Ishigami D, Namba S, Miyawaki S
… +16 more, Mitsui J, Imai H, Shimizu M, Hongo H, Dofuku S, Torazawa S, Teranishi Y, Ohara K, Sakai Y, Shimada D, Ono H, Nakatomi H, Morishita S, Tsuji S, Okada Y, Saito N
Eur J Hum Genet
· 2026 Jun · PMID 41680453
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Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the...Moyamoya disease (MMD) is an idiopathic cerebrovascular disorder characterized by progressive stenosis of the internal carotid artery termini and the formation of an abnormal network of fragile perforators. Although the RNF213 gene has been implicated as a susceptibility factor for MMD, the precise genetic basis of the disease remains elusive. This study aimed to investigate other genetic factors contributing to differences in disease manifestation and vascular phenotypes. We conducted whole-exome sequencing of patients with RNF213-related vasculopathy and healthy controls. In total, 122 patients (comprising 69 with bilateral MMD, 13 with unilateral MMD, and 40 with intracranial artery stenosis [ICAS]) and 458 controls were enrolled. Following appropriate quality control measures, case-control analysis and in-case analysis (bilateral MMD vs. unilateral MMD and ICAS) were conducted using single-variant association testing and gene-based aggregation testing. Although no significant locus or gene was found in the case-control analysis, the PKHD1 gene emerged as a top candidate associated with bilateral MMD in the in-case analysis. Two rare damaging variants, p.Ile2364Asn and p.Ser3210Cys, were significantly more prevalent in the bilateral MMD group and were further validated in an independent cohort of 216 individuals. Publicly available single-cell transcriptome data of mouse cerebrovascular and perivascular cells revealed that Pkhd1 expression was significantly higher in specific endothelial-cell clusters. Despite some limitations, our study provides new insights into the potential role of the PKHD1 gene in bilateral MMD, highlighting the need for further investigation of endothelial gene expression in patients with RNF213 and PKHD1 mutations.
Newborn screening (NBS) aims to identify rare but treatable conditions in newborns to offer early interventions. The possibilities of genomic sequencing are being researched to further strengthen NBS. This scoping review...Newborn screening (NBS) aims to identify rare but treatable conditions in newborns to offer early interventions. The possibilities of genomic sequencing are being researched to further strengthen NBS. This scoping review explores public and parent perspectives on genomic sequencing in NBS. We performed a literature search in Embase and Psych-abs databases to find relevant articles from 2005 until August 2024. Twenty-seven articles describing 20 studies from 7 countries were included, mostly describing survey studies. The public and parents reported a positive interest in genomic sequencing in NBS, but were overall more willing to participate in standard NBS compared to genomic NBS. Respondents' perceived benefits of genomic NBS included increased health gain for newborns, preparedness for parents and their child, enabling family planning, and benefits for other family members and population health. Most perceived concerns related to the storage and privacy of genomic sequencing data, fear of insurance discrimination, and psychological worries as a result of genomic sequencing test results. Articles reported limited public concerns regarding test accuracy or the possibility of receiving uncertain results. Preferences on how genomic sequencing should be offered were mentioned regarding decision-making and informed consent, result delivery, data storage, and program offer and costs. In conclusion, the public and parents seem generally supportive of genomic sequencing in NBS. However, to uphold support and participation comparable with current NBS programs, arguments and beliefs of the public and parents should be further explored if genomic sequencing is to be successfully implemented into or alongside NBS programs.
