European journal of medical genetics最新文献

{"title":"Comparison of bilateral tibial lengthening with circular external fixator and simultaneous deformity correction with hexapod external fixator in Achondroplasia","authors":"Maria Beatrice Bocchi PhDs ,&nbsp;Osvaldo Palmacci ,&nbsp;Raffaele Vitiello PhD ,&nbsp;Cristina Giuli ,&nbsp;Antonio Ziranu PhD ,&nbsp;Giulio Maccauro Prof","doi":"10.1016/j.ejmg.2025.105017","DOIUrl":"10.1016/j.ejmg.2025.105017","url":null,"abstract":"<div><div>Achondroplasia is a growth plate dysplasia caused by FGFR-3 gene mutation. In addition to dysmorphic short stature, genu varum is very common. Therefore, a certain part of the achondroplasic population is interested in extensive cosmetic limb lengthening and deformity correction to achieve a functional height so that they can attain total autonomy in everyday life. All patients who underwent bone lengthening treatment from March 2014 to December 2022, were retrospectively analyzed in terms of inclusion and exclusion criteria. To determine any angular deformity in the coronal plane, the Mechanical Axis Deviation was calculated. Patients were divided into two groups: group A included patients who had no angular deformity and therefore performed exclusively cosmetic bilateral tibial lengthening, group B included patients undergoing cosmetic lengthening and simultaneous bilateral multiplanar correction of tibial deformities with hexapod external fixator. The achieved distraction, the external fixator index and the consolidation index were calculated and compared for the two groups. Any adverse event was recorded. According to inclusion and exclusion criteria, 14 patients (28 tibias) diagnosed with Achondroplasia were included (20 tibias group A and 8 tibias group B). We found a statistically significant difference between the two groups regarding the mean age at the time of surgery (p 0.01). The mean MAD value within group B showed a substantial improvement from 56.50 ± 19.1 mm to 14.6 ± 5 mm. Comparing the two groups, we observed a statistically significant difference between both preoperative (p 0.0001) and postoperative (p 0.006) MAD values. The difference found between the two groups was significant also in terms of mean external fixator index (35.9 days/cm versus 52.5 days/cm) and consolidation index (24.2 days/cm versus 37.9 days/cm). Comparing the adverse events found in the two groups no significant differences emerged (p 0.7). In the context of cosmetic lower limb lengthening program for achondroplasic patients, most studies have focused on linear lengthening often underestimating the importance of any associated deformities correction. In our experience, the genu varum correction with the hexapod system showed relevant results in term of MAD improvement. Our results show a significant difference between the two groups in consolidation (p 0.002) and thus also in external fixation (p 0.001) time to the disadvantage of the hexapod group probably due to: higher age (p 0.01) with lower healing potential, greater difficulty in weightbearing and in dynamizing the fixator.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105017"},"PeriodicalIF":1.6,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143922086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic delays in rare genetic disorders with neuropsychiatric manifestations: A systematic review","authors":"Isaac J. Siegel ,&nbsp;Sarah L. Vaithilingam ,&nbsp;Madeline M. Hartig ,&nbsp;Ella C. Patty ,&nbsp;Lily E. Mantsch ,&nbsp;Sheldon R. Garrison","doi":"10.1016/j.ejmg.2025.105016","DOIUrl":"10.1016/j.ejmg.2025.105016","url":null,"abstract":"<div><div>A systematic review of case reports, case series, and case-control studies was conducted to quantify the diagnostic delay in 84 rare genetic diseases where neuropsychiatric symptoms may be primary or part of the early clinical presentation. Data abstracted from 1221 published articles encompassing 1838 individual cases revealed a mean diagnostic delay of 9.3 ± 8.7 years, with no significant improvement in time to diagnosis over the 65-year period from 1958 to 2023. Subanalysis of the most recent 10 years, 2014–2023, revealed no change in diagnostic delay, even when stratifying by genetic and other diagnostic tests. Neuropsychiatric symptoms were reported in 68 % of the included cases. Following a definitive diagnosis and optimized management of the underlying rare genetic disease, 66 % of individuals experienced an improvement in their neuropsychiatric symptoms. Despite increasing access to, and substantial advancement in, genetic and other testing, diagnostic delays remain lengthy for individuals affected by these rare genetic diseases. This often results in suboptimal management of the associated neuropsychiatric symptoms. Thus, earlier implementation of genetic testing and other diagnostic tools may reduce these delays, improving patient outcomes and alleviating the burden of diagnostic uncertainty.