European Journal of Human Genetics最新文献

{"title":"RICTOR variants are associated with neurodevelopmental disorders.","authors":"Raphael Carapito, Anne Molitor, Lisa Pavinato, Alaa Skeyni, Magalie Lambert, Angélique Pichot, Jiuhong Jiang, Perrine Spinnhirny, Lucie Zimmermann, Philippe Boucher, Clara W T Chung, Noha Elserafy, Edward M Blair, Dong Li, Bhoj Elisabeth, Urania Kotzaeridou, Stephanie Karch, Matias Wagner, Roelineke J Lunsing, Rolph Pfundt, Kym M Boycott, Ange-Line Bruel, Frédéric Tran Mau-Them, Sébastien Moutton, Valerio Conti, Davide Mei, Valentina Cetica, Renzo Guerrini, Theresa Brunet, Patrick Rump, Alessandro Mussa, Alfredo Brusco, Gabrielle Lemire, Bert B A de Vries, Zhichao Miao, Bertrand Isidor, Seiamak Bahram","doi":"10.1038/s41431-024-01774-w","DOIUrl":"https://doi.org/10.1038/s41431-024-01774-w","url":null,"abstract":"<p><p>RICTOR is a key component of the mTORC2 signaling complex which is involved in the regulation of cell growth, proliferation and survival. RICTOR is highly expressed in neurons and is necessary for brain development. Here, we report eight unrelated patients presenting with intellectual disability and/or development delay and carrying variants in the RICTOR gene. The phenotypic presentation is diverse with associated features including growth failure, feeding difficulties, abnormal behavior, seizure, hypertonia, brain anomalies and various other congenital organ and skeletal malformations. All patients carried de novo or heterozygous variants inherited from one affected parent, including three missense variants, four loss-of-function variants and one 3 kb deletion encompassing RICTOR. The mTORC2 pathway was hyperactivated in a patient's fibroblasts carrying a missense variant, while the expression of RICTOR remained unchanged, indicating a gain-of-function mechanism. RNA sequencing on RICTOR knock-out mouse embryonic fibroblasts confirmed the potential role of RICTOR in neuronal cell development.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142909520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vascular Ehlers-Danlos syndrome in children: evaluating the importance of diagnosis and follow-up during childhood","authors":"Niamh R. Wilkinson,&nbsp;Elena Cervi,&nbsp;Bart Wagner,&nbsp;Deborah Morris-Rosendahl,&nbsp;Duncan Baker,&nbsp;Harpaul Flora,&nbsp;Kate von Klemperer,&nbsp;Toby Andrew,&nbsp;Neeti Ghali,&nbsp;Fleur S. van Dijk","doi":"10.1038/s41431-024-01773-x","DOIUrl":"10.1038/s41431-024-01773-x","url":null,"abstract":"Vascular Ehlers-Danlos syndrome (vEDS) is a rare inherited connective tissue disorder predominantly caused by pathogenic COL3A1 variants. Characteristic arterial and intestinal fragility and generalised severe tissue friability can lead to clinical events from childhood. We highlight a paucity of literature regarding children diagnosed with vEDS, possibly explained by a restraint in predictive testing, and present data on 63 individuals (23 index cases) with a clinical and genetic diagnosis of vEDS in childhood (&lt;18 years) to address this. Patients were identified through the National Ehlers-Danlos Syndrome (EDS) Service London. We report on 18 events in childhood, recorded in 13 individuals. First events occurred at a median age of 11 years (IQR 0–13) and genetic testing was initiated as a direct result of the first event in 11/13 cases. In the cohort majority, diagnosis was the result of familial genetic testing (55%). Our findings emphasise the importance of offering genetic testing in childhood when there is a positive family history of vEDS and/or features suggestive of a potential inherited connective tissue disorder. Diagnosis in childhood allows for follow-up surveillance and informed multi-disciplinary management, in addition to genetic counselling and patient-led management including lifestyle modification. As seen in adult cohorts, we anticipate children with vEDS will experience the same protective benefit afforded by early diagnosis and present preliminary data on follow-up in childhood. Formal evaluation of the impact that diagnosis of vEDS in childhood has on disease management is needed when sufficient data is internationally available.","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":"33 3","pages":"368-376"},"PeriodicalIF":3.7,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41431-024-01773-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMCHD1 genetic variants in type 2 facioscapulohumeral dystrophy and challenges in predicting pathogenicity and disease