European journal of medical genetics最新文献

{"title":"A systematic review of the assessment of the clinical utility of genomic sequencing: Implications of the lack of standard definitions and measures of clinical utility","authors":"Claudia Azuelos ,&nbsp;Marc-Antoine Marquis ,&nbsp;Anne-Marie Laberge","doi":"10.1016/j.ejmg.2024.104925","DOIUrl":"10.1016/j.ejmg.2024.104925","url":null,"abstract":"<div><h3>Purpose</h3><p>Exome sequencing (ES) and genome sequencing (GS) are diagnostic tests for rare genetic diseases. Studies report clinical utility of ES/GS. The goal of this systematic review is to establish how clinical utility is defined and measured in studies evaluating the impacts of ES/GS results for pediatric patients.</p></div><div><h3>Methods</h3><p>Relevant articles were identified in PubMed, Medline, Embase, and Web of Science. Eligible studies assessed clinical utility of ES/GS for pediatric patients published before 2021. Other relevant articles were added based on articles’ references. Articles were coded to assess definitions and measures of clinical utility.</p></div><div><h3>Results</h3><p>Of 1346 articles, 83 articles met eligibility criteria. Clinical utility was not clearly defined in 19% of studies and 92% did not use an explicit measure of clinical utility. When present, definitions of clinical utility diverged from recommended definitions and varied greatly, from narrow (diagnostic yield of ES/GS) to broad (including decisions about withdrawal of care/palliative care and/or impacts on other family members).</p></div><div><h3>Conclusion</h3><p>Clinical utility is used to guide policy and practice decisions about test use. The lack of a standard definition of clinical utility of ES/GS may lead to under- or overestimations of clinical utility, complicating policymaking and raising ethical issues.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104925"},"PeriodicalIF":1.9,"publicationDate":"2024-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400017X/pdfft?md5=9b5e70319407f11c453377cf08fa49d2&pid=1-s2.0-S176972122400017X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disclosure of genetic risk to family members: A qualitative study on healthcare professionals' perceived roles and responsibilities","authors":"Álvaro Mendes ,&nbsp;Milena Paneque ,&nbsp;Jorge Sequeiros","doi":"10.1016/j.ejmg.2024.104931","DOIUrl":"10.1016/j.ejmg.2024.104931","url":null,"abstract":"<div><p>This paper presents the perspectives of healthcare professionals regarding their roles and responsibilities in supporting patients with the disclosure of genetic risk to their families. The study involved eight focus groups and two individual interviews with 34 healthcare professionals working in medical genetics services across Portugal. The data were analyzed thematically, resulting in three primary themes: i) informing patients about the risk to relatives; ii) ensuring patient confidentiality; and iii) encouraging family communication. Participants believed it is their responsibility to inform patients about the genetic risk to their relatives, with patients bearing a moral responsibility to convey this information. They explained that the principles of medical confidentiality of the patient take precedence over any direct responsibility to patients' relatives. Treating personal and familial genetic information separately was perceived as challenging to implement and potentially problematic. While most participants reported encouraging patients to inform their relatives, the extent to which they facilitate this communication varies and is also constrained by lack of resources and concerns about complying with legal requirements. Some participants called for clearer national guidelines. These results contribute for ongoing discussions regarding the scope of practice and the roles and responsibilities of healthcare professionals in appropriately cascading pertinent information to at-risk relatives.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104931"},"PeriodicalIF":1.9,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000235/pdfft?md5=a0069856e1eccc704d967b55fa8d5d73&pid=1-s2.0-S1769721224000235-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140021258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal onset GAPO syndrome with a novel ANTXR1 variant in an Indian child: Expansion of the phenotype & literature review","authors":"Surya Balakrishnan ,&nbsp;Iravathy Goud ,&nbsp;Madhavi Latha Teegala","doi":"10.1016/j.ejmg.2024.104929","DOIUrl":"10.1016/j.ejmg.2024.104929","url":null,"abstract":"<div><p>GAPO syndrome is a rare genetic condition caused by bi-allelic variants in <em>ANTXR1</em> gene &amp; is an abbreviation for its core features - growth retardation, alopecia, pseudo-anodontia &amp; optic atrophy. Certain additional features involving various other systems have been reported over the years &amp; contribute to the expanding spectrum of this evolving phenotype. We report GAPO syndrome in a 3.75 year old Indian female child, who presented with some unique features such as sagittal craniosynostosis with scaphocephaly &amp; bilateral choroid plexus cysts, alongside the core phenotype. We also report a novel frameshift variant in our patient &amp; offer first evidence for the prenatal onset of some features.