European journal of medical genetics最新文献

{"title":"Mother and daughter with Kenny-Caffey syndrome: the adult phenotype","authors":"L. Tonelli ,&nbsp;M. Sanchini ,&nbsp;A. Margutti ,&nbsp;B. Buldrini ,&nbsp;A. Superti-Furga ,&nbsp;A. Ferlini ,&nbsp;R. Selvatici ,&nbsp;S. Bigoni","doi":"10.1016/j.ejmg.2024.104943","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104943","url":null,"abstract":"<div><p>Kenny-Caffey Syndrome (KCS) is a genetic syndrome characterized by growth retardation with short stature, cortical thickening and medullary stenosis of long bones, and hypoparathyroidism with hypocalcemia. KCS and the related but more severe condition osteocraniostenosis are determined by monoallelic variants in the <em>FAM111A</em> gene. Here we describe the KCS phenotype resulting from the monoallelic <em>FAM111A</em> variant p.Y511H in a 31-year-old woman and in her 56-year-old mother, who is one of the oldest affected individuals known so far. To our knowledge, it is also one of the few molecularly confirmed cases of a mother-to-child transmission of KCS.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104943"},"PeriodicalIF":1.9,"publicationDate":"2024-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000351/pdfft?md5=315048c346c43b0d74615ecb80217881&pid=1-s2.0-S1769721224000351-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140824137","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":"How many phenotypes for the FBXO11 related disease? Report on a new patient with a tricho-rhino-phalangeal like phenotype","authors":"Andre Mégarbané ,&nbsp;Cybel Mehawej ,&nbsp;Daniel Mahfoud ,&nbsp;Eliane Chouery ,&nbsp;Koenraad Devriendt ,&nbsp;Mariam Hijazi ,&nbsp;Seung W. Ryu ,&nbsp;JiHye Kim ,&nbsp;Alisdair McNeill","doi":"10.1016/j.ejmg.2024.104944","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104944","url":null,"abstract":"<div><p>Here we report the case of a young boy with developmental delay, thin sparse hair, early closure of the anterior fontanel, bilateral choanal atresia, brachyturicephaly; and dysmorphic features closely resembling those seen in trichorhinophalangeal syndrome (TRPS). These features include sparse hair, sparse lateral eyebrows, a bulbous pear shaped nose, a long philtrum, thin lips, small/hypoplastic nails, pes planovalgus; bilateral cone-shaped epiphyses at the proximal 5th phalanx, slender long bones, coxa valga, mild scoliosis, and delayed bone age.</p><p>Given that TRPS had been excluded by a thorough genetic analysis, whole exome sequencing was performed and a heterozygous likely pathogenic variant was identified in the <em>FBXO11</em> gene (NM_001190274.2: c.1781A &gt; G; p. His594Arg), confirming the diagnosis of the newly individualized IDDFBA syndrome: Intellectual Developmental Disorder, dysmorphic Facies, and Behavioral Abnormalities (OMIM# 618,089).</p><p>Our findings further delineate the clinical spectrum linked to <em>FBXO11</em> and highlight the importance of investigating further cases with mutations in this gene to establish a potential genotype-phenotype correlation.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104944"},"PeriodicalIF":1.9,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000363/pdfft?md5=f10415c3c7393a707f92c31d01d7bcdf&pid=1-s2.0-S1769721224000363-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140815820","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":"PRKD1-related telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly syndrome: Case report and review of the literature","authors":"Fiona Leduc ,&nbsp;Thomas Smol ,&nbsp;Benoit Catteau ,&nbsp;Odile Boute ,&nbsp;Florence Petit","doi":"10.1016/j.ejmg.2024.104942","DOIUrl":"10.1016/j.ejmg.2024.104942","url":null,"abstract":"<div><p>Telangiectasia-ectodermal dysplasia-brachydactyly-cardiac anomaly (TEBC) syndrome is a rare autosomal dominant condition, recently linked to the <em>protein kinase D1 (PRKD1)</em> gene. The phenotype of TEBC remains incomplete at this point. Our aim is to improve the characterization of the clinical and molecular aspects of the TEBC syndrome.