penetrance.","authors":"Laurène Gérard, Mégane Delourme, Charlotte Tardy, Benjamin Ganne, Pierre Perrin, Charlene Chaix, Jean Philippe Trani, Nathalie Eudes, Camille Laberthonnière, Karine Bertaux, Chantal Missirian, Guillaume Bassez, Anthony Behin, Pascal Cintas, Florent Cluse, Elisa De La Cruz, Emilien Delmont, Teresinha Evangelista, Mélanie Fradin, Nawale Hadouiri, Ludivine Kouton, Pascal Laforêt, Claire Lefeuvre, Armelle Magot, Véronique Manel, Juliette Nectoux, Antoine Pegat, Guilhem Sole, Marco Spinazzi, Tanya Stojkovic, Juliette Svahn, Celine Tard, Christel Thauvin, Camille Verebi, Emmanuelle Salort Campana, Shahram Attarian, Karine Nguyen, Ali Badache, Rafaëlle Bernard, Frédérique Magdinier","doi":"10.1038/s41431-024-01781-x","DOIUrl":"https://doi.org/10.1038/s41431-024-01781-x","url":null,"abstract":"<p><p>The molecular diagnosis of type 1 facioscapulohumeral muscular dystrophy (FSHD1) relies on the detection of a shortened D4Z4 array at the 4q35 locus. Until recently, the diagnosis of FSHD2 relied solely on the absence of a shortened D4Z4 allele in clinically affected patients. It is now established that most FSHD2 cases carry a heterozygous variant in the SMCHD1 gene. A decrease in D4Z4 DNA methylation is observed in both FSHD1 and FSHD2 patients. To refine the molecular diagnosis of FSHD2, we performed a molecular diagnosis of SMCHD1 in 54 patients with a clinical diagnosis of FSHD. All patients carry a D4Z4 array of more than 10 D4Z4 units, or a cis-duplication of the locus. Forty-eight of them carry a variant in SMCHD1 and six other cases are hemizygous for the 18p32 locus encompassing SMCHD1. Genetic and epigenetic analyses were considered to assess the pathogenicity of new SMCHD1 variants and of variants previously classified as likely pathogenic. In comparison to the healthy population and FSHD1 patients, we defined a threshold of 40% of methylation at the D4Z4 DR1 site as associated with SMCHD1 variants or SMCHD1 hemizygosity. We also showed that the number of D4Z4 on the shortest 4q allele ranges from 11 up to 35 units in these same patients. Using variant interpretation and protein structure prediction tools, we also highlight the difficulty in interpreting the impact of pathogenic variants on SMCHD1 function. Our study further emphasizes the intriguing relationship between D4Z4 methylation, SMCHD1 variants with SMCHD1 protein structure-function in FSHD.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142893238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and allelic heterogeneity in 248 Indians with skeletal dysplasia.","authors":"Prince Jacob, Swati Singh, Gandham SriLakshmi Bhavani, Kalpana Gowrishankar, Dhanya Lakshmi Narayanan, Sheela Nampoothiri, S J Patil, J P Soni, Mamta Muranjan, Seema Kapoor, Bhavna Dhingra, Ballambattu Vishnu Bhat, Shruti Bajaj, Amrita Banerjee, Mahabaleshwar Mamadapur, Sankar V Hariharan, Nutan Kamath, Rathika D Shenoy, Deepti Suri, Anju Shukla, Ashwin Dalal, Shubha R Phadke, Gen Nishimura, Geert Mortier, Hitesh Shah, Katta M Girisha","doi":"10.1038/s41431-024-01776-8","DOIUrl":"https://doi.org/10.1038/s41431-024-01776-8","url":null,"abstract":"<p><p>Skeletal dysplasias are a clinically and genetically heterogeneous group of rare disorders. Studies from large cohorts are essential to provide insights into the disease epidemiology, phenotypic spectrum, and mutational profiles. Here we enumerate additional 248 Indians from 197 families with a skeletal dysplasia, following a similar study earlier. We achieved a clinical-molecular diagnosis in 145 families by targeted analysis in 37 and next generation sequencing (exomes and genomes) in 108 families that resulted in a diagnostic yield of 73.6% (145 of 197 families). We identified 149 causal variants, of which 85 were novel, across 73 genes. Eighty-one distinct monogenic forms of skeletal dysplasia were observed with a high proportion of autosomal recessive skeletal dysplasias (60%, 84 families). We observed consanguinity in 35% of the families. Lysosomal storage diseases with skeletal involvement, FGFR3-related skeletal dysplasia and disorders of bone mineralisation were most frequent in this cohort. We expand the phenotypic and genotypic spectrum of rarely reported conditions (RAB33B, TRIP11, NEPRO, RPL13, COL27A1, PTHR1, EXOC6B, PRKACA, FUZ and RSPRY1) and noted novel gene-disease relationships for PISD, BNIP1, TONSL, CCN2 and SCUBE3 related skeletal dysplasia. We successfully implemented genomic testing for skeletal dysplasia in clinical and research settings. Our study provides valuable information on the spectrum of skeletal dysplasia and disease-causing variants for Asian Indians.