European journal of medical genetics最新文献

{"title":"A spectrum of TP63-related disorders with eight affected individuals in five unrelated families","authors":"Merve Soğukpınar,&nbsp;Gülen Eda Utine,&nbsp;Koray Boduroğlu,&nbsp;Pelin Özlem Şimşek-Kiper","doi":"10.1016/j.ejmg.2024.104911","DOIUrl":"10.1016/j.ejmg.2024.104911","url":null,"abstract":"<div><p><em>TP63</em>-related disdorders broadly involve varying combinations of ectodermal dysplasia (sparse hair, hypohydrosis, tooth abnormalities, nail dysplasia), cleft lip/palate, acromelic malformation, split-hand/foot malformation/syndactyly, ankyloblepharon filiforme adnatum, lacrimal duct obstruction, hypopigmentation, and hypoplastic breasts and/or nipples. <em>TP63</em>-related disorders are associated with heterozygous pathogenic variants in <em>TP63</em> and include seven overlapping phenotypes; Ankyloblepharon‐ectodermal defects‐cleft lip/palate syndrome (AEC), Ectrodactyly‐ectodermal dysplasia‐cleft lip/palate syndrome 3 (EEC3), Limb‐mammary syndrome (LMS), Acro‐dermo‐ungual‐lacrimal‐tooth syndrome (ADULT), Rapp–Hodgkin syndrome (RHS), Split-hand/foot malformation 4 (SHFM4), and Orofacial cleft 8. We report on five unrelated families with 8 affected individuals in which the probands presented with varying combinations of ectodermal dysplasia, cleft lip/palate, split-hand/foot malformation, lacrimal duct obstruction, and ankyloblepharon filiforme adnatum. The clinical diagnosis involved AEC syndrome (2 patients), EEC3 syndrome (2 patients), and a yet hitherto unclassified <em>TP63</em>-related disorder. Sanger sequence analysis of the <em>TP63</em> gene was performed revealing five different variants among which four were novel and three were <em>de novo.</em> The identificated <em>TP63</em> variants co-segregated with the other affected individuals in the families. The abnormalities of ectoderm derived structures including hair, nails, sweat glands, and teeth should alert the physician to the possibility of <em>TP63</em>-related disorders particularly in the presence of orofacial clefting.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104911"},"PeriodicalIF":1.9,"publicationDate":"2024-01-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400003X/pdfft?md5=1b05fa487a519837a704213e6b552006&pid=1-s2.0-S176972122400003X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139570133","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":"Lenz-Majewski syndrome and recurrent otitis media: Are they related or not?","authors":"Fayize Maden Bedel ,&nbsp;Özgür Balasar ,&nbsp;Selma Erol Aytekin ,&nbsp;Sevgi Keleş ,&nbsp;Hüseyin Çaksen","doi":"10.1016/j.ejmg.2024.104910","DOIUrl":"10.1016/j.ejmg.2024.104910","url":null,"abstract":"<div><p>Lenz-Majewski hyperostotic dwarfism (LMHD) is a rare condition characterized by intellectual disability, sclerosing bone dysplasia, dysmorphic facial features, brachydactyly, symphalangism and cutis laxa. Nineteen cases have been reported in the literature so far, eleven of them with PTDSS1 mutations. Although studies have had clinically similar findings, in some cases the authors have reported even rarer features such as hydrocephalus, facial paralysis, and cleft palate. We, hereby, report the case of the first patient with Lenz-Majewski syndrome (LMS) with molecular confirmation from Turkey. Although our patient had characteristic features described in the literature, she also had immunodeficiency, which has not been reported before. Although there is no established phenotype-genotype correlation, molecular mechanisms can be explained with the reporting of more patients.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"68 ","pages":"Article 104910"},"PeriodicalIF":1.9,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000028/pdfft?md5=49b8a7221ddf184aa42f6309d71eec82&pid=1-s2.0-S1769721224000028-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139516355","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":"Evaluating ClinGen variant curation expert panels' application of PVS1 code","authors":"Xiaoyan Wang ,&nbsp;Haibo Li ,&nbsp;Haiyan Luo ,&nbsp;Yongyi Zou ,&nbsp;Haoxian Li ,&nbsp;Yayun Qin ,&nbsp;Jieping Song","doi":"10.1016/j.ejmg.2024.104909","DOIUrl":"10.1016/j.ejmg.2024.104909","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;The 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines articulates that the effects of certain types of variants on gene function can often be seen as a complete absence of the gene product by leading to a lack of transcription or nonsense-mediated decay(NMD). However, detailed information considering different types of loss of function(LOF) variants, refined steps assimilating details concerning location of variant, changes in strength levels, NMD boundary, or any additional information pointing to a true null effect, were all left to expert judgement. As part of its Clinical Genome Resource (ClinGen) initiative, Variant Curation Expert Panels (VCEPs) are designated to make gene/disease-centric specifications in accordance with the ACMG/AMP guidelines, including a more detailed definition of what constitutes an appropriate LOF evidence. Our goal was to evaluate the current LOF guidelines developed by the VCEPs and analyse the prior curated variants concerning the PVS1 criteria, bringing people occupied in genetic data analysis a comprehensive understanding of this code.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Our study evaluated 7 VCEPs for their LOF criteria (PVS1). Subsequently, we assessed the predictive criteria by considering the underlying disease mechanism, protein transcript, and variant types delineated. Then, we meticulously curated the LOF evidence referenced by each VCEP in their preliminary variant classification, thereby scrutinizing the recommendations put forth by VCEPs and their application in the interpretation of the aforementioned predictive criteria. Based on these, an extensive curation of evidence summary considering PVS1 applied by VCEPs according to their classification of pilot variants for the purpose of analyzing VCEP criteria specifications and their use in the understanding of LOF was conducted.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;We observed in this article that the VCEPs discussed followed the majority of Sequence Variant Interpretation (SVI) recommendations concerning the application of this LOF criteria, except for some disease/gene specific considerations. We highlighted the wide range of PVS1 strength levels approved by VCEP, reflecting the diversity of evidence for each variants type. In addition, we observed substantial differences in the approach used to determine relative strengths for different types of null variants and in the attitude towards these principles concerning variant location, NMD and influence to protein function between VCEPs.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;It is difficult to understand the intricacies of the predictive data(PVS1), which often requires expert-level knowledge of disease/gene. The VCEP criteria specifications for the predictive evidence play an important role in making it more accessible for the curators to apply the predictive data by providing details concerning this complex criteria.","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104909"},"PeriodicalIF":1.9,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000016/pdfft?md5=073ce930fed3d21be8e878635cf9bc57&pid=1-s2.0-S1769721224000016-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139398026","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 VASCERN PPL working group patient pathway for primary and paediatric lymphoedema","authors":"Nele Devoogdt ,&nbsp;Sarah Thomis ,&nbsp;Florence Belva ,&nbsp;Janine Dickinson-Blok ,&nbsp;Caroline Fourgeaud ,&nbsp;Guido Giacalone ,&nbsp;Tonny Karlsmark ,&nbsp;Heli Kavola ,&nbsp;Vaughan Keeley ,&nbsp;Manuela Lourenço Marques ,&nbsp;Sahar Mansour ,&nbsp;Christoffer V. Nissen ,&nbsp;Susan Nørregaard ,&nbsp;Michael Oberlin ,&nbsp;Tanja Planinšek Ručigaj ,&nbsp;Gloria Somalo-Barranco ,&nbsp;Sinikka Suominen ,&nbsp;Kirsten Van Duinen ,&nbsp;Stéphane Vignes ,&nbsp;Robert Damstra","doi":"10.1016/j.ejmg.2023.104905","DOIUrl":"10.1016/j.ejmg.2023.104905","url":null,"abstract":"<div><p>Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104905"},"PeriodicalIF":1.9,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721223002112/pdfft?md5=26bf0e7644055740993c78cb96f919da&pid=1-s2.0-S1769721223002112-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139018013","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":"Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: clinical report and review of the literature","authors":"Alice Moroni ,&nbsp;Evelise Brizola ,&nbsp;Alessia Di Cecco ,&nbsp;Morena Tremosini ,&nbsp;Marta Sergiampietri ,&nbsp;Alberto Bianchi ,&nbsp;Barbara Tappino ,&nbsp;Maria Piana ,&nbsp;Maria Gnoli","doi":"10.1016/j.ejmg.2023.104904","DOIUrl":"10.1016/j.ejmg.2023.104904","url":null,"abstract":"<div><p>Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in <em>CTSK</em> gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing.</p><p>We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of <em>CTSK</em> gene revealed the presence of the pathogenic homozygous variant c.746T&gt;A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis.</p><p>We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature.</p><p>This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104904"},"PeriodicalIF":1.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721223002100/pdfft?md5=4931d6fea0917ee049aae0c1b766e538&pid=1-s2.0-S1769721223002100-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139024693","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":"Genetic counselling supervision: Luxury or necessity? A qualitative study with genetic healthcare professionals in Portugal","authors":"Lídia Guimarães ,&nbsp;Ruxanda Baião ,&nbsp;Catarina Costa ,&nbsp;Marina Lemos ,&nbsp;Margarida Rangel Henriques ,&nbsp;Milena Paneque","doi":"10.1016/j.ejmg.2023.104908","DOIUrl":"10.1016/j.ejmg.2023.104908","url":null,"abstract":"<div><p>In recent years, there has been a significant technological evolution in the field of genetics, leading to an increase in the number of professionals working in medical genetics and, consequently, a tremendous growth in genetic counselling. At the same time, there has been a growing recognition of the parameters on which to base a safe practice, not only regarding the technical skills of the professional but also regarding their counselling skills, including relational and empathy skills and the acknowledgement of the emotional impact that genetic counselling practice can have. However, despite this growing knowledge, there are still significant differences between the various European countries, and one area where this discrepancy is particularly evident is genetic counselling supervision. Thus, if there are countries where genetic counselling supervision is not even known by the professionals, there are others where it is mandatory for practice. This research had as an objective to understand if and how genetic counselling supervision is provided in Portugal, to identify routines, challenges and impacts of genetic counselling that should be explored in a supervision process and comprehend how professionals believe supervision should be conducted to be effective. A total of sixteen medical geneticists from main Portuguese genetic services were present in two online focus groups. None of the participants had access to genetic counselling supervision as a programmed routine and there was a consensus that a service of this kind would be particularly important for the professionals as genetic counselling has frequently challenging and emotional moments. Aspects regarding clinical supervision, the characteristics of the supervisor and the practical aspects of genetic counselling supervision implementation were also mentioned during the discussions. These results highlight the relevancy of the establishment of GC supervision routines and standardized guidelines in our country, as well as a need for evidence-based research focused on its impact at professional and practice level.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104908"},"PeriodicalIF":1.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721223002148/pdfft?md5=1f08425c6556ac7b74ad673a8246d504&pid=1-s2.0-S1769721223002148-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139017868","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":"Fetal hepatic calcification in severe KAT6A (Arboleda-Tham) syndrome","authors":"Antonella Di Caprio, Cecilia Rossi, Emma Bertucci, Luca Bedetti, Natascia Bertoncelli, Francesca Miselli, Lucia Corso, Carolina Bondi, Lorenzo Iughetti, Alberto Berardi, Licia Lugli","doi":"10.1016/j.ejmg.2023.104906","DOIUrl":"https://doi.org/10.1016/j.ejmg.2023.104906","url":null,"abstract":"<p>Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (<em>KAT6A</em>) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of <em>KAT6A</em> syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach.</p><p>In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift <em>KAT6A</em> pathogenic variant, displaying a severe phenotype with previously unreported clinical features.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"54 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139018312","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":"Pathological mandibular fracture complicated by osteonecrosis in an adult patient with pycnodysostosis: Clinical report and review of the literature","authors":"Alice Moroni, Evelise Brizola, Alessia Di Cecco, Morena Tremosini, Marta Sergiampietri, Alberto Bianchi, Barbara Tappino, Maria Piana, Maria Gnoli","doi":"10.1016/j.ejmg.2023.104904","DOIUrl":"https://doi.org/10.1016/j.ejmg.2023.104904","url":null,"abstract":"<p>Pycnodysostosis is an ultra-rare osteosclerotic skeletal disorder characterized by short stature, susceptibly to fractures, acroosteolysis of the distal phalanges, and craniofacial features (frontal bossing, prominent nose, obtuse mandibular angle, micrognathia). Dental abnormalities (delayed eruption of teeth, hypodontia, malocclusion, dental crowding, persistence of deciduous teeth, enamel hypoplasia, and increased caries) are also frequent; due to bone metabolism alteration, the patients have an increased risk for jaw osteomyelitis, especially after tooth extraction or mandible fracture. Other complications are obstructive sleep apnea, endocrine alterations and cytopenia. Pycnodysostosis is caused by biallelic loss of function variants in <em>CTSK</em> gene, coding the lysosomal protease cathepsin K. CTSK is involved in the degradation of bone matrix proteins, such as type I and type II collagen. In pycnodysostosis, this degradation is decreased, leading to increased bone density and bone fragility with pathological fractures and poor healing.</p><p>We present a clinical report of a female adult patient with typical pycnodysostosis phenotype. At the age of 52 years, she had a pathological spontaneous fracture of the right mandible complicated by osteonecrosis, treated with load bearing osteosynthesis. The direct sequencing of <em>CTSK</em> gene revealed the presence of the pathogenic homozygous variant c.746 T &gt; A, (p.Ile249Asn), that confirmed the diagnosis of pycnodysostosis.</p><p>We also review the literature case series published to date, that suggest to always consider the diagnosis of pycnodysostosis in case of osteosclerosis, even in the absence of brachydactyly or short stature.</p><p>This report details the natural history of the disease in this patient, from childhood to adulthood, and highlights the importance of a quality of life assessment. In addition, we describe a case of mandibular osteonecrosis and spontaneous fracture in pycnodysostosis, drawing attention on the maxillofacial complications in these patients and on the importance of a personalized follow-up.</p>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"9 1","pages":""},"PeriodicalIF":1.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139018016","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":"Fetal hepatic calcification in severe KAT6A (Arboleda-Tham) syndrome","authors":"Antonella Di Caprio ,&nbsp;Cecilia Rossi ,&nbsp;Emma Bertucci ,&nbsp;Luca Bedetti ,&nbsp;Natascia Bertoncelli ,&nbsp;Francesca Miselli ,&nbsp;Lucia Corso ,&nbsp;Carolina Bondi ,&nbsp;Lorenzo Iughetti ,&nbsp;Alberto Berardi ,&nbsp;Licia Lugli","doi":"10.1016/j.ejmg.2023.104906","DOIUrl":"10.1016/j.ejmg.2023.104906","url":null,"abstract":"<div><p>Arboleda-Tham syndrome (ARTHS, MIM 616268) is a rare genetic disease, due to a pathogenic variant of Lysine (K) Acetyltransferase 6A (<em>KAT6A</em>) with autosomal dominant inheritance. Firstly described in 2015, ARTHS is one of the more common causes of undiagnosed syndromic intellectual disability. Due to extreme phenotypic variability, ARTHS clinical diagnosis is challenging, mostly at early stage of the disease. Moreover, because of the wide and unspecific spectrum of ARTHS, identification of the syndrome during prenatal life rarely occurs. Therefore, reported cases of <em>KAT6A</em> syndrome have been identified primarily through clinical or research exome sequencing in a gene-centric approach.</p><p>In order to expands the genotypic and phenotypic spectrum of ARTHS, we describe prenatal and postnatal findings in a patient with a novel frameshift <em>KAT6A</em> pathogenic variant, displaying a severe phenotype with previously unreported clinical features.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104906"},"PeriodicalIF":1.9,"publicationDate":"2023-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721223002124/pdfft?md5=4e32d8a31f826a15255c7f3521c22167&pid=1-s2.0-S1769721223002124-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139015711","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":"Deep intronic variant causes aberrant splicing of ATP7A in a family with a variable occipital horn syndrome phenotype","authors":"J. Robert Harkness ,&nbsp;Huw B. Thomas ,&nbsp;Jill E. Urquhart ,&nbsp;Peter Jamieson ,&nbsp;Genomics England Research Consortium,&nbsp;Raymond T. O'Keefe ,&nbsp;Helen M. Kingston ,&nbsp;Charulata Deshpande ,&nbsp;William G. Newman","doi":"10.1016/j.ejmg.2023.104907","DOIUrl":"10.1016/j.ejmg.2023.104907","url":null,"abstract":"<div><p>Genetic variants in <em>ATP7A</em> are associated with a spectrum of X-linked disorders. In descending order of severity, these are Menkes disease, occipital horn syndrome, and X-linked distal spinal muscular atrophy. After 30 years of diagnostic investigation, we identified a deep intronic <em>ATP7A</em> variant in four males from a family affected to variable degrees by a predominantly skeletal phenotype, featuring bowing of long bones, elbow joints with restricted mobility which dislocate frequently, coarse curly hair, chronic diarrhoea, and motor coordination difficulties. Analysis of whole genome sequencing data from the Genomics England 100,000 Genomes Project following clinical re-evaluation identified a deep intronic <em>ATP7A</em> variant, which was predicted by SpliceAI to have a modest splicing effect. Using a mini-gene splicing assay, we determined that the intronic variant results in aberrant splicing. Sanger sequencing of patient cDNA revealed <em>ATP7A</em> transcripts with exon 5 skipping, or inclusion of a novel intron 4 pseudoexon. In both instances, frameshift leading to premature termination are predicted. Quantification of <em>ATP7A</em> mRNA transcripts using a qPCR assay indicated that the majority of transcripts (86.1 %) have non-canonical splicing, with 68.0 % featuring exon 5 skipping, and 18.1 % featuring the novel pseudoexon. We suggest that the variability of the phenotypes within the affected males results from the stochastic effects of splicing. This deep intronic variant, resulting in aberrant <em>ATP7A</em> splicing, expands the understanding of intronic variation on the <em>ATP7A</em>-related disease spectrum.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"67 ","pages":"Article 104907"},"PeriodicalIF":1.9,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721223002136/pdfft?md5=bb3e0f88d3668032e706f2e7bc170915&pid=1-s2.0-S1769721223002136-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139017995","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}