</p><p>We report on the 8th patient carrying a heterozygous <em>de novo</em> variation of <em>PRKD1</em> c.2134G &gt; A, p. (Val712Met) identified by trio exome sequencing. The proband presents with partial atrioventricular septal defect, brachydactyly, ectodermal dysplasia, telangiectasia that developed in childhood, intellectual disability with microcephaly, multicystic renal dysplasia and moderate hormonal resistance. In view of this 8th description and review of the literature, it appears that neurodevelopmental disorders and microcephaly are frequently associated with <em>PRKD1</em> missense variants, adding to the four main clinical signs described initially in the TEBC syndrome. Further descriptions are required to confirm the observed endocrine and kidney abnormalities. This should contribute to a more comprehensive understanding of the phenotypic spectrum and may help establish genotype-phenotype correlations.</p><p>In the context of genotype-first strategy, accurate patient descriptions are fundamental. Characterization of specific syndromic associations is essential for variant interpretation support and patient follow-up, even in very rare diseases, such as the TEBC syndrome.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104942"},"PeriodicalIF":1.9,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S176972122400034X/pdfft?md5=e519464dc8acb78d9555afe914a6a92d&pid=1-s2.0-S176972122400034X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140793879","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":"From biology to personalized medicine: Recent knowledge in osteosarcoma","authors":"Audrey Mohr ,&nbsp;Maria Eugenia Marques Da Costa ,&nbsp;Olivia Fromigue ,&nbsp;Baptiste Audinot ,&nbsp;Thierno Balde ,&nbsp;Robin Droit ,&nbsp;Samuel Abbou ,&nbsp;Pierre Khneisser ,&nbsp;Pablo Berlanga ,&nbsp;Esperanza Perez ,&nbsp;Antonin Marchais ,&nbsp;Nathalie Gaspar","doi":"10.1016/j.ejmg.2024.104941","DOIUrl":"10.1016/j.ejmg.2024.104941","url":null,"abstract":"<div><p>High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104941"},"PeriodicalIF":1.9,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000338/pdfft?md5=812709253c44588726d53ae2cef05526&pid=1-s2.0-S1769721224000338-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140772795","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":"Characteristic phenotypes of ADH5/ALDH2 deficiency during childhood","authors":"Mio Matsumoto ,&nbsp;Momoko Oyake ,&nbsp;Tomoyo Itonaga ,&nbsp;Miwako Maeda ,&nbsp;Soichi Suenobu ,&nbsp;Daichi Sato ,&nbsp;Yoji Sasahara ,&nbsp;Hiroyuki Mishima ,&nbsp;Koh-Ichiro Yoshiura ,&nbsp;Kenji Ihara","doi":"10.1016/j.ejmg.2024.104939","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104939","url":null,"abstract":"<div><p>ADH5/ALDH2 deficiency is a rare inherited syndrome characterized by short stature, microcephaly, delayed mental development, and hematopoietic dysfunction and has recently been proposed as a disease paradigm. Acute and severe presentations include aplastic anemia, myelodysplastic syndrome, or leukemia, requiring bone marrow transplantation during childhood. Conversely, non-hematological manifestations may exhibit a prolonged and nonspecific clinical trajectory, with growth failure and developmental delay, most of which are often overlooked, particularly in patients with milder symptoms. Here, we describe the clinical course of a girl with a wide spectrum of clinical presentations, including nonspecific hematopoietic disorders, growth retardation, mild developmental delay, amblyopia, hemophagocytic lymphohistiocytosis, and verruca vulgaris, culminating in a genetic diagnosis of AMeD syndrome at 12 years of age. We also summarized the clinical manifestations of previously reported cases of AMeD syndrome. Cumulatively, 13 females and 5 males have been documented, with a cardinal triad of symptoms, aplastic anemia, short stature, and intellectual disability. Additional characteristic observations included pigmentary deposition in approximately half of the cases and skeletal difficulties in one-quarter. We propose that early diagnosis of patients who exhibit relatively mild phenotypes of skin or skeletal lesions is important for managing and improving the quality of life of patients with AMeD syndrome.