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104929"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000211/pdfft?md5=ee69e08cc83df9db80ab76f456f3332a&pid=1-s2.0-S1769721224000211-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Two siblings with PEX11B-related peroxisome biogenesis disorder","authors":"Somayeh Khoddam ,&nbsp;Neda Kamal ,&nbsp;Amirmasoud Shiri ,&nbsp;Hossein Jafari Khamirani ,&nbsp;Jamal Manoochehri ,&nbsp;Mehdi Dianatpour ,&nbsp;Seyed Mohammad Bagher Tabei ,&nbsp;Seyed Alireza Dastgheib","doi":"10.1016/j.ejmg.2024.104928","DOIUrl":"10.1016/j.ejmg.2024.104928","url":null,"abstract":"<div><p>The <em>PEX11β</em> gene contains four exons and encodes peroxisomal membrane protein 11β, which is involved in peroxisome proliferation and division. Pathogenic variants in this gene result in a rare genetic disorder with autosomal recessive inheritance called peroxisome biogenesis disorder 14B (MIM: 614920). Here, we report two affected siblings with a novel variant (NM_003846: c.11G &gt; A, p. Trp4Ter) in the <em>PEX11β</em> gene that was identified by whole exome sequencing and confirmed by Sanger sequencing. The proband is a 22-year-old Iranian female who was born to consanguineous parents. The homozygous variant (NM_003846: c.11G &gt; A, p. Trp4Ter) in the <em>PEX11β</em> gene was identified in the proband, who presented with cataracts, strabismus, nystagmus, intellectual disability, developmental delay, speech disorders, dry skin, and behavioral problems. Her younger affected brother, who had the same homozygous variant, suffered from similar but slightly milder symptoms. This paper reports the seventh family in the world with novel pathogenic variants in the <em>PEX11β</em> gene as the cause of peroxisome biogenesis disorder 14B. Additionally, the phenotypes of the previously reported patients are reviewed. Some of the phenotypes, such as bilateral congenital cataracts and intellectual disability, were present in all patients. However, other observed symptoms in previous cases, such as abnormal gait, myopia, abnormal muscle strength, hearing loss, gastrointestinal problems, skeletal disorders, and seizures, were not observed in the patients of this study. Further studies on this disorder could be valuable in determining the precise phenotype characteristics of this disease.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104928"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400020X/pdfft?md5=5871df2da6abe02184bff13c62a15a90&pid=1-s2.0-S176972122400020X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139995945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ligamentous laxity in children with achondroplasia: Prevalence, joint involvement, and implications for early intervention strategies","authors":"Domenico Marco Romeo ,&nbsp;Virginia Pironi ,&nbsp;Chiara Velli ,&nbsp;Elisabetta Sforza ,&nbsp;Donato Rigante ,&nbsp;Valentina Giorgio ,&nbsp;Chiara Leoni ,&nbsp;Cristina De Rose ,&nbsp;Eliza Maria Kuczynska ,&nbsp;Domenico Limongelli ,&nbsp;Roberta Ruiz ,&nbsp;Cristiana Agazzi ,&nbsp;Eugenio Mercuri ,&nbsp;Giuseppe Zampino ,&nbsp;Roberta Onesimo","doi":"10.1016/j.ejmg.2024.104930","DOIUrl":"10.1016/j.ejmg.2024.104930","url":null,"abstract":"<div><p>Achondroplasia (ACH), the most common form of skeletal dysplasia, is characterized by severe disproportionate short stature, rhizomelia, exaggerated lumbar lordosis, brachydactyly, macrocephaly with frontal bossing and midface hypoplasia.</p><p>Ligamentous laxity has been reported as a striking feature of ACH, but its prevalence and characteristics have not been systematically evaluated yet. There is growing evidence that ligamentous laxity can be associated with chronic musculoskeletal problems and may affect motor development leading to abnormal developmental trajectories.</p><p>This study aimed to assess the prevalence of ligamentous laxity in children with ACH through standardized tools, the Beighton scale and its modified version for preschool-age children.</p><p>A total of 33 children (mean age 6.4 ± 3.2 years; age range 1–12.5 years) diagnosed with ACH by the demonstration of a pathogenic variant in the <em>FGFR3</em> gene and 33 age- and sex-matched healthy controls were included in the study. Both ligamentous laxity assessment and neurological examinations were performed; medical history was also collected from caregivers.