Bruins D, Bührman EAM, Cornel MC
… +4 more, van Mil MHW, Ausems MGEM, Damman OC, Rigter T
Eur J Hum Genet
· 2026 Apr · PMID 41639597
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Insights into the perspectives, decision-making and experiences of non-US consumers regarding health-related direct-to-consumer genetic testing (DTC-GT) are currently lacking. These insights are essential to allow the im...Insights into the perspectives, decision-making and experiences of non-US consumers regarding health-related direct-to-consumer genetic testing (DTC-GT) are currently lacking. These insights are essential to allow the implementation of consumer-tailored approaches that facilitate responsible use of DTC-GT. To fill this knowledge gap, the present study employed interviews to examine the consumer journeys of twenty Dutch health-related DTC-GT consumers. Overall, participants appeared quite satisfied with their DTC-GT consumer journeys. Participants' initial contacts with DTC-GT, as well as their pre-test information acquisition, occurred via a diversity of sources. Participants' pre-test expectations revealed considerable presumed clinical utility of DTC-GT. Feeling unheard within the regular healthcare system supported multiple participants' decisions to undergo health-related DTC-GT. Participants mentioned a modifying effect of price on their decision-making, and several participants stated not having considered potential negative consequences of DTC-GT prior to DTC-GT usage. Several potentially adverse consequences of undergoing DTC-GT were identified that could affect individual consumers, the regular healthcare system, and society as a whole. Three considerations to potentially stimulate responsible use of DTC-GT aligning with participants' needs and preferences were derived, namely improving pre-test information provision, implementing adequate post-test support systems for consumers, and development, implementation and enforcement of cross-border regulation and legislation. Based on these findings, we advocate for stakeholder discussions to further explore the feasibility and desirability of translating these considerations into deliverables. Ultimately, these deliverables could aid in empowering (potential) consumers for responsible use of health-related DTC-GT.
Albuainain F, Venema M, Schot R
… +4 more, Huigen G, Mancini GMS, van Ham TJ, Barakat TS
Eur J Hum Genet
· 2026 Apr · PMID 41639596
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Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32. So far, CFNDS has only been described in four living individuals and one terminate...Cardiofacioneurodevelopmental syndrome (CFNDS, MIM:619123) is a rare genetic disorder caused by bi-allelic pathogenic variants in CCDC32. So far, CFNDS has only been described in four living individuals and one terminated fetus from four families, and the clinical phenotype can include microcephaly, facial malformations, developmental delay, cerebellar hypoplasia, and cardiac anomalies. We present a family with two affected individuals who were diagnosed through clinical RNA sequencing (RNA-seq) after conventional DNA diagnostics did not yield a molecular cause. Skipping of two exons in CCDC32 transcript was identified, consistent with a bi-allelic deletion including exons 3 and 4 of CCDC32. This deletion was not detected in previous SNP array analyses and trio exome sequencing focusing on genes related to intellectual disability and congenital malformations, highlighting the complementary value of RNA-seq. Furthermore, we review the clinical phenotype of this rare disorder and its potential disease mechanisms.
Gorny M, Just KS, Krüger T
… +5 more, Begemann M, Kraft F, Eggermann T, Krause J, Elbracht M
Eur J Hum Genet
· 2026 May · PMID 41639595
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The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognize...The clinical relevance of pharmacogenetics (PGx) is becoming increasingly evident as knowledge in this field expands. As of May 2025, 209 clinical guideline annotations are already listed on the internationally recognized ClinPGx website. Nevertheless, except for a few indications, the implementation of PGx in clinical practice currently remains limited in most countries. At the same time, whole genome sequencing (WGS) is increasingly applied in clinical diagnostics, particularly for rare and oncological diseases. These data could also be used for simultaneous PGx analysis. In a retrospective study, we analysed short-read WGS data from 1,000 individuals, including index patients with suspected rare disorders and their relatives. For a subset of 359 individuals, medical reports were reviewed to document drug prescriptions. Guidelines published by PGx consortia on ClinPGx were used for phenotype assignment and interpretation. Clinically relevant PGx variants were detected in 97% (n = 970) of the cohort. Among patients with drug prescriptions (n = 359), 30% (n = 111) had been prescribed at least one medication for which their PGx profile would recommend therapy adjustment. Additionally, CNVs and rare variants were detected, which in 28% (n = 8) resulted in modified therapeutic recommendations. While the most (cost)-efficient strategy for broad PGx implementation remains subject of future research, our findings demonstrate that existing WGS data, such as those generated in the context of rare disease patients, could provide substantial benefits for PGx diagnostics with minimal additional effort.