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105016"},"PeriodicalIF":1.6,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143863320","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluating parental satisfaction and empowerment with genetic testing in the Neonatal Intensive Care Unit (NICU)","authors":"Sunu Kim ,&nbsp;Horacio Osiovich ,&nbsp;Sylvie Langlois ,&nbsp;Alice Virani ,&nbsp;Ye Shen ,&nbsp;GenCOUNSEL Study ,&nbsp;Alison M. Elliott","doi":"10.1016/j.ejmg.2025.105014","DOIUrl":"10.1016/j.ejmg.2025.105014","url":null,"abstract":"<div><div>Genetic disorders are highly represented in the neonatal intensive care unit (NICU). Genetic testing (in particular rapid genome-wide sequencing) has transformed the ability to diagnose and manage these infants. The NICU is a place of stress and overwhelm for parents and implementing genetic testing can pose additional challenges, including anxiety. There is a critical gap in knowledge related to parents’ empowerment and satisfaction with the NICU experience for those undergoing genetic testing. The goal of this mixed-methods study was to identify the key contributing factors related to empowerment and areas for improvement in care of parents undergoing genetic testing in the NICU by using validated tools that have not been previously implemented in Canada. A demographic survey and validated online survey tools were distributed to eligible parents. Descriptive statistics and linear regression analysis were performed. We conducted semi-structured interviews to gain insight into the genetic testing experience. The transcribed interviews were analyzed using an interpretive description framework and thematic analysis. A total of 31 surveys and 17 interviews were completed. We have identified self-reported demographic predictors of decreased satisfaction and empowerment for parents, including high income, English-speaking, ethnicity, sex of the parent, prematurity of the newborn, and length of hospital stay. Emerging themes from interviews fall under the broad category of communication and include information, logistics, parental perspective, and support. Subthemes include expectations and delivery of information, attention to timing and organization, comprehensive support, and parental distress and expectations when ordering genetic testing. The findings suggest the need for systematic improvement of the current genetic testing process in NICUs.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105014"},"PeriodicalIF":1.6,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial inheritance of 14q terminal deletion syndrome and review of the literature","authors":"Krista M. Vincent ,&nbsp;Bradley Prince ,&nbsp;Jean McGowan-Jordan ,&nbsp;Melissa T. Carter","doi":"10.1016/j.ejmg.2025.105015","DOIUrl":"10.1016/j.ejmg.2025.105015","url":null,"abstract":"<div><div>Terminal deletions of chromosome 14q are characterized by a spectrum of phenotypes that can include microcephaly, growth deficiency, intellectual disability, characteristic facial features, and various congenital anomalies. The rarity of this syndrome, together with the broad spectrum of phenotypes, has made genotype-phenotype correlations difficult. Herein, we describe a family with the core features of the condition and a heterozygous 3.7 Mb deletion at 14q32.32qter. To our knowledge, this is the first case of vertical transmission of a terminal 14q deletion. In addition to this family, we review 19 previously reported individuals. Additional descriptions of individuals with terminal 14q deletions will help to fully characterize the phenotypic spectrum and define the natural history of this condition.