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142871767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Health professionals contacting patients' relatives directly about genetic risk (with patient consent): current clinical practice and perspectives.","authors":"Ami Stott, Evanthia O Madelli, Tiffany Boughtwood, Kristen J Nowak, Margaret Otlowski, Jane Tiller","doi":"10.1038/s41431-024-01730-8","DOIUrl":"https://doi.org/10.1038/s41431-024-01730-8","url":null,"abstract":"<p><p>Genetic testing can provide risk information to individuals and their blood relatives. Cascade testing uptake by at-risk relatives is <50%, with suboptimal family communication a key barrier to risk notification. The practice of health professionals (HPs) directly contacting relatives (with patient consent) to assist with risk notification has significant international support, but little is known about the practices and views of HPs in Australia. We surveyed Australian clinical genetics and laboratory services (public and private) which offer genetic testing of relevance to relatives, about current practices and views. Of 104 services invited, 78 responded to our online survey (75.0% response rate; clinical n = 59/81; laboratory n = 19/23). Most clinical services (83.3%) agreed it would be beneficial to contact at-risk relatives directly. However, the majority (80.4%) do not routinely contact relatives directly, with inadequate resources (80.0%) and privacy concerns (62.2%) cited as primary reasons. If direct contact methods were used, most clinical services (65.4%) prefer a letter which includes specific information about the genetic condition. Most clinical (86.5%) and laboratory (88.2%) services saw benefit in the development of a national clinical guideline for HPs regarding direct contact. This study confirms that most clinical genetics services would see benefits to being able to assist patients by contacting relatives directly about their potential genetic risk. Our findings highlight the need for a national clinical guideline clarifying HPs' legal and privacy obligations, and provide an opportunity for clinical services to reconsider their allocation of resources to prioritise assisting patients with risk notification.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of ZFHX4 in orofacial clefting based on human genetic data and zebrafish models.","authors":"Nina Ishorst, Selina Hölzel, Carola Greve, Öznur Yilmaz, Tobias Lindenberg, Jessica Lambertz, Dmitriy Drichel, Berina Zametica, Enrico Mingardo, Jeshurun C Kalanithy, Khadija Channab, Duygu Kibris, Sabrina Henne, Franziska Degenhardt, Anna Siewert, Michael Dixon, Teresa Kruse, Edwin Ongkosuwito, Katta M Girisha, Shruti Pande, Stefanie Nowak, Gregor Hagelueken, Matthias Geyer, Carine Carels, Iris A L M van Rooij, Kerstin U Ludwig, Benjamin Odermatt, Elisabeth Mangold","doi":"10.1038/s41431-024-01775-9","DOIUrl":"https://doi.org/10.1038/s41431-024-01775-9","url":null,"abstract":"<p><p>Orofacial clefting (OFC) is a frequent congenital anomaly and can occur either in the context of underlying syndromes or in isolation (nonsyndromic). The two common OFC phenotypes are cleft lip with/without cleft palate (CL/P) and cleft palate only (CPO). In this study, we searched for penetrant CL/P genes, by evaluating de novo copy number variants (CNV) from an exome sequencing dataset of 50 nonsyndromic patient-parent trios. We detected a heterozygous 86 kb de novo deletion affecting exons 4-11 of ZFHX4, a gene previously associated with OFC. Genetic and phenotypic data from our in-house and the AGORA cohort (710 and 229 individuals with nonsyndromic CL/P) together with literature and database reviews demonstrate that ZFHX4 variants can lead to both nonsyndromic and syndromic forms not only of CL/P but also CPO. Expression analysis in published single-cell RNA-sequencing data (mouse embryo, zebrafish larva) at relevant time-points support an important role of Zfhx4/zfhx4 in craniofacial development. To characterize the role of zfhx4 in zebrafish craniofacial development, we knocked out/down the zebrafish orthologue. Cartilage staining of the zfhx4 CRISPR F0 knockout and morpholino knockdown at 4 days post-fertilization showed an underdeveloped and abnormally shaped ethmoid plate and cartilaginous jaw (resembling micrognathia). While there is evidence for the dominant inheritance of ZFHX4 variants in OFC, we here present a patient with a possible recessive inheritance. In conclusion, ZFHX4 has a highly heterogeneous phenotypic spectrum and variable mode of inheritance. Our data highlight that ZFHX4 should be considered in genetic testing in patients with nonsyndromic clefting.