Eur J Hum Genet
· 2026 Apr · PMID 41639594
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Observational epidemiology suggests a link between the dermatological disorder acne vulgaris and several psychiatric disorders. However, the biological mechanisms that underlie the relationship between acne and mental he...Observational epidemiology suggests a link between the dermatological disorder acne vulgaris and several psychiatric disorders. However, the biological mechanisms that underlie the relationship between acne and mental health are poorly characterised. Here, we employed a genetic approach using large-scale genome-wide association studies of acne and ten psychiatric disorders to both estimate causal effects and uncover potential shared genetic risk factors. Multiple psychiatric disorders displayed evidence of small-to-moderate genetic correlations with acne. However, only genetic liability to schizophrenia displayed some evidence of a causal effect on the risk of acne, though horizontal pleiotropy cannot be fully excluded. Using a Gaussian mixture-model based approach, we then identified a cluster of schizophrenia-associated variants with distinct effects on acne liability, refining the molecular mechanisms that may link schizophrenia and acne. Shared genetic risk architecture between schizophrenia and acne was also investigated using Bayesian approaches. This revealed a subset of genetic loci associated with both acne and schizophrenia via shared or different causal variants, implicating biological processes including glutamatergic signalling. Finally, we found that genetic risk for schizophrenia was also associated with increased acne severity using a population-based cohort. In summary, we revealed genetic support for a biological relationship between acne and schizophrenia that may at least partially drive the elevated rates of acne amongst people living with schizophrenia.
Pancreatic ductal adenocarcinoma occur in the context of a suspected or proven genetic predisposition in 5-10% of cases. While universal germline multigene panel testing is currently recommended by NCCN and ASCO, this ap...Pancreatic ductal adenocarcinoma occur in the context of a suspected or proven genetic predisposition in 5-10% of cases. While universal germline multigene panel testing is currently recommended by NCCN and ASCO, this approach was previously limited to patients with personal and/or family criteria suggestive of hereditary predisposition. We report the results of this « selective » approach applied in our institution from January 2018 to June 2023. Germline testing of a panel of 13 « clinically actionable » genes (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D, STK11) was performed in 496 patients with pancreatic ductal adenocarcinoma and suspected genetic predisposition based on the validation of prespecified clinical criteria. A germline pathogenic/likely pathogenic variant of one of these genes was identified in 49 patients corresponding to 9.9% of the study population. ATM and BRCA2 were the two most frequently implicated genes (18 and 16 cases, respectively) and the prevalence of pathogenic/likely pathogenic variants of these genes was significantly higher than in gnomAD controls. The overall contribution of core and non-core genes of the Homologous Recombination DNA repair system was 83.7% while the contribution of the Mismatch Repair system was 10.2%. An exploratory approach consisting of unmasking the results of the NGS analysis of 123 « research » genes involved in the carcinogenesis was applied to the 447 patients tested negative for the different genes of our diagnostic panel. This approach failed to identify other susceptibility genes to pancreatic adenocarcinoma.
Farncombe KM, Sobotka JA, Aronson M
… +31 more, Basik M, Bombard Y, Born L, Cheifetz R, Clausen M, Coburn N, Dawson L, Doria AS, Elbanna KY, Etchegary H, Foulkes WD, Hessels C, Hyde A, Kazazian K, Kinnaird A, Koch CA, Laframboise S, Lerner-Ellis J, Lheureux S, Malkin D, Metser U, Penney LS, Ridd S, Schrader KA, Tiano T, Tone AA, Veit-Haibach P, Wong S, Xu W, Pugh TJ, Kim RH
Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with...Individuals with hereditary cancer syndromes are born with germline genetic variants that significantly increase their lifetime risk of developing multiple cancers. Cancer rates and overall mortality can be reduced with intensive surveillance to facilitate early cancer detection. However, participating in diagnostic imaging and endoscopy surveillance programs is often time-consuming, overwhelming, inconvenient, and anxiety-inducing. To improve this, multi-cancer early detection tests are being developed using cell-free DNA (cfDNA) sequencing analysis to detect cancers with more sensitivity than conventional screening methods. Our community (the CHARM consortium: Cell-free DNA in Hereditary And high-Risk Malignancies) has been exploring the use of cfDNA sequencing in hereditary cancer, and has launched the CHARM2 prospective randomized controlled trial, which is enrolling 1000 participants with Hereditary Breast and Ovarian Cancer, Lynch syndrome, Li-Fraumeni syndrome, Neurofibromatosis type 1 and Hereditary Diffuse Gastric Cancer to improve equitable access, early detection and surveillance for high-risk individuals. All participants will have screening as per conventional syndrome-specific surveillance recommendations. Half the participants (experimental cohort) will also have cfDNA analysis at least three times a year, with abnormal results triggering dedicated clinical imaging and diagnostic evaluation, and heightened surveillance. Vetted by our patient advisors, validated patient-reported outcome and experience measures assessing participant psychosocial outcomes, engagement, and test preferences will be administered to both arms. Our goal is to inform if and how cfDNA analysis could be implemented into routine clinical care and offer a path to equitable and more convenient cancer screening for all high-risk Canadians.