</p><p>Children with ACH showed a 2 times higher risk of ligamentous laxity than the group without skeletal dysplasia (OR = 2.2; 95% CI = 1.0 to 4.7), with 55% of children meeting the diagnostic criteria for hypermobility. No significant difference in ligamentous laxity was observed between males and females.</p><p>Joint involvement analysis revealed characteristic patterns, with knee hypermobility observed in 67% of patients, while rare was elbow hypermobility. Longitudinal assessments indicated a decreasing trend in ligamentous laxity scores over time, suggesting a potential decrease in hypermobility issues during adulthood.</p><p>The findings of this study provide valuable insights into the prevalence and characteristics of ligamentous laxity in ACH. Implementation of standardized ligamentous laxity assessments might guide patients’ follow-up and facilitate early interventions, helping to prevent pain and improve outcomes and quality of life for such patients. Further prospective studies are needed to explore the natural history of ligamentous laxity in ACH and investigate the potential impact of emerging pharmacological treatments upon hypermobility.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104930"},"PeriodicalIF":1.9,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000223/pdfft?md5=9c0212b9351488775dadcf08870fae66&pid=1-s2.0-S1769721224000223-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long-term clinical evaluation of patients with alpha-mannosidosis – A multicenter study","authors":"Engin Köse ,&nbsp;Çiğdem Seher Kasapkara ,&nbsp;Aslı İnci ,&nbsp;Yılmaz Yıldız ,&nbsp;İlknur Sürücü Kara ,&nbsp;Ayça Burcu Kahraman ,&nbsp;Leyla Tümer ,&nbsp;Ali Dursun ,&nbsp;Fatma Tuba Eminoğlu","doi":"10.1016/j.ejmg.2024.104927","DOIUrl":"10.1016/j.ejmg.2024.104927","url":null,"abstract":"<div><h3>Background</h3><p>Alpha mannosidosis is an autosomal recessive lysosomal storage disorder caused by biallelic pathogenic variants in the <em>MAN2B1</em> gene. It manifests with clinical features, including intellectual disability, hearing impairment, coarse facial appearance, skeletal anomalies, immunodeficiency, central nervous system involvement, psychiatric comorbidities, corneal opacity, and hepatosplenomegaly.</p><p>This multicenter study assesses the long-term outcomes of individuals diagnosed with alpha-mannosidosis, examining demographic, clinical, laboratory, and molecular characteristics.</p></div><div><h3>Method</h3><p>Sixteen patients diagnosed with alpha-mannosidosis who presented to four pediatric metabolic units were included in the study. The patients' medical records were analyzed and data on demographics, clinical presentation and laboratory findings were recorded.</p></div><div><h3>Results</h3><p>Of the 16 patients (6 females, 10 males) with alpha mannosidosis included in the study, the mean age at the time of diagnosis was 79.4 ± 56.1 (16–208) months, and the mean diagnosis delay time was 57.9 ± 51.9 (4–181) months.</p><p>Hearing loss was the primary manifestation found in seven out of 16 patients (43.8%), followed by speech delay in 37.8%. On clinical follow-up, 87.5% of patients experienced recurrent infections, mainly in the upper respiratory tract, with 12 requiring the use of a hearing aid. Hepatomegaly was found in six out of 13 patients who received abdominal ultrasonography; two out of 12 patients who underwent echocardiography were found to have mitral valve prolapse (16.6%).</p><p>Upon neurological evaluation, five patients displayed no neurological manifestation. Delayed language development was observed in nine (56.3%) patients, intellectual disability in eight (50%) patients, and hypertonicity was identified in one (6.3%) patient with the severe form of the disease.</p><p>Homozygous c.2477C&gt;A (p.Ser826Ter) and homozygous c.967G&gt;A (p.Glu323Lys) novel variants were detected in four patients and one patient, respectively. The most common variant observed in the study was c.2477C&gt;A (p.Ser826Ter).</p></div><div><h3>Conclusion</h3><p>The present study identified two novel <em>MAN2B1</em> variants. An evaluation of the long-term outcome of alpha-mannosidosis, in which the early initiation of enzyme replacement therapy (ERT) may lead to a better clinical outcome, can permit a better analysis of the effect of ERT on the natural progression of the disease.