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patients' perspectives regarding health professionals contacting their relatives about genetic risk directly (with patient consent).","authors":"Jane Tiller, Keri Finlay, Evanthia O Madelli, Melissa Monnik, Matilda R Jackson, Nicola Poplawski, Tiffany Boughtwood, Kristen J Nowak, Margaret Otlowski","doi":"10.1038/s41431-024-01764-y","DOIUrl":"https://doi.org/10.1038/s41431-024-01764-y","url":null,"abstract":"<p><p>Genetic testing of blood relatives of individuals at high risk of dominant conditions has significant preventive health benefits. However, cascade testing uptake is <50%. Research shows increased testing uptake when health professionals (HPs) contact at-risk relatives directly, with patient consent. Despite international support, this is not standard practice in Australia. We aimed to gather perspectives of genetic testing patients about direct-contact methods. Using an online survey, we surveyed Australian adults with genetic results of relevance for relatives, including patients who (i) self-categorised as being directly contacted by a clinical service, (ii) self-categorised as being referred by a HP, and (iii) received genetic results through a research study. Overall, 442 patients responded (clinical n = 363; research n = 79). Clinical patients self-categorised as 49.0% directly-contacted and 51.0% referred. Overall, the majority of patients had no privacy concerns about direct-contact methods (direct-contact 97%; referred 77%; research 76%). Less than 5% of the combined cohort (n = 19/442) reported significant concerns. The most prevalent concerns were the need for consent to provide HPs with relatives' contact details, and a patient preference to notify relatives before HP contact. Other key findings include preferences about contact methods, including that most patients who received a letter from a genetics service preferred a letter with specific information about the familial genetic condition (n = 141/149; 94.6%) than one with general information about genetic risk. Our findings indicate Australian patients support HPs using direct-contact methods to assist with risk communication to relatives. Findings also identify concerns to be addressed in the design of direct-contact programs.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction between SLCO1B1 and statins and CYP2C9 and sulfonylureas.","authors":"David F G J Wolthuis, Marga Nijenhuis, Bianca Soree, Nienke J de Boer-Veger, Anne Marie Buunk, Henk-Jan Guchelaar, Arne Risselada, Gerard A P J M Rongen, Ron H N van Schaik, Jesse J Swen, Daan J Touw, Roos van Westrhenen, Vera H M Deneer, Elisa J F Houwink","doi":"10.1038/s41431-024-01769-7","DOIUrl":"10.1038/s41431-024-01769-7","url":null,"abstract":"<p><p>Aligned with the mission of the Dutch Pharmacogenetics Working Group (DPWG) to promote the implementation of pharmacogenetics (PGx), this guideline is specifically designed to optimize pharmacotherapy of cholesterol lowering medication (statins) and glucose lowering medication (sulfonylureas). The SLCO1B1 c.521 T > C variant reduces the activity of the SLCO1B1 transporter involved in statin transport out of the blood into the liver. High blood concentrations of statins increase the risk of serious myopathy. For simvastatin, the DPWG recommends choosing an alternative in homozygotes for these gene variant and to preferably choose an alternative in heterozygotes. For atorvastatin, the DPWG recommends to preferably choose an alternative in carriers of this gene variant having additional risk factors for myopathy. For rosuvastatin, the DPWG recommends keeping the dose as low as possible in carriers of this gene variant with additional risk factors. No therapy adjustment is required for fluvastatin and pravastatin in carriers of this gene variant. Gene variants can diminish the activity of the enzyme CYP2C9, that converts sulfonylurea to less effective metabolites. Although CYP2C9 gene variants may lead to increased levels of glibenclamide, gliclazide, glimepiride, and tolbutamide, no therapy adjustments are required in patients with these variants. The main reason is that there was either no negative clinical effect or an increase in hypoglycemic, which is of less importance than the increase in effectiveness it signals. The DPWG classifies pre-emptive SLCO1B1 testing as 'essential' for simvastatin 80 mg/day, 'beneficial' for simvastatin up to 40 mg/day, and 'potentially beneficial' for atorvastatin and rosuvastatin.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142827979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Use of Estonian Biobank data and participant recall to improve Wilson's disease management.","authors":"Miriam Nurm, Anu Reigo, Tarmo Annilo, Toomas Toomsoo, Margit Nõukas, Tiit Nikopensius, Vasili Pankratov, Tuuli Reisberg, Georgi Hudjashov, Toomas Haller, Neeme Tõnisson","doi":"10.1038/s41431-024-01767-9","DOIUrl":"https://doi.org/10.1038/s41431-024-01767-9","url":null,"abstract":"<p><p>Population-based biobanks enable genomic screening to support initiatives that prevent disease onset or slow its progression and to estimate the prevalence of genetic diseases in the population. Wilson's disease (WD) is a rare genetic copper-accumulation disorder for which timely intervention is crucial, as treatment is readily available. We studied WD in the Estonian Biobank population to advance patient screening, swift diagnosis, and subsequent treatment. Combined analysis of genotype and phenotype data from electronic health records (EHRs) consolidated at the Estonian biobank led to the identification of 17 individuals at high risk of developing WD, who were recalled for further examination and deep phenotyping. All recall study participants, regardless of phenotype, age, and prior WD diagnosis, had low serum ceruloplasmin and copper levels, and 87% also exhibited signs of early to late neurodegeneration. The p.His1069Gln variant in ATP7B, a prevalent pathogenic mutation, showed a striking four- to five-fold enrichment in Estonians compared with other populations. Based on our analysis of genetic and nationwide health registry data, we estimate that WD remains underdiagnosed and undertreated in Estonia. Our study demonstrates that personalized medicine, implemented with the collaboration of medical professionals, has the potential to reduce the healthcare burden by facilitating the accurate diagnosis of rare genetic diseases. To our knowledge, this report is the first to describe a large-scale national biobank-based study of WD.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142823632","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variants in the AGBL5 gene are responsible for autosomal recessive Retinitis pigmentosa with hearing loss.","authors":"Marianthi Karali, Gema García-García, Karolina Kaminska, Alaa AlTalbishi, Francesca Cancellieri, Francesco Testa, Maria Rosaria Barillari, Evangelia S Panagiotou, George Psillas, Veronika Vaclavik, Viet H Tran, Lucas Janeschitz-Kriegl, Hendrik Pn Scholl, Manar Salameh, Pilar Barberán-Martínez, Ana Rodríguez-Muñoz, Miguel Armengot, Margherita Scarpato, Roberta Zeuli, Mathieu Quinodoz, Francesca Simonelli, Carlo Rivolta, Sandro Banfi, José M Millán","doi":"10.1038/s41431-024-01768-8","DOIUrl":"https://doi.org/10.1038/s41431-024-01768-8","url":null,"abstract":"<p><p>The AGBL5 gene encodes for the Cytoplasmic Carboxypeptidase 5 (CCP5), an α-tubulin deglutamylase that cleaves the γ-carboxyl-linked branching point of glutamylated tubulin. To date, pathogenic variants in AGBL5 have been associated only with isolated retinitis pigmentosa (RP). Hearing loss has not been reported in AGBL5-caused retinal disease. In this study, we performed exome sequencing in probands of eight unrelated families from Italy, Spain, Palestine, Switzerland, and Greece. All subjects had a clinical diagnosis of (suspected) Usher syndrome type II for the concurrent presence of RP and post-verbal sensorineural hearing loss (SNHL) that ranged from mild to moderate.We identified biallelic sequence variants in AGBL5 in all analysed subjects. Four of the identified variants were novel. The variants co-segregated with the retinal and auditory phenotypes in additional affected family members. We did not detect any causative variants in known deafness or Usher syndrome genes that could explain the patients' hearing loss. We therefore conclude that SNHL is a feature of a syndromic presentation of AGBL5 retinopathy. This study provides the first evidence that mutations in AGBL5 can cause syndromic RP forms associated with hearing loss, probably due to dysfunction of sensory cilia in the retina and the inner ear.</p>","PeriodicalId":12016,"journal":{"name":"European Journal of Human Genetics","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}