Jost C, Busa T, Wegner D
… +33 more, Shinawi M, Schaefer E, Piton A, Schluth-Bolard C, Charles P, Keren B, Mayerhanser K, Brunet T, Schatz U, Neil JE, Walsh CA, Sisco K, J Paul A, Undiagnosed Diseases Network, Lee C, Dykzeul N, Bonner D, Bernstein JA, Sutcliffe E, Wentzensen IM, Froehlich C, Liebler K, Galvin Parton P, Weiss-Burns J, Sagnol C, Delanne J, Racine C, Thauvin-Robinet C, Safraou H, Tran Mau-Them F, Duffourd Y, Bruel AL, Faivre L
Eur J Hum Genet
· 2026 Apr · PMID 41606215
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Neurodevelopmental disorders (NDD) are a wide and heterogenous group of conditions due to impaired brain development, orchestrated by the crosstalk between genome and environment. Dynamic chromatin regulation during cort...Neurodevelopmental disorders (NDD) are a wide and heterogenous group of conditions due to impaired brain development, orchestrated by the crosstalk between genome and environment. Dynamic chromatin regulation during cortical development is fundamental, and chromatin remodelers are critical determinants of this process. Recently, numerous chromatin remodeling genes have been implicated in NDDs. By altering genes' epigenetic state, mutated chromatin remodelers disrupt the spatiotemporal regulation of gene expression during development, potentially leading to severe consequences. The Remodeling and Spacing Factor 1 (RSF1) gene encodes a ubiquitous nuclear protein involved in chromatin remodeling, crucial for processes such as DNA transcription, replication, and repair. In this study, we identified by gene matching (n = 7) and literature search (n = 4) eleven unrelated individuals harboring de novo or inherited from a symptomatic parent heterozygous variants in RSF1. All individuals had an NDD, whether intellectual disability, autism spectrum disorder or developmental delay. From the seven individuals with detailed clinical information, unspecific and inconsistent associated features were described, including cranio-facial morphological features, musculoskeletal, digestive, vision, tone, epilepsy and brain MRI anomalies. Our data support the hypothesis that RSF1 is important for brain development and a novel candidate gene for syndromic NDDs.
Soriano-Sexto A, Sánchez-Lijarcio O, Beccari L
… +13 more, Castejón-Fernández N, Leal F, Alcaide P, de la Morena-Barrio B, Bahíllo-Curieses MDP, Correcher P, Hencke-Tresbach R, López L, Martín-Hernández E, Yahyaoui R, Ugarte M, Rodríguez-Pombo P, Pérez B
Eur J Hum Genet
· 2026 Apr · PMID 41588148
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Although next-generation sequencing has emerged as a powerful tool for diagnosing rare diseases (RD), many cases of inherited metabolic diseases (IMD) remain unsolved, hindering the diagnosis, clinical and therapeutic ma...Although next-generation sequencing has emerged as a powerful tool for diagnosing rare diseases (RD), many cases of inherited metabolic diseases (IMD) remain unsolved, hindering the diagnosis, clinical and therapeutic management of the patients. The primary aim of this study is to address the most elusive cases by applying long-read sequencing (LRS) targeted to the gene of interest on seven patients (FARS2, GYS2, PEX1, SLC2A1, AGL, ACAT1, and ACADM), identifying six novel pathogenic variants including two intronic variants, a structural variant and three transposable elements (TE) insertions. In addition, we have demonstrated the effect on splicing of an exonic variant previously reported as missense. Functional genetic tests specific for the expected effect of each variant of uncertain significance were designed, such as minigenes analysis or chromatin conformation capture assay. From the TE insertions, two were located in the genomic region of GYS2 or PEX1, causing a reduction in their mRNA expression. The third was located 7.6 kb downstream of SLC2A1; it alters the interaction between the SLC2A1 promoter and its distal regulatory element via the establishment of a loop with the 3' border of the native topologically associating domain. This study shows that the combination of LRS and functional genetic assays confers a powerful approach for expanding the mutational spectrum of IMD, adding data to improve the diagnosis of this large group of RD.
Lildballe DL, Huno MR, Ridder LOR
… +8 more, Balle CM, Drue SO, Berglund A, Dunø M, Bak EN, Viuff MH, Rasmussen LS, Gravholt CH
Eur J Hum Genet
· 2026 Apr · PMID 41571809
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Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, commonly caused by variants in CYP21A2 (chr6p21.33), which encodes the 21-hydroxylase enzyme. Genetic diagnosis is challenging due to the high homo...Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder, commonly caused by variants in CYP21A2 (chr6p21.33), which encodes the 21-hydroxylase enzyme. Genetic diagnosis is challenging due to the high homology between CYP21A2 and its nearby pseudogene CYP21A1P. The current gold standard, PCR-based Sanger sequencing combined with multiplex ligation-dependent probe amplification (MLPA), is labor-intensive, costly, and amenable to PCR bias. Furthermore, it is not reliable in detecting complex structural variants, and it provides no information on whether variants are located on the same allele or not. The purpose of this study was to develop a method based on long-read sequencing (LRS) for accurate diagnostics of CYP21A2 variants and their phasing. Adaptive sampling (AS-)-LRS with chromosome 6 as region-of-interest was applied to DNA from 34 patients clinically diagnosed with CAH. To overcome mapping challenges in the highly homologous regions, we developed NanoCAH, a custom bioinformatic tool that accurately distinguishes between CYP21A2 and CYP21A1P reads. Using AS-LRS and NanoCAH, we genetically confirmed CYP21A2-associated CAH in 32 (94%) of the patients, including reliable phasing of the variants without the need for parental testing. AS-LRS clarified previously ambiguous findings, including the detection of chimeric genes, deletions, and missed variants. Compared to current gold standard methods, AS-LRS proved to be faster and more scalable, while providing greater accuracy in detecting variants within the CYP21A2 region. This makes AS-LRS a promising tool not only for CAH diagnosis but also for genetic testing in other regions with complex genomic architecture.
The concepts of uncertainty and trust in genomic research and clinical care have not been consistently defined across studies, leading to varied claims about the relationship between them. The role that social groups pla...The concepts of uncertainty and trust in genomic research and clinical care have not been consistently defined across studies, leading to varied claims about the relationship between them. The role that social groups play in this relationship is also therefore unclear. A categorisation of themes of trust and uncertainty will help to clarify and compare research claims. A review was conducted of peer-reviewed literature that discussed both 'trust' and 'uncertainty' in genomics research and/or medicine from 1 January 2018 to 28 June 2024. Exclusion criteria removed studies that did not focus on human genomics, and did not mention 'trust' or 'uncertainty'. Discussions of 'trust', 'uncertainty' and 'social groups' were coded into distinct categories. The search returned 1070 unique abstracts from which 26 studies passed the exclusion criteria. Sixteen distinct uses of 'trust' and fifteen uses of 'uncertainty' were identified alongside sixteen social groups. Relationships between uncertainty and trust were often described as being mediated by a third variable. Irreducible forms of uncertainty reported in studies suggest a need to move towards assisting patients and data donors understand and feel comfortable with uncertainty and make use of 'productive uncertainties' to foster trust. More research is needed to understand how social group belonging may shape the relationship between trust and uncertainty.
Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This...Colorectal cancer (CRC) is increasingly diagnosed in individuals under 50 years of age, yet the underlying genetic predisposition remains largely unexplained, particularly in mismatch repair (MMR)-proficient cases. This study aimed to identify novel hereditary CRC susceptibility genes by integrating germline and tumour whole-exome sequencing (WES) with transcriptomic profiling across a cohort of early-onset CRC (EOCRC) patients. Tumours were categorised using Consensus Molecular Subtypes (CMS) classification and analysed for mutational signature and burden. We used a novel 'All vs One' multi-omic integration approach to identify loss-of-function rare germline variants with concordant gene expression alterations in tumour tissue. Five candidate genes (ADCY4, NOXO1, CDHR2, ARHGAP10, EEF2K) were prioritised based on this approach and potential biological relevance in CRC. These findings highlight the molecular heterogeneity of EOCRC and demonstrate the utility of multi-omic approaches in refining germline variant interpretation. Integrating tumour transcriptomics enhances gene discovery efforts and supports a more comprehensive understanding of CRC heritability in younger individuals.
Correa FA, Habibi I, Zhai J
… +22 more, Adamo M, Wang Y, Boizot A, Zouaghi Y, Rauch A, Pekic S, Quinton R, Bonomi M, Cangiano B, Dhillo WS, Fluck CE, Nemeth A, Bouloux PM, Ferrara JM, Pignatelli D, Halász Z, Perdices-Lopez C, Messina A, Niederländer NJ, Santoni F, Acierno JS, Pitteloud N
Eur J Hum Genet
· 2026 Mar · PMID 41535479
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Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of in...Congenital hypogonadotropic hypogonadism (CHH) is a rare and genetically heterogeneous disorder characterized by absent or incomplete puberty due to impaired gonadotropin-releasing hormone (GnRH) function. A subset of individuals with CHH also present with developmental anomalies, including midline defects such as cleft lip and/or palate (CLP). This study investigates the genetic overlap between CHH and CLP. A total of 336 individuals diagnosed with CHH were clinically assessed for associated phenotypes, including CLP. High-throughput sequencing was performed using a targeted gene panel encompassing known CHH- and CLP-related genes. Variants were analyzed and classified according to the American College of Medical Genetics and Genomics (ACMG) criteria for pathogenicity. CLP was present in 21 patients with CHH (6%). Pathogenic or likely pathogenic variants in genes associated with both CHH and CLP-such as FGFR1 and CHD7-were identified in eight individuals. Furthermore, 17% of the patients with CHH without CLP harbored deleterious variants in genes implicated in clefting, including DVL3, PLCB4, NIPBL, and EDNRA. Evidence of digenic inheritance involving both CHH- and CLP-related genes was observed in multiple cases. FGFR1 variants were the most frequently detected and were commonly associated with anosmia and additional developmental anomalies. These findings highlight a genetic and phenotypic continuum between CHH and CLP, underscoring the involvement of shared developmental pathways. The high prevalence of FGFR1 variants in patients with CHH and CLP supports its role as a pleiotropic gene. Understanding the overlapping genetic mechanisms may enhance diagnostic precision and inform personalized management strategies for affected individuals.
Salsi V, Losi F, Pini S
… +2 more, Chiara M, Tupler R
Eur J Hum Genet
· 2026 Mar · PMID 41535478
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Facioscapulohumeral muscular dystrophy (FSHD) is genetically associated with reduction of the D4Z4 macrosatellite array at 4q35 on a permissive 4qA haplotype, a configuration that enables the stable expression of the DUX...Facioscapulohumeral muscular dystrophy (FSHD) is genetically associated with reduction of the D4Z4 macrosatellite array at 4q35 on a permissive 4qA haplotype, a configuration that enables the stable expression of the DUX4 transcription factor. Current diagnostic and mechanistic models, however, rely heavily on the incomplete GRCh38/hg38 reference and assume that D4Z4 repeats are predominantly confined to 4q35 and 10q26 loci. Here we present a systematic re-analysis of the configuration of D4Z4-like repeats in the human genome using the Telomere-to-Telomere human genome assembly (T2T-CHM13 v2.0/hs1) and complementary experimental validation. Using the terminal 4q35 repeat as a query, we annotated the full repertoire of D4Z4-like loci across the genome and characterized their structural completeness, flanking sequences, and coding potential. This survey uncovered clusters and isolated monomers on at least ten additional chromosomes, several of which harbor intact DUX4 open reading frames or polyadenylation signals. In silico PCR and assays on monochromosomal hybrid cell lines demonstrate that primer sets widely employed for DUX4 or DBE-T detection amplify multiple loci beyond 4q/10q. Together, these findings demonstrate that many signals historically attributed to the pathogenic 4q locus may in fact arise from paralogous arrays. Our study establishes the necessity of locus-resolved, repeat-aware approaches, combining long-read sequencing, methylation-aware profiling, and isoform-resolved transcriptomics, for accurate diagnostics and to define the molecular basis of FSHD.
Van Niel H, Lauretta M, Baker E
… +14 more, O'Donnell L, Boulton C, Brenchley C, Coman D, Michellis E, Goel H, Thompson G, Webster R, Paxton G, Stark Z, Scheffer IE, Hildebrand MS, Amor DJ, Morgan AT
Eur J Hum Genet
· 2026 May · PMID 41530369
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The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, howeve...The aetiology of childhood motor speech disorders of dysarthria and apraxia has been poorly understood. Recent evidence suggests a moderate genetic contribution for these rare and severe speech disorders. To date, however, no studies have examined genetic diagnostic yield for childhood apraxia of speech (CAS) and dysarthria in a clinical setting. Here, we used a clinically accredited genomics pipeline to investigate genetic diagnostic yield and variables predictive of a genetic diagnosis in a tertiary hospital speech clinic. A cohort of 153 children (range 2;7-16;5 years, 42 female) ascertained for motor speech disorder were assessed by a clinical geneticist and speech pathologist and underwent chromosomal microarray, Fragile X and exome sequencing. Odds ratios identified predictors of genetic diagnosis. 44/153 (29%, 15 female) had pathogenic variants (30 de novo), encompassing monogenic conditions (n = 35) and copy number variants (n = 9) across 38 distinct disorders. Delayed walking, fine and gross motor disorder, receptive language impairment and/or cognitive impairment, and dysmorphism were associated with a genetic diagnosis. The presence of CAS and dysarthria was more commonly associated with a genetic diagnosis than CAS alone. Autism spectrum disorder was less commonly associated with a genetic diagnosis. No child had a Fragile X diagnosis. The clinical genetic diagnostic yield for motor speech disorders is comparable to epilepsy and cerebral palsy, conditions where genetic testing is routine in most centres, unlike for motor speech disorders. Children with motor speech disorder with co-occurring motor, language and/or learning deficits, should be prioritised for genomic testing.
Farschtschi SC, Kumps C, Milagre TH
… +20 more, Makrythanasis P, Van Tongerloo A, Denayer E, van Kouwen M, Carrasco López E, Berghoff AS, Testa S, Cesaretti C, Trevisson E, d' Oliveira R, Fianchi F, Röhl C, Salinas-Chaparro D, Slegers I, Geilswijk M, Suerink M, Spinelli I, Janssens S, Pugh S, Sønderberg Roos LK
Eur J Hum Genet
· 2026 Mar · PMID 41530368
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Cancer predisposition syndromes (CPSs), including genetic tumour risk syndromes (genturis), are a heterogeneous group of genetic disorders characterised by an increased risk of developing tumours compared to the general...Cancer predisposition syndromes (CPSs), including genetic tumour risk syndromes (genturis), are a heterogeneous group of genetic disorders characterised by an increased risk of developing tumours compared to the general population. CPSs raise reproductive issues for affected individuals because of the risk of passing the disease-causing genetic alterations on to offspring. The demand for reproductive counselling is often unmet due to the lack of sufficient healthcare professionals with the specialised knowledge, experience and skill. Based on a comprehensive literature review of 851 publications and expert consensus (multidisciplinary medical experts and patient representatives), the European Reference Network on genetic tumour risk syndromes (ERN GENTURIS) developed a guideline providing 16 recommendations for reproductive counselling in CPSs. The central recommendation is to offer reproductive counselling proactively to all individuals with a CPS and their relevant family members, together with psychological support and in multidisciplinary collaborations. This guideline aims to standardize the offer of reproductive counselling for individuals with a CPS across Europe, empowers healthcare professionals for their specific tasks, and helps patients dealing with their own challenges.