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104927"},"PeriodicalIF":1.9,"publicationDate":"2024-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000193/pdfft?md5=e070835ad551252ae75c0c87c59ce9e2&pid=1-s2.0-S1769721224000193-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139926805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging in osteogenesis imperfecta: Where we are and where we are going","authors":"S. Gazzotti ,&nbsp;R. Sassi ,&nbsp;M.P. Aparisi Gómez ,&nbsp;A. Moroni ,&nbsp;E. Brizola ,&nbsp;M. Miceli ,&nbsp;A. Bazzocchi","doi":"10.1016/j.ejmg.2024.104926","DOIUrl":"10.1016/j.ejmg.2024.104926","url":null,"abstract":"&lt;div&gt;&lt;p&gt;Osteogenesis imperfecta (OI) is a rare phenotypically and genetically heterogeneous group of inherited skeletal dysplasias. The hallmark features of OI include bone fragility and susceptibility to fractures, bone deformity, and diminished growth, along with a plethora of associated secondary features (both skeletal and extraskeletal). The diagnosis of OI is currently made on clinical grounds and may be confirmed by genetic testing. However, imaging remains pivotal in the evaluation of this disease. The aim of this article is to review the current role played by the various radiologic techniques in the diagnosis and monitoring of OI in the postnatal setting as well as to discuss recent advances and future perspectives in OI imaging. Conventional Radiography and Dual-energy X-ray Absorptiometry (DXA) are currently the two most used imaging modalities in OI. The cardinal radiographic features of OI include generalized osteopenia/osteoporosis, bone deformities, and fractures. DXA is currently the most available technique to assess Bone Mineral Density (BMD), specifically areal BMD (aBMD). However, DXA has important limitations and cannot fully characterize bone fragility in OI based on aBMD. Novel DXA-derived parameters, such as Trabecular Bone Score (TBS), may provide further insight into skeletal changes induced by OI, but evidence is still limited. Techniques like Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) can be useful as problem-solvers or in specific settings, including the evaluation of cranio-cervical abnormalities. Recent evidence supports the use of High-Resolution peripheral Quantitative Computed Tomography (HR-pQCT) as a promising tool to improve the characterization of bone fragility in OI. However, HR-pQCT remains a primarily research technique at present. Quantitative Computed Tomography (QCT) is an alternative to DXA for the determination of BMD at central sites, with distinct advantages but considerably higher radiation exposure. Quantitative Ultrasound (QUS) is a portable, inexpensive, and radiation-free modality that may complement DXA evaluation, providing information on bone quality. However, evidence of usefulness of QUS in OI is poor. Radiofrequency Echographic Multi Spectrometry (REMS) is an emerging non-ionizing imaging method that holds promise for the diagnosis of low BMD and for the prediction of fracture risk, but so far only one published study has investigated its role in OI. To conclude, several different radiologic techniques have proven to be effective in the diagnosis and monitoring of OI, each with their own specificities and peculiarities. Clinicians should be aware of the strategic role of the various modalities in the different phases of the patient care process. In this scenario, the development of international guidelines including recommendations on the role of imaging in the diagnosis and monitoring of OI, accompanied by continuous active research in the field, could significantly ","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104926"},"PeriodicalIF":1.9,"publicationDate":"2024-02-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000181/pdfft?md5=bbff8f6389bdde9f1e7b5cfab22fb19f&pid=1-s2.0-S1769721224000181-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139899550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rare skeletal dysplasia in the etiology of severe scoliosis: Diaphanospondylodysostosis","authors":"Tuğba Daşar ,&nbsp;Adalet Elçin Yıldız ,&nbsp;Gökhan Demirkıran ,&nbsp;Gülen Eda Utine ,&nbsp;Pelin Özlem Şimşek Kiper","doi":"10.1016/j.ejmg.2024.104924","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104924","url":null,"abstract":"<div><p>Diaphanospondylodysostosis is a rare genetic skeletal disorder caused by biallelic variants in the <em>BMPER</em> gene. The term, diaphanospondylodysostosis, includes ischiospinal dysotosis, which was previously known as a distinct entity with milder clinical features. The clinical phenotype of diaphanospondylodysostosis is quite variable with mortality in early postnatal life in some patients. Main clinical and radiographic features are narrow thorax, vertebral segmentation defects, rib anomalies, ossification defects of vertebrae, ischium and sacrum, and renal cysts. In this study, we report on a 14-year-old girl patient with diaphanospondylodysostosis harbouring a novel <em>BMPER</em> mutation. The patient presented with severe scoliosis and severely hypoplastic/aplastic distal phalanges of the fingers and toes, findings yet hitherto not described in this syndrome.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104924"},"PeriodicalIF":1.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000168/pdfft?md5=4d9a1bcee3b7bb411f2a9626e2106322&pid=1-s2.0-S1769721224000168-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139733184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genome sequencing identify chromosome 9 inversions disrupting ENG in 2 unrelated HHT families","authors":"M. Tusseau ,&nbsp;M. Eyries ,&nbsp;N. Chatron ,&nbsp;F. Coulet ,&nbsp;A. Guichet ,&nbsp;E. Colin ,&nbsp;B. Demeer ,&nbsp;H. Maillard ,&nbsp;J. Thevenon ,&nbsp;C. Lavigne ,&nbsp;V. Saillour ,&nbsp;C. Paris ,&nbsp;J.M. De Sainte Agathe ,&nbsp;M. Pujalte ,&nbsp;A. Guilhem ,&nbsp;S. Dupuis-Girod ,&nbsp;G. Lesca","doi":"10.1016/j.ejmg.2024.104919","DOIUrl":"10.1016/j.ejmg.2024.104919","url":null,"abstract":"<div><p>Hereditary hemorrhagic telangiectasia (HHT), also known as Rendu-Osler-Weber disease, is a dominant inherited vascular disorder. The clinical diagnosis is based on the Curaçao criteria and pathogenic variants in the <em>ENG</em> and <em>ACVRL1</em> genes are responsible for most cases of HHT.</p><p>Four families with a negative targeted gene panel and selected by a multidisciplinary team were selected and whole-genome sequencing was performed according to the recommendations of the French National Plan for Genomic Medicine. Structural variations were confirmed by standard molecular cytogenetic analysis (FISH).</p><p>In two families with a definite diagnosis of HHT, we identified two different paracentric inversions of chromosome 9, both disrupting the <em>ENG</em> gene. These inversions are considered as pathogenic and causative for the HHT phenotype of the patients.</p><p>This is the first time structural variations are reported to cause HHT. As such balanced events are often missed by exon-based sequencing (panel, exome), structural variations may be an under-recognized cause of HHT. Genome sequencing for the detection of these events could be suggested for patients with a definite diagnosis of HHT and in whom no causative pathogenic variant was identified.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104919"},"PeriodicalIF":1.9,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000119/pdfft?md5=e8bd561a1b79324d6847166202353e14&pid=1-s2.0-S1769721224000119-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734685","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Beyond 'speech delay': Expanding the phenotype of BRPF1-related disorder","authors":"Lottie D. Morison ,&nbsp;Olivia Van Reyk ,&nbsp;Emma Baker ,&nbsp;Lyse Ruaud ,&nbsp;Nathalie Couque ,&nbsp;Alain Verloes ,&nbsp;David J. Amor ,&nbsp;Angela T. Morgan","doi":"10.1016/j.ejmg.2024.104923","DOIUrl":"10.1016/j.ejmg.2024.104923","url":null,"abstract":"<div><p>Pathogenic variants in <em>BRPF1</em> cause intellectual disability, ptosis and facial dysmorphism. Speech and language deficits have been identified as a manifestation of <em>BRPF1-</em>related disorder but have not been systematically characterized. We provide a comprehensive delineation of speech and language abilities in <em>BRPF1</em>-related disorder and expand the phenotype. Speech and language, and health and medical history were assessed in 15 participants (male = 10, median age = 7 years 4 months) with 14 <em>BRPF1</em> variants. Language disorders were common (11/12), and most had mild to moderate deficits across receptive, expressive, written, and social-pragmatic domains. Speech disorders were frequent (7/9), including phonological delay (6/9) and disorder (3/9), and childhood apraxia of speech (3/9). All those tested for cognitive abilities had a FSIQ ≥70 (4/4). Participants had vision impairment (13/15), fine (8/15) and gross motor delay (10/15) which often resolved in later childhood, infant feeding impairment (8/15), and infant hypotonia (9/15). We have implicated <em>BRPF1-</em>related disorder as causative for speech and language disorder, including childhood apraxia of speech. Adaptive behavior and cognition were strengths when compared to other monogenic neurodevelopmental chromatin-related disorders. The universal involvement of speech and language impairment is noteable, relative to the high degree of phenotypic variability in <em>BRPF1-</em>related disorder.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104923"},"PeriodicalIF":1.9,"publicationDate":"2024-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000156/pdfft?md5=381f1a56300a0473ef2d84a5ba13915a&pid=1-s2.0-S1769721224000156-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139722164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}