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105015"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779383","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A rare triplication of 16p11.2: Unravelling the genomic complexity and review of the literature","authors":"Liselot van der Laan ,&nbsp;Lotte Kleinendorst ,&nbsp;Martin A. Haagmans ,&nbsp;Laura Roquas ,&nbsp;Jasper J. van der Smagt ,&nbsp;Klaas Koop ,&nbsp;Peter Henneman ,&nbsp;Mieke M. van Haelst","doi":"10.1016/j.ejmg.2025.105013","DOIUrl":"10.1016/j.ejmg.2025.105013","url":null,"abstract":"<div><div>16p11.2 triplication is a rare chromosomal disorder associated with developmental delay, behavioral abnormalities, and various dysmorphic features. Here, we present a case study of a four-year-old girl with 16p11.2 triplication, whose healthy father has a smaller 16p11.2 duplication that partially overlaps with that of the daughter. She has a global developmental delay, autism spectrum disorder, anxiety, and sensory processing issues, alongside dysmorphic features. Genetic analysis revealed triplication within the 16p11.2 duplication region. We used different technical approaches to pinpoint the exact genetic architecture of the triplication and to gain further functional insights. Using array-CGH and Fluorescence In Situ Hybridization (FISH), we detected the location of the triplication. We later sought to confirm this with Oxford Nanopore Technologies (ONT); however, detecting duplications and triplications proved to be challenging. Finally, RNA sequencing showed overexpression of genes within the triplication region, including <em>INO80E, PAGR1, SPN, KIF22, HIRIP3, TAOK2, and TMEM219</em>, some of which had been associated with neurodevelopmental disorders and/or increased body mass index by GWAS (1). Our findings contribute to the understanding of the phenotypic spectrum and molecular mechanisms of 16p11.2 triplication. Moreover, the challenges in detecting triplications using current sequencing methods highlight the need for improved diagnostic techniques.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105013"},"PeriodicalIF":1.6,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777222","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":"Lack of behavioural improvement with sirolimus in a patient with MTOR-related macrocephaly with pigmentary mosaicism: A new case report","authors":"Bertille Bonniaud ,&nbsp;Maxime Luu ,&nbsp;Coline Cormier ,&nbsp;Caroline Racine ,&nbsp;Aurélie Espitalier ,&nbsp;Charlotte Malbranche ,&nbsp;Adélaïde Rega ,&nbsp;Théo Gaumet ,&nbsp;Paul Kuentz ,&nbsp;Pierre Vabres ,&nbsp;Christel Thauvin-Robinet ,&nbsp;Marc Bardou ,&nbsp;Sébastien Gay ,&nbsp;Laurence Faivre ,&nbsp;Julian Delanne","doi":"10.1016/j.ejmg.2025.105012","DOIUrl":"10.1016/j.ejmg.2025.105012","url":null,"abstract":"<div><div>Postzygotic activating <em>MTOR</em> variants result in neurocutaneous mosaic phenotypes including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism (hypomelanosis of Ito), whereas germline activating variants cause Smith-Kinsgmore syndrome. The <em>MTOR</em> gene encodes the mechanistic target of rapamycin (mTOR), which is a core component of the PI3K-AKT-mTOR signaling pathway. As rapamycin downregulates the increased activity caused by the mosaic mTOR variant, it may result in improvement of clinical outcomes, as shown for refractory epilepsy in tuberous sclerosis, another genetic disease of the mTOR pathway. However, results of treatment have been reported in only three genotyped patients so far, one with pigmentary mosaicism, megalencephaly and epilepsy, and two with focal cortical dysplasia, with conflicting results. Here we report on a 12-year-old male patient with megalencephaly-pigmentary mosaicism and a mTOR mosaic gain-of-function variant (p.(Ser2413Ile)) in 23 % of affected skin cells, who received compassionate off-label sirolimus for severe behavioural disorder. Sirolimus was initiated at 1.3 mg twice a day with regular blood monitoring. After a 6-months period, no improvement was observed, neither on family environment-reported outcomes nor on neuropsychology scales, leading to treatment discontinuation. Despite physiopathological rationale, case reports have failed so far to suggest efficacy on the outcomes studied, which questioned the implementation of clinical trials.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105012"},"PeriodicalIF":1.6,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143700053","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":"Identifying patients with neurofibromatosis type 1 related optic pathway glioma using the OMOP CDM","authors":"Britt A.E. Dhaenens ,&nbsp;Maxim Moinat ,&nbsp;Eva-Maria Didden ,&nbsp;Nadir Ammour ,&nbsp;Rianne Oostenbrink ,&nbsp;Peter Rijnbeek","doi":"10.1016/j.ejmg.2025.105011","DOIUrl":"10.1016/j.ejmg.2025.105011","url":null,"abstract":"<div><div>Neurofibromatosis type 1 (NF1) is a rare tumour predisposition syndrome. Optic pathway gliomas (NF1-related OPG) are a well-characterised tumour type. There is great need for tools that can efficiently identify patients with NF1-related OPG at hospitals. Computable phenotypes algorithms can be used to find patients with certain clinical features in an electronic database. We developed