Clinical Genetics最新文献

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Outcomes of a universal germline screening program in a community urology practice 社区泌尿科普遍开展种系筛查计划的成果。
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-05-07 DOI: 10.1111/cge.14541
Neil Mendhiratta, Herman Hauver Jr, Whitley Hatton, Andrew Ostrusky, Devika S. Sathe, Sandeep Gurram, Patricia Rice, Heather Chalfin
{"title":"Outcomes of a universal germline screening program in a community urology practice","authors":"Neil Mendhiratta,&nbsp;Herman Hauver Jr,&nbsp;Whitley Hatton,&nbsp;Andrew Ostrusky,&nbsp;Devika S. Sathe,&nbsp;Sandeep Gurram,&nbsp;Patricia Rice,&nbsp;Heather Chalfin","doi":"10.1111/cge.14541","DOIUrl":"10.1111/cge.14541","url":null,"abstract":"<p>The role of germline genetic testing in urologic oncology has expanded in recent years. However, implementation of genetic testing in community practices remains a challenge, often due to limited access to qualified genetics trained providers. In this study, we report outcomes of a universal germline screening program in a community urology practice. Between November 2021 and September 2022, all patients referred for urology clinic visits at Frederick Health (Frederick, MD, USA) were provided an online genetics screening questionnaire prior to the visit. Responses were compared against National Comprehensive Cancer Network (NCCN) criteria for germline testing. Those who met criteria were provided educational materials at the end of the questionnaire, and then counseled by a trained urologic oncologist (HC) in the clinic or referred to a genetic counselor prior to testing. Testing was performed with a 36-gene pan-cancer panel (CancerNext) or a 14-gene targeted prostate cancer panel (ProstateNext), with or without additional RNA analysis (RNAinsight) (Ambry Genetics, CA, USA). Demographic and clinical parameters, as well as genetic testing results, were retrospectively collected under IRB approval. In the study period, 765 patients were seen over 1370 clinic visits. Of these, 505 patients (66.0%) completed the screening questionnaire. The majority were completed via email (54.5%) with the remainder (45.5%) via text message. Of the patients who completed screening, 125/505 (24.7%) met NCCN criteria for germline testing. 58/125 patients (46.4%) who met criteria underwent germline testing, of whom 5/58 (8.6%) had distinct pathogenic mutations identified. These included actionable mutations in <i>BRCA1</i>, <i>BRCA2</i>, and <i>CHEK2</i>, as well as an additional pathogenic mutation in <i>NBN</i>. Variants of unknown significance were identified in 8/58 patients (13.8%) in 11 total genes. Challenges to implementation of this program included meeting institutional requirements for genetic testing consent, facilitating specimen collection in clinic, and integration of results into the electronic health record. Genetic risk assessment for high-risk individuals is feasible as part of a universal screening program in a community urology practice. Approximately 8% of tested patients were found to have pathogenic germline mutations, which is consistent with contemporary tertiary referral cohorts.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140847439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome SATB2 相关综合征的咽弓衍生结构异常
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-05-01 DOI: 10.1111/cge.14540
Yuri A. Zarate, Katherine Bosanko, Nada Derar, Jennifer L. Fish
{"title":"Abnormalities in pharyngeal arch-derived structures in SATB2-associated syndrome","authors":"Yuri A. Zarate,&nbsp;Katherine Bosanko,&nbsp;Nada Derar,&nbsp;Jennifer L. Fish","doi":"10.1111/cge.14540","DOIUrl":"10.1111/cge.14540","url":null,"abstract":"<p>SATB2-associated syndrome (SAS, glass syndrome, OMIM#612313) is a neurodevelopmental autosomal dominant disorder with frequent craniofacial abnormalities including palatal and dental anomalies. To assess the role of Satb2 in craniofacial development, we analyzed mutant mice at different stages of development. Here, we show that <i>Satb2</i> is broadly expressed in early embryonic mouse development including the mesenchyme of the second and third arches. <i>Satb2</i><sup>−/−</sup> mutant mice exhibit microglossia, a shortened lower jaw, smaller trigeminal ganglia, and larger thyroids. We correlate these findings with the detailed clinical phenotype of four individuals with SAS and remarkable craniofacial phenotypes with one requiring mandibular distraction in childhood. We conclude that the mouse and patient data presented support less well-described phenotypic aspects of SAS including mandibular morphology and thyroid anatomical/functional issues.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14540","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140836498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Heritability of cancers in Japanese population: Estimation from recent cohort data 日本人口中癌症的遗传率:近期队列数据的估计
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-29 DOI: 10.1111/cge.14535
Yoshiro Nagao, Kei Takeshita
{"title":"Heritability of cancers in Japanese population: Estimation from recent cohort data","authors":"Yoshiro Nagao,&nbsp;Kei Takeshita","doi":"10.1111/cge.14535","DOIUrl":"10.1111/cge.14535","url":null,"abstract":"<p>Cancers are genetically categorized into common diseases showing a so-called multifactorial inheritance except for rare familial cancers. And as a measure to estimate the strength of genetic factors in the multifactorial diseases, heritability (<i>h</i><sup>2</sup>) is generally used. However, there have been few reports on the estimation of heritability for cancers. We calculated the heritability from the incidence in subject population and the familial recurrence rate in first-degree relatives of the affected for cancers quoting the data from a large-scale prospective cohort study by Hidaka et al. published in 2020. This is the first report for heritability of any cancers in Japanese population. The results showed that heritability of overall cancers in Japanese population is 0.064, which is much lower than Nordic population reported by Mucci et al. that was 0.33. For individual cancers, stomach cancer (<i>h</i><sup>2</sup> = 0.14), colorectum cancer (0.006), lung cancer (0.08) and uterine cancer (0.16) accounted for half of the total patients, and each heritability tends to be lower than previously reported for the European descent. The results of this study suggest that heritability of cancers varies greatly by ethnicity. And these results should be important in terms of cancer genetics and in the genetic counseling for cancers.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140837145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines 面囊肱肌营养不良症基因诊断最佳实践指南:2012年指南更新版
IF 3.5 3区 医学
Clinical Genetics Pub Date : 2024-04-29 DOI: 10.1111/cge.14533
Emiliano Giardina, Pilar Camaño, Sarah Burton-Jones, Gina Ravenscroft, Franclo Henning, Frederique Magdinier, Nienke van der Stoep, Patrick J. van der Vliet, Rafaëlle Bernard, Pedro J. Tomaselli, Mark R. Davis, Ichizo Nishino, Piraye Oflazer, Valerie Race, Venugopalan Y. Vishnu, Victoria Williams, Cláudia F. R. Sobreira, Silvere M. van der Maarel, Steve A. Moore, Nicol C. Voermans, Richard J. L. F. Lemmers
{"title":"Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: Update of the 2012 guidelines","authors":"Emiliano Giardina,&nbsp;Pilar Camaño,&nbsp;Sarah Burton-Jones,&nbsp;Gina Ravenscroft,&nbsp;Franclo Henning,&nbsp;Frederique Magdinier,&nbsp;Nienke van der Stoep,&nbsp;Patrick J. van der Vliet,&nbsp;Rafaëlle Bernard,&nbsp;Pedro J. Tomaselli,&nbsp;Mark R. Davis,&nbsp;Ichizo Nishino,&nbsp;Piraye Oflazer,&nbsp;Valerie Race,&nbsp;Venugopalan Y. Vishnu,&nbsp;Victoria Williams,&nbsp;Cláudia F. R. Sobreira,&nbsp;Silvere M. van der Maarel,&nbsp;Steve A. Moore,&nbsp;Nicol C. Voermans,&nbsp;Richard J. L. F. Lemmers","doi":"10.1111/cge.14533","DOIUrl":"10.1111/cge.14533","url":null,"abstract":"<p>The gold standard for facioscapulohumeral muscular dystrophy (FSHD) genetic diagnostic procedures was published in 2012. With the increasing complexity of the genetics of FSHD1 and 2, the increase of genetic testing centers, and the start of clinical trials for FSHD, it is crucial to provide an update on our knowledge of the genetic features of the FSHD loci and renew the international consensus on the molecular testing recommendations. To this end, members of the FSHD European Trial Network summarized the evidence presented during the 2022 ENMC meeting on Genetic diagnosis, clinical outcome measures, and biomarkers. The working group additionally invited genetic and clinical experts from the USA, India, Japan, Australia, South-Africa, and Brazil to provide a global perspective. Six virtual meetings were organized to reach consensus on the minimal requirements for genetic confirmation of FSHD1 and FSHD2. Here, we present the clinical and genetic features of FSHD, specific features of FSHD1 and FSHD2, pros and cons of established and new technologies (Southern blot in combination with either linear or pulsed-field gel electrophoresis, molecular combing, optical genome mapping, FSHD2 methylation analysis and FSHD2 genotyping), the possibilities and challenges of prenatal testing, including pre-implantation genetic testing, and the minimal requirements and recommendations for genetic confirmation of FSHD1 and FSHD2. This consensus is expected to contribute to current clinical management and trial-readiness for FSHD.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140836496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Syndromic craniosynostosis caused by a novel missense variant in MAP4K4: Expanding the genotype–phenotype relationship in RASopathies 由 MAP4K4 的一个新型错义变体引起的综合征颅颧骨发育不良:拓展 RAS 病的基因型与表型关系
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-28 DOI: 10.1111/cge.14539
Jihoon G. Yoon, Jung Woo Yu, Kyu Won Shim, Yong Oock Kim, Min Goo Lee
{"title":"Syndromic craniosynostosis caused by a novel missense variant in MAP4K4: Expanding the genotype–phenotype relationship in RASopathies","authors":"Jihoon G. Yoon,&nbsp;Jung Woo Yu,&nbsp;Kyu Won Shim,&nbsp;Yong Oock Kim,&nbsp;Min Goo Lee","doi":"10.1111/cge.14539","DOIUrl":"10.1111/cge.14539","url":null,"abstract":"<p>RASopathies represent a distinct class of neurodevelopmental syndromes caused by germline variants in the Ras/MAPK pathways. Recently, a novel disease-gene association was implicated in MAPK kinase kinase kinase 4 (<i>MAP4K4</i>), which regulates the upstream signals of the MAPK pathways. However, to our knowledge, only two studies have reported the genotype–phenotype relationships in the <i>MAP4K4</i>-related disorder. This study reports on a Korean boy harboring a novel de novo missense variant in <i>MAP4K4</i> (NM_001242559:c.569G&gt;T, p.Gly190Val), revealed by trio exome sequencing, and located in the hotspot of the protein kinase domain. The patient exhibited various clinical features, including craniofacial dysmorphism, language delay, congenital heart defects, genitourinary anomalies, and sagittal craniosynostosis. Our study expands the phenotypic association of the <i>MAP4K4</i>-related disorder to include syndromic craniosynostosis, thereby providing further insights into the role of the RAS/MAPK pathways in the development of premature fusion of calvarial sutures.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14539","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828314","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Usmani-Riazuddin syndrome can have a recognizable phenotype: Report of a novel AP1G1 variant Usmani-Riazuddin 综合征可有可识别的表型:报告一种新型 AP1G1 变异体。
IF 3.5 3区 医学
Clinical Genetics Pub Date : 2024-04-25 DOI: 10.1111/cge.14531
Maria Gnazzo, Giulia Pascolini, Giovanni Parlapiano, Francesco Petrizzelli, Daniele Perrino, Luigina Porco, Andrea Bartuli, Antonio Novelli, Anwar Baban
{"title":"Usmani-Riazuddin syndrome can have a recognizable phenotype: Report of a novel AP1G1 variant","authors":"Maria Gnazzo,&nbsp;Giulia Pascolini,&nbsp;Giovanni Parlapiano,&nbsp;Francesco Petrizzelli,&nbsp;Daniele Perrino,&nbsp;Luigina Porco,&nbsp;Andrea Bartuli,&nbsp;Antonio Novelli,&nbsp;Anwar Baban","doi":"10.1111/cge.14531","DOIUrl":"10.1111/cge.14531","url":null,"abstract":"<p>Usmani-Riazuddin syndrome (USRISR, MIM# 619548; USRISD, MIM#619467) is a very rare genetic condition. recently associated with deleterious variants in <i>AP1G1</i> (MIM* 603533). It is characterized by multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, muscular tone disorders, seizures, limb defects, and unspecified facial gestalt. In this report, we describe this syndrome for the second time, in association to a novel <i>AP1G1</i> variant identified in a toddler with multisystemic involvement including intellectual disability, speech and developmental delay, behavioral anomalies, arrhythmias, hearing loss, skin changes, and limb defects. Next generation sequencing (NGS) analysis through clinical exome disclosed <i>AP1G1</i>: c.1969C&gt;G (p.Leu657Val), de novo, likely pathogenic variant, according to ACMG classification criteria. Proband's facial features resembled the spectrum of chromatinopathies. Clinical pictures were analyzed and a clinