A structural aberration (SA) with secondary implications (SASIs) involving a cancer susceptibility gene is identified on chromosome microarray in approximately 0.6% tests performed on index cases. Identifying a SASI involving a high actionability cancer susceptibility gene (HA-CSG) has important genetic counselling and management implications for the individual and families. In 2019, a UK working group published recommendations for laboratories reporting SASIs involving HA-CSG. This study aims to evaluate whether these recommendations are reflected in the current UK practice. Data from a total of 63 cases of SASIs involving HA-CSGs from nine UK genetics centres were included for audit. The results have shown that 92% of microarray reports have the HA-CSG clearly named on the report, with 70% of reports having the anticipated increased risk of cancer stated. 73% of patients were appropriately managed for the associated cancer risk. For SAs where management was not given as per recommended guidelines, the identified variants were all within-gene duplications, which may represent the uncertainty around their potential to disrupt gene function and their association with true increased cancer susceptibility. This study demonstrates the practical implications of identifying a SA involving a HA-CSG and suggests room for improvement in clinical practice in reporting and management.

BackgroundRoutine genetic testing for germline pathogenic variants (GPVs) in cancer susceptibility genes (CSGs) in individuals with suspected hereditary cancer risk, and subsequent cascade testing in close relatives, has led to a significantly increased number of individuals identified to be at increased lifetime cancer risk in the UK. These individuals have differing clinical needs over their lifetime to implement cancer surveillance and discuss risk-reducing interventions, to advise on risk to close relatives and counsel on reproductive options. Regional clinical genetics services across the UK have implemented a range of clinical pathways to manage this patient cohort, with differences in practice across centres. Our aim was to provide consensus guidelines on best practice for recontact and follow-up for individuals with GPVs in BRCA1, BRCA2, PALB2, ATM, CHEK2, BARD1, BRIP1, RAD51C, RAD51D and mismatch repair (MMR) genes (MLH1, MSH2, MSH6 and PMS2) to ensure appropriate lifelong clinical management.MethodsThe UK Cancer Genetics Group convened a virtual consensus meeting involving key stakeholders. Consensus for best practice guidance was achieved through premeeting surveys, structured discussions and in-meeting polling.ResultsWe identified variability in the extent of active recontact and follow-up for individuals with a GPV in CSGs across the UK. The availability of resources was a key determinant of the level of follow-up currently provided. We achieved consensus on best practice guidelines on key time points for recontact for those with a GPV in a CSG, processes for referral to specialist services and follow-up, the preferred method for recontact and the content of information given during recontact.ConclusionThe consensus meeting broadly supported recontact and follow-up for most individuals with a GPV in a CSG. The consensus achieved by the multidisciplinary and expert group of healthcare professionals gives clear guidance on the long-term management of this patient cohort at increased lifetime risk of cancer and highlights the additional resources that would be required to effectively deliver this.

BackgroundA substantial fraction of hereditary hearing loss (HL) remains unexplained by known HL genes. Tbx2 is a developmental transcription factor critical for inner ear hair cell differentiation in mice, while its pathogenic role in genetic HL in humans has yet to be documented. Here, we identified heterozygous TBX2 frameshift variants that cause human HL, establishing a previously unrecognised genetic link.MethodsLinkage analysis combined with whole-genome sequencing (WGS) was applied to identify the causative gene in two unrelated Chinese families with autosomal dominant progressive sensorineural HL (SNHL) accompanied by incomplete penetrance nystagmus. Functional evaluation of TBX2 variants was performed through protein expression, localisation and transcriptional activity analysis in vitro, phenotypic analysis and mechanism study in knockout and knock-in mice model in vivo.ResultsLinkage analysis in Family 1 mapped SNHL to chr17q23.2 (maximum logarithm of odds=3.01), WGS identified two rare heterozygous TBX2 variants (c.977delA, p.Asp326Alafs*42 and c.987delC, p.Ala330Argfs*38) each segregating with the phenotype in a separate family. Affected individuals exhibited isolated auditory and oculomotor phenotypes, without additional syndromic features seen in previously described TBX2-associated disorders. In vitro assays demonstrated that the truncated TBX2 proteins maintained normal expression and nuclear localisation but exhibited 80% reduction in transcriptional activity. In vivo, heterozygous Tbx2 knockout mice (Tbx2+/−) developed progressive HL and transient postnatal misexpression of outer hair cell marker in inner hair cells, supporting haploinsufficiency as the pathogenic mechanism.ConclusionThese findings establish TBX2 as a novel gene for syndromic HL, defining a new autosomal dominant disorder characterised by progressive HL with variable nystagmus. This discovery expands the spectrum of T-box transcription factor disorders and informs molecular diagnosis and genetic counselling in hereditary HL.

RNU4ATAC is a non-coding gene involved in the minor spliceosome, and is mutated in a spectrum of syndromic skeletal disorders with recessive inheritance. Recently, biallelic RNU4ATAC pathogenic variants were detected in five patients presenting a complex syndromic phenotype and a brain malformation resembling the ‘molar tooth sign’ (MTS). This is the hallmark of Joubert syndrome (JS), a neurodevelopmental ciliopathy with multiorgan involvement.We reanalysed exome sequencing (ES) from 53 patients with JS, who lacked coding variants in known JS-associated genes. Four RNU4ATAC variants (n.16G>A, n.51G>A, n.13C>T and n.30G>A) were identified in compound heterozygosity in three probands, accounting for 5.6% of negative cases. All patients displayed the MTS and clinical features overlapping those of JS and RNU4ATAC-related skeletal disorders.These findings expand the phenotypic spectrum of RNU4ATAC-related disorders to include a complex neurological-skeletal ciliopathy phenotype, and highlight the relevance of ES reanalysis to uncover non-coding variants often undetected by conventional diagnostics.

BackgroundAPC c.3920T>A; p.Ile1307Lys (I1307K), prevalent in individuals of Ashkenazi Jewish (AJ) origin, has been associated with a modestly increased colorectal cancer (CRC) risk. Clinical recommendations for I1307K heterozygotes vary across countries and expert groups, reflecting differences in population frequencies, modest risk estimates and limited data in non-AJ individuals.MethodsWe analysed UK Biobank data comprising 466 315 individuals (8944 with CRC), using genomic analysis to classify AJ and non-AJ ancestries.ResultsI1307K was identified in 7.1% of AJ and 0.08% of non-AJ white participants. No significant association with CRC was observed in AJ (OR: 0.71; 95% CI: 0.17 to 2.95) or non-AJ white individuals (OR: 1.05; 95% CI: 0.50 to 2.22). The previously established OR of 1.7–1.8 for AJ individuals lies within our 95% CI, indicating underpowered results due to limited CRC cases. No significant associations were detected for other cancers. Unbiased, adequately powered CRC case–control studies in non-AJ populations would require cohorts far larger than current resources for feasible analysis.ConclusionClinical actionability of I1307K should prioritise risk stratification based on overall CRC risk and ancestry-dependent variant detection rates. However, management strategies need not differ by ancestry once a carrier is identified, as the biological impact of I1307K should be consistent across populations.

5 years have passed since the formation of the multidisciplinary consortium 'Knowing & Treating Kosaki and Penttinen Syndromes', two ultra-rare degenerative multisystem syndromes caused by heterozygous activating variants in PDGFRB. Neurological, orthopaedic and vascular deterioration can occur. Case reports of patients treated with tyrosine kinase inhibitors (TKIs) suggest that these drugs may be a therapeutic option in the future. The bi-annual remote meetings provide an opportunity to share knowledge on these syndromes. The consortium has validated the communication process, standardised follow-up guidelines, established a database to improve the natural history of these syndromes and evaluated the real-world safety and efficacy profile of TKIs by comparing treated and untreated patients. The regulatory framework is in place. As of November 2024, 18 teams in 13 countries have joined the consortium. More than 25 patients have been identified worldwide, either published or unpublished; 7 of them were treated with a TKI. The guidelines include retrospective and prospective sections for each organ affected by the disease and are based on literature and expert opinion. They also include recommendations to standardise the assessment of the efficacy and safety of treatments prescribed under compassionate use. The consortium welcomes new teams on an ongoing basis. Recommendations are especially useful in such ultra-rare degenerative diseases. The real-life observational study seems to be an appropriate model to improve knowledge, including the assessment of treatment efficacy when the prevalence of the disease does not allow the setting up of clinical trials.

Background:Scoliosis is the most common pediatric spinal deformity. More than 80% of scoliosis is idiopathic and appears during the adolescent growth spurt. Spinal fusion surgery is often required for patients with progressive adolescent idiopathic scoliosis (AIS), and the genetic risk factors for severe disease (defined here as curve >35 degrees) are largely unknown.Methods:To explore the role of rare variants in severe AIS, exome sequence data from 1,221 individuals with AIS were compared to both 1,397 in-house European ancestry controls and 56,885 gnomAD non-Finish European controls. Segregation analysis of variants in prioritized genes was performed in additional family members. Replication study was performed using the Geisinger MyCode cohort. FNDC1 function was investigated in fndc1 null mutant zebrafish.Results:Rare variants were enriched in 84 genes, including RAF1 (Noonan Syndrome), FBN1 (Marfan syndrome), and FNDC1, in individuals with severe AIS. FNDC1, which had previously been associated with joint hypermobility, harbored missense variants in 4.0% of individuals with AIS compared to 2.3% of controls (p=0.00764, OR=1.78). FNDC1 variants segregated with AIS in 5 multiplex families with incomplete penetrance. In addition, FNDC1 rare variants were also associated with scoliosis in the Geisinger MyCode cohort (p=0.0002, OR=3.6). Disruption of the fndc1 locus in zebrafish resulted in increased bone mineral density.Conclusion:We broadened the phenotype associated with RAF1 and FBN1 variants and identified FNDC1 as a novel gene associated with severe AIS. Mechanistic alterations of bone mineral density or joint hypermobility may explain the association of FNDC1 missense variants with AIS.

Approximately 1-3% of patients with Huntington disease (HD) present with HD-like phenotype but test negative for the HD gene, suggesting other causes. This study presents the first case of Huntington disease-like 1 (HDL-1) in a Chinese family and summarises the clinical features of previously reported HDL-1 cases and patients with octapeptide repeat insertion (OPRI) mutations. The proband, a 36-year-old woman, presented with progressive involuntary movements, bradykinesia, cognitive decline and personality changes over 6 years, worsening over the past year. Similar manifestations were noted in her grandmother, father and aunt. Genetic testing revealed an 8-OPRI mutation in PRNP, confirming HDL-1. Neuroimaging showed increased T2-Fluid Attenuated Inversion Recovery (FLAIR) signals in the hippocampi and atrophic changes in the frontal and parietal lobes. Electroencephalography indicated a slowed background rhythm. A 1-year follow-up visit showed amelioration of choreic movements. A literature review identified five families with HDL-1, with age of onset ranging from 18 years to 54 years and disease duration from 3 months to over 20 years. Common manifestations included movement disorders, dementia, personality changes and heterogeneous symptoms such as epilepsy. Imaging showed ventricular enlargement and diffuse brain atrophy, primarily affecting the basal ganglia, frontal lobes, temporal lobes and cerebellum. Pathologically, prion protein antibody staining was positive, although spongiform changes were not prominent. These cases highlight the importance of considering familial prion diseases in patients with hereditary chorea and a negative HD gene test. Careful attention to treatment and follow-up can provide valuable insights for managing these patients.

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.