computable phenotype algorithms using the Observational Medical Outcome Partnership (OMOP) Common Data Model. We subsequently assessed if these algorithms could identify patients with NF1-related OPG in an electronic health records (EHR) derived database. We created phenotype algorithms based on diagnosis codes, visits, and radiologic procedures. These phenotypes were applied to the EHR-derived database of an academic hospital. To assess the performance of the phenotypes, we calculated the precision, recall, and F2 score against a list of known cases (<em>n</em> = 61), provided by a clinician. To evaluate the ability of the phenotypes to identify additional cases, we manually reviewed the predicted positives of each phenotype algorithm. The phenotype algorithm based on the diagnosis codes ‘Neurofibromatosis syndrome’ and ‘Neoplasm of optic nerve’ performed best (precision = 1.000, recall = 0.614, F2-score = 0.665). The phenotype ‘Neurofibromatosis syndrome and three or more Ophthalmology visits and one or more MRI of brain’ performed best of the phenotypes based on visits and radiologic procedures (precision = 0.489, recall = 0.511, F2-score = 0.507). Generally, increased precision came at the cost of a decrease in recall. Following review of the predicted positives of each phenotype, 27 additional cases were identified. OMOP computable phenotype algorithms successfully identified NF1-related OPG patients in an EHR-derived database. They provided swift insight into the number of NF1-related OPG cases and were able to identify additional cases, which were not included in the original list of known cases. Phenotype algorithms created with OMOP could be an invaluable tool to facilitate patient screening, especially in multi-centric trials for rare diseases.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105011"},"PeriodicalIF":1.6,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143663028","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":"The craniofacial, dental and systemic manifestations of Enamel Renal Syndrome: A Scoping review","authors":"Imaan Amina Roomaney,&nbsp;Salma Kabbashi,&nbsp;Manogari Chetty","doi":"10.1016/j.ejmg.2025.105008","DOIUrl":"10.1016/j.ejmg.2025.105008","url":null,"abstract":"<div><h3>Introduction</h3><div>Enamel Renal Syndrome (ERS) (OMIM 204690) is a rare genetic condition characterised by a distinct oral profile and sometimes nephrocalcinosis. This autosomal recessive condition, caused by pathogenic variants in the <em>FAM20A</em> gene, is linked to ectopic mineralisation in tissues such as dental pulp, follicles, gingiva, and kidneys. Although the oral phenotype has been well-characterised, less common features have been described, highlighting possible gaps in the literature on the phenotypic variability of the condition.</div></div><div><h3>Methods</h3><div>This scoping review follows PRISMA-ScR guidelines and aimed to synthesise existing literature on ERS, focusing on clinical and radiographic features, oral histology, systemic manifestations, and molecular findings. A comprehensive search was conducted in multiple databases, with inclusion criteria broad enough to capture relevant studies under various nomenclatures. The screening process involved independent review and data extraction with a custom tool.</div></div><div><h3>Results</h3><div>The initial search yielded 430 references, supplemented by additional publications identified through Google Scholar and citation searching. After removing duplicates and resolving inter-rater discrepancies, 62 studies were included, encompassing a diverse global sample. Publications spanned from the first report in 1972 to recent studies in 2024. The included studies highlight the characteristic oral profile of ERS and less consistently reported renal manifestations<strong>.</strong> While the pathognomonic oral profile remains consistent, long-term studies are required to fully understand renal and systemic impacts. Current management strategies are patient-specific, with a need for standardised reporting and long-term follow-up to develop evidence-based guidelines. Until more comprehensive data is available, vigilant monitoring of kidney function in ERS patients remains essential.</div></div><div><h3>Conclusion</h3><div>This review confirms that ERS presents with a distinct oral and dental profile. However, inconsistencies in the reporting of craniofacial, renal, and other systemic features were noted. To improve patient care, further research is essential to better understand the systemic implications and long-term outcomes of ERS. This will support the development of evidence-based guidelines and foster a more holistic approach to managing the condition.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105008"},"PeriodicalIF":1.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633751","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":"Isolated congenital vertebral anomaly and Sprengel's deformity in a WBP11 pathogenic variant","authors":"Bo Kyung Shin ,&nbsp;Jaewon Kim ,&nbsp;Myung Shin Kim ,&nbsp;Dae-Hyun Jang","doi":"10.1016/j.ejmg.2025.105010","DOIUrl":"10.1016/j.ejmg.2025.105010","url":null,"abstract":"<div><div>The pathogenic variant of <em>WBP11</em> has been known as one of the various genetic causes of VACTERL syndrome. VACTERL syndrome is usually diagnosed with at least three clinical features of vertebral, heart, tracheal, esophageal, kidney, and limb anomalies. So far, only four <em>WBP11</em> pathogenic variants have been documented from 13 patients, first and latest described in 2020. In this clinical report, we present a patient with an isolated vertebral anomaly and Sprengel's deformity, carrying a pathogenic variant of <em>WBP11</em>, representing a distinctive case of patient that has never been described before. An eight-month-old boy with a 5°–10° head tilt to the right was referred to our institution and the cervical X-ray imaging showed the vertebral anomaly. Three-dimensional (3D) volume-rendered computed tomography (CT) of the cervical spine revealed the fusion state of the right C2 and C3 facet joints. And the right shoulder appeared to be raised and right scapula elevation was identified in the 3D chest CT. In addition, whole genome sequencing presented a <em>de novo</em> novel <em>WBP11</em> heterozygous pathogenic variant, with frameshift resulting in a loss of function. <em>WBP11</em> is a cell cycle-related pleiotropic gene that encodes a pre-messenger RNA splicing factor involved in centriole duplication. Pathogenic variants in <em>WBP11</em> are genetically implicated in the development of multiple congenital anomalies. Clinically, <em>WBP11</em> has been previously associated with VACTERL syndrome. In this report, we document clinical manifestations, including vertebral anomalies and Sprengel's deformity. The findings presented in this report indicate that haploinsufficiency of <em>WBP11</em>, resulting from a heterozygous pathogenic variant, may give rise to a more diverse array of clinical phenotypes than previously documented.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105010"},"PeriodicalIF":1.6,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633834","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":"Paracentric inversion disrupting the SHANK2 gene","authors":"Jolien Huyghebaert ,&nbsp;Bregje Christiaenssen ,&nbsp;Marjan De Rademaeker ,&nbsp;Jenneke Van den Ende ,&nbsp;Geert Vandeweyer ,&nbsp;R. Frank Kooy ,&nbsp;Ligia Mateiu ,&nbsp;Dale Annear","doi":"10.1016/j.ejmg.2025.105009","DOIUrl":"10.1016/j.ejmg.2025.105009","url":null,"abstract":"<div><div>In this study, we employed a multifaceted approach combining short-read whole genome sequencing (WGS) analyzed using Delly, cytogenomics using Bionano technology, and Sanger sequencing to identify the breakpoints of a balanced de novo paracentric inversion on chromosome 11, spanning approximately 64 Mb (inv11q13.3; q25). This inversion was discovered in a girl who presented with mild intellectual disability (ID), speech and language delays, a delay in motor development and attention deficit hyperactivity disorder (ADHD). Detailed analysis of the breakpoints revealed the disruption of two genes; <em>SHANK2</em>, which is critical for encoding a postsynaptic scaffolding protein at glutamatergic synapses in the brain, and <em>LINC02714</em>, a long non-coding RNA (lncRNA). Although <em>SHANK2</em> is not listed in the OMIM database as a causative gene to this date, literature reports at least 21 cases where (likely) pathogenic variants in <em>SHANK2</em> have been identified in patients with neurodevelopmental disorders (NDDs). A loss of function variant of the <em>SHANK2</em> gene is in line with the clinical presentation of this patient. No additional genetic variants that could explain her phenotype were identified. In conclusion, by combining WGS, cytogenomics and Sanger sequencing techniques, we identified the exact breakpoints of a large inversion providing a likely molecular diagnosis for our patient.</div></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"75 ","pages":"Article 105009"},"PeriodicalIF":1.6,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143584206","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}