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104939"},"PeriodicalIF":1.9,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000314/pdfft?md5=e26b39c9d9568c3b7fe5f76fc2751eba&pid=1-s2.0-S1769721224000314-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140552242","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":"Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gapsOn behalf of the European calcified tissue society and ERN BOND","authors":"Thomas Funck-Brentano ,&nbsp;M. Carola Zillikens ,&nbsp;Gavin Clunie ,&nbsp;Heide Siggelkow ,&nbsp;Natasha M. Appelman-Dijkstra ,&nbsp;Martine Cohen-Solal","doi":"10.1016/j.ejmg.2024.104936","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104936","url":null,"abstract":"<div><p>Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene <em>CLCN7</em> encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104936"},"PeriodicalIF":1.9,"publicationDate":"2024-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000284/pdfft?md5=b25a8a93c9f3967f51c7247023844c96&pid=1-s2.0-S1769721224000284-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140543365","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":"First case of Hajdu-Cheney syndrome in Lithuania caused by novel NOTCH2 gene likely pathogenic variant","authors":"Ieva Tėvelytė ,&nbsp;Paulius Bertašius ,&nbsp;Kristina Aleknavičienė ,&nbsp;Rimvydas Jonikas ,&nbsp;Justina Klimaitė ,&nbsp;Edita Jašinskienė ,&nbsp;Rasa Traberg","doi":"10.1016/j.ejmg.2024.104938","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104938","url":null,"abstract":"<div><p>Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the <em>NOTCH2</em> gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of <em>NOTCH2</em> gene c.6449delC, p.(Pro2150LeufsTer5).</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104938"},"PeriodicalIF":1.9,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000302/pdfft?md5=4849b7130208fd760f1e1699068d035c&pid=1-s2.0-S1769721224000302-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140543340","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":"Clinical presentation and genetics of tricho-rhino-phalangeal syndrome (TRPS) type 1: A single-center case series of 15 patients and seven novel TRPS1 variants","authors":"Laura Krogh Herlin ,&nbsp;Morten Krogh Herlin ,&nbsp;Jenny Blechingberg ,&nbsp;Kirsten Rønholt ,&nbsp;Lise Graversen ,&nbsp;Sigrun A.J. Schmidt ,&nbsp;Mette Warming Jørgensen ,&nbsp;Michel Bach Hellfritzsch ,&nbsp;Jannie Dahl Hald ,&nbsp;Signe Sparre Beck-Nielsen ,&nbsp;Hans Gjørup ,&nbsp;Brian Nauheimer Andersen ,&nbsp;Pernille Axél Gregersen ,&nbsp;Mette Sommerlund","doi":"10.1016/j.ejmg.2024.104937","DOIUrl":"https://doi.org/10.1016/j.ejmg.2024.104937","url":null,"abstract":"<div><p>Tricho-rhino-phalangeal syndrome (TRPS) is a rare malformation syndrome characterized by distinctive facial, ectodermal, and skeletal features. TRPS is divided into TRPS type I/III caused by pathogenic variants in <em>TRPS1</em> and TRPS type II caused by contiguous gene deletions also spanning <em>EXT1</em> and <em>RAD21</em>. Due to its rarity, knowledge of the clinical course of TRPS remains limited.</p><p>Therefore, we collected and characterized a case series of 15 TRPS type I patients (median age at diagnosis 15 [interquartile range: 10–18] years, 11 females [73%]) seen at Aarhus University Hospital, Denmark, with a median follow-up period of 10 years. We estimated a minimum point prevalence of 0.5 in 100,000 (95% CI: 0.3–0.8 per 100,000) persons.</p><p>Common craniofacial features included fine and sparse hair with a high anterior hairline, eyebrows with lateral thinning and a thicker medial part, prominent ears, a bulbous nose tip with small nasal alae, a low-hanging, and often wide columella, and a long philtrum with a thin upper vermillion. Specific skeletal features included short stature and deviating and short fingers with cone-shaped epiphyses and shortened metacarpals on radiographs. The most significant morbidity of the cohort was joint complaints, which were reported by all patients, often already before the TRPS diagnosis was established.</p><p>We identified ten different <em>TRPS1</em> variants including both frameshift/nonsense, missense, and splice-site variants, including seven variants not previously reported in the literature. In accordance with previous literature, no genotype-phenotype correlation was identified.</p><p>The clinical trajectories were heterogeneous involving pediatrics, dermatology, orthopedic surgery, clinical genetics, and/or odontology, emphasizing that close multidisciplinary collaboration is essential for early diagnosis of TRPS and to ensure proper and timely patient care and counseling.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104937"},"PeriodicalIF":1.9,"publicationDate":"2024-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000296/pdfft?md5=bd46259febf30bd57bbedec11df65999&pid=1-s2.0-S1769721224000296-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140351336","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":"Genotype-phenotype of autosomal dominant polycystic kidney disease in Malta","authors":"Natalie Ciantar ,&nbsp;Graziella Zahra ,&nbsp;Julian Delicata ,&nbsp;Fiona Sammut ,&nbsp;Jean Calleja-Agius ,&nbsp;Emanuel Farrugia ,&nbsp;Edith Said","doi":"10.1016/j.ejmg.2024.104934","DOIUrl":"10.1016/j.ejmg.2024.104934","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple renal cysts causing kidney enlargement and end-stage renal disease (ESRD) in half the patients by 60 years of age. The aim of the study was to determine the genetic aetiology in Maltese patients clinically diagnosed with ADPKD and correlate the clinical features.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;A total of 60 patients over 18 years of age clinically diagnosed with ADPKD were studied using a customized panel of genes that had sufficient evidence of disease diagnosis using next generation sequencing (NGS). The genes studied were &lt;em&gt;PKD1&lt;/em&gt;, &lt;em&gt;PKD2&lt;/em&gt;, &lt;em&gt;GANAB&lt;/em&gt;, &lt;em&gt;DNAJB11&lt;/em&gt;, &lt;em&gt;PKHD1&lt;/em&gt; and &lt;em&gt;DZIP1L&lt;/em&gt;. Selected variants were confirmed by bidirectional Sanger sequencing with specifically designed primers. Cases where no clinically significant variant was identified by the customized gene panel were then studied by Whole Exome Sequencing (WES). Microsatellite analysis was performed to determine the origin of an identified recurrent variant in the &lt;em&gt;PKD2&lt;/em&gt; gene. Clinical features were studied for statistical correlation with genetic results.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Genetic diagnosis was reached in 49 (82%) of cases studied. Pathogenic/likely pathogenic variants &lt;em&gt;PKD1&lt;/em&gt; and &lt;em&gt;PKD2&lt;/em&gt; gene were found in 25 and in 23 cases respectively. The relative proportion of genetically diagnosed &lt;em&gt;PKD1&lt;/em&gt;:&lt;em&gt;PKD2&lt;/em&gt; cases was 42:38. A pathogenic variant in the &lt;em&gt;GANAB&lt;/em&gt; gene was identified in 1 (2%) case. A potentially significant heterozygous likely pathogenic variant was identified in &lt;em&gt;PKHD1&lt;/em&gt; in 1 (2%) case. Potentially significant variants of uncertain significance were seen in 4 (7%) cases of the study cohort. No variants in &lt;em&gt;DNAJB11&lt;/em&gt; and &lt;em&gt;DZIP1L&lt;/em&gt; were observed. Whole exome sequencing (WES) added the diagnostic yield by 10% over the gene panel analysis. Overall no clinically significant variant was detected in 6 (10%) cases of the study population by a customized gene panel and WES. One recurrent variant the &lt;em&gt;PKD2&lt;/em&gt; c.709+1G &gt; A was observed in 19 (32%) cases. Microsatellite analysis showed that all variant cases shared the same haplotype indicating that their families may have originated from a common ancestor and confirmed it to be a founder variant in the Maltese population.&lt;/p&gt;&lt;p&gt;The rate of decline in eGFR was steeper and progression to ESRD was earlier in cases with &lt;em&gt;PKD1&lt;/em&gt; variants when compared to cases with &lt;em&gt;PKD2&lt;/em&gt; variants. Cases segregating truncating variants in &lt;em&gt;PKD1&lt;/em&gt; showed a significantly earlier onset of ESRD and this was significantly worse in cases with frameshift variants. Overall extrarenal manifestations were commoner in cases segregating truncating variants in &lt;em&gt;PKD1&lt;/em&gt;.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;This study helps to show that a customized gene panel is the first-line method of choice for stu","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104934"},"PeriodicalIF":1.9,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000260/pdfft?md5=70a251f2e08cf605b5c690f8ac0fe66b&pid=1-s2.0-S1769721224000260-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140305245","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":"Penetrance, variable expressivity and monogenic neurodevelopmental disorders","authors":"Servane de Masfrand ,&nbsp;Benjamin Cogné ,&nbsp;Mathilde Nizon ,&nbsp;Wallid Deb ,&nbsp;Alice Goldenberg ,&nbsp;François Lecoquierre ,&nbsp;Gaël Nicolas ,&nbsp;Marie Bournez ,&nbsp;Antonio Vitobello ,&nbsp;Frédéric Tran Mau-Them ,&nbsp;Gwenaël le Guyader ,&nbsp;Frédéric Bilan ,&nbsp;Peter Bauer ,&nbsp;Christiane Zweier ,&nbsp;Juliette Piard ,&nbsp;Laurent Pasquier ,&nbsp;Stéphane Bézieau ,&nbsp;Bénédicte Gerard ,&nbsp;Laurence Faivre ,&nbsp;Pascale Saugier-Veber ,&nbsp;Bertrand Isidor","doi":"10.1016/j.ejmg.2024.104932","DOIUrl":"10.1016/j.ejmg.2024.104932","url":null,"abstract":"<div><h3>Purpose</h3><p>Incomplete penetrance is observed for most monogenic diseases. However, for neurodevelopmental disorders, the interpretation of single and multi-nucleotide variants (SNV/MNVs) is usually based on the paradigm of complete penetrance.</p></div><div><h3>Method</h3><p>From 2020 to 2022, we proposed a collaboration study with the French molecular diagnosis for intellectual disability network. The aim was to recruit families for whom the index case, diagnosed with a neurodevelopmental disorder, was carrying a pathogenic or likely pathogenic variant for an OMIM morbid gene and inherited from an asymptomatic parent. Grandparents were analyzed when available for segregation study.</p></div><div><h3>Results</h3><p>We identified 12 patients affected by a monogenic neurodevelopmental disorder caused by likely pathogenic or pathogenic variant (SNV/MNV) inherited from an asymptomatic parent. These genes were usually associated with <em>de novo</em> variants. The patients carried different variants (1 splice-site variant, 4 nonsense and 7 frameshift) in 11 genes: <em>CAMTA1, MBD5, KMT2C, KMT2E, ZMIZ1, MN1, NDUFB11, CUL3, MED13, ARID2</em> and <em>RERE</em>. Grandparents have been tested in 6 families, and each time the variant was confirmed <em>de novo</em> in the healthy carrier parent.</p></div><div><h3>Conclusion</h3><p>Incomplete penetrance for SNV and MNV in neurodevelopmental disorders might be more frequent than previously thought. This point is crucial to consider for interpretation of variants, family investigation, genetic counseling, and prenatal diagnosis. Molecular mechanisms underlying this incomplete penetrance still need to be identified.</p></div>","PeriodicalId":11916,"journal":{"name":"European journal of medical genetics","volume":"69 ","pages":"Article 104932"},"PeriodicalIF":1.9,"publicationDate":"2024-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1769721224000247/pdfft?md5=fad69324e654d733a7e4fed05d79fbe8&pid=1-s2.0-S1769721224000247-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140059028","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}