prolyl endopeptidase whose exact function remains largely unknown. A homozygous PREP variant has been reported once as a candidate gene in two siblings with intellectual disability but no functional studies were conducted. Methods Exome and trio genome sequencing were performed in two unrelated families as part of larger cohorts. Segregation analysis, RNA sequencing and immunoblots were performed to further examine the pathogenicity of detected PREP variants. Results We report three individuals from two unrelated families who presented with intellectual disability, behavioural abnormalities, strabismus, generalised muscular hypotonia, dysmorphic facial features and epilepsy. Exome and genome sequencing identified two different homozygous rare PREP variants: c.1570_1573dup, p.(Asn525Thrfs*5) and c.1839-2A>G, p.?. RNA sequencing confirmed the detected intronic variant to result in two aberrant mRNA isoforms. In patient-derived cells immunoblots showed absence of PREP protein. Conclusion Our data suggest PREP deficiency as the underlying cause of a syndromic neurodevelopmental disorder.
BACKGROUND:Inherited retinal diseases (IRDs) typically follow a single inheritance pattern, but some genes cause disease through both autosomal recessive (AR) and autosomal dominant (AD) patterns, challenging genetic counselling. This study aims to identify dual inheritance genes in a Portuguese cohort and characterise the prevalence of each inheritance mode and associated phenotypes. METHODS:Cross-sectional study at Portugal's largest IRD referral centre. Genes reported with dual inheritance were identified through literature search and screened in IRD-PT registry. For each gene, AR versus AD proportion was determined and clinical features were analysed to establish genotype-phenotype correlations. RESULTS:Among 40 genes reported with dual inheritance, 22 were present in the IRD-PT registry and nine displayed both patterns (102 families, 141 patients). PRPH2 (95.0% AD) was associated with retinitis pigmentosa (RP) and macular dystrophies. ABCC6 (91.3% AR) was linked to pseudoxanthoma elasticum (PXE). BEST1 (91.7% AD) mainly caused Best disease, while PROM1 (76.9% AR) was linked to RP, macular dystrophy and cone-rod dystrophy. PRPF31 (88.9% AD) was exclusively associated with RP. IMPG2 (75.0% AR) and IMPG1 (87.5% AD) caused RP and adult-onset vitelliform macular dystrophy. NR2E3 (85.7% AR) was linked to enhanced S-cone syndrome and RP, and RP1 was detected in two families (one AR, one AD), presenting with RP. CONCLUSIONS:Dual inheritance genes accounted for 12% of our genetic diagnoses. This spectrum, modulated by variant location and allele dosage, determines phenotypes and contributes to IRD heterogeneity. Deep phenotyping and comprehensive molecular diagnosis are essential for accurate genetic counselling and patient management.
We present two illustrative cases highlighting diagnostic, surveillance and management complexities of TP53 pathogenic variants (PVs). Case 1 describes a 24-year-old female with early-onset breast cancer and a somatic mosaic TP53 PV with a variant allele frequency of 19% in blood, initially missed by panel sequencing. Case 2 concerns a 59-year-old female with multiple primary tumours and two identical TP53 variants detected in two different tissues which initially suggested somatic mosaicism but were consistent with a myelodysplastic syndrome-related clone secondary to homozygous germline ERCC6L2-associated bone marrow failure. These cases highlight the importance of accurately interpreting TP53 variants for correct clinical decision-making. Contextual factors such as age, phenotype, family history and tissue testing must guide diagnosis, treatment and surveillance.
Epithelial cell adhesion molecule (EPCAM)-associated Lynch syndrome arises from deletions at the 3'-end of EPCAM that disrupt transcriptional termination, generate read-through transcripts and cause epigenetic silencing of MSH2 in EPCAM-expressing tissues. However, the clinical significance of deletions confined to the EPCAM-MSH2 intergenic region remains uncertain without in-depth investigation.We investigated a family with a strong history of Lynch syndrome-related cancers in whom diagnostic testing by short-read sequencing identified a heterozygous deletion spanning the EPCAM-MSH2 intergenic region that was initially classified as a variant of uncertain significance. The variant was further characterised using long-read Oxford Nanopore sequencing with adaptive sampling and methylation profiling.Long-read sequencing defined precise breakpoints, and tumour analysis demonstrated MSH2 promoter hypermethylation with complete loss of MSH2 protein expression in the absence of germline promoter methylation. The molecular phenotype closely mirrored the recognised mechanism for 3'-end EPCAM deletions, whereby aberrant EPCAM transcription interferes with MSH2 promoter regulation in a tissue-specific manner.These findings support reclassification of this variant to likely pathogenic and establish a diagnosis of EPCAM-associated Lynch syndrome. This report provides the first evidence that intergenic EPCAM-MSH2 deletions are associated with MSH2 epimutations and highlights the diagnostic utility of long-read sequencing for noncoding structural variants.
Epidemiological data such as birth incidence or population prevalence for rare conditions is difficult to obtain because of the large sample size required in order to obtain a valid estimate (ie based on a reasonable number of cases) and the difficulty of either identifying all cases or meeting the cost and logistics of screening the whole general population in that large sample. This article illustrates these difficulties in the case of the rare neurodevelopmental condition Prader-Willi syndrome (PWS). Before reviewing attempts that have been made over the years to estimate birth incidence and/or population prevalence in this condition, this review discusses aspects of PWS, clear definitions of the measures themselves and aspects of general populations that are pertinent to estimates of birth incidence and population prevalence. Although most published studies on PWS quote a prevalence (meaning not always clear) estimate, very few quote the original study on which it is based. Our review found very few (12) original studies. These are described in some detail and where relevant methodological details that render the findings suspect are discussed. Finally, we answer the question of the existence of global estimates for birth incidence and population prevalence of PWS, showing that they will vary from one population to another at a given time and from one time period to another for a given population. However, for very similar populations at a given time, the values may lie within a very close range.
Precise breast cancer risk assessment (BCR) is essential for personalised prevention in women with a family history of hereditary breast and ovarian cancer (HBOC). The CanRisk model integrates monogenic variants with reproductive, lifestyle and familial factors and can be extended by Polygenic Risk Scores (PRS). We evaluated the impact of PRS-BC313 in three groups: (1) healthy carriers of (likely) pathogenic variants (LP/P), (2) affected LP/P carriers and (3) healthy female relatives from variant-negative HBOC families.In healthy LP/P carriers, median 10-year breast cancer (BC) risk remained stable, while individual estimates ranged from+25% to -16% compared with calculations without PRS. Among affected LP/P carriers, contralateral BC risk shifted by+24% to -11%, indicating PRS effects even in high-risk individuals.In healthy relatives, applying the recently introduced German threshold of an 8% BC risk between ages 40 and 50 years resulted in escalation to intensified surveillance in ~6% (5/86) (2.4-14%, Wilson binomial CI with Yates' correction) and de-escalation in ~1% (1/86) (0.061-7.2%).Here, we provide new evidence of PRS clinical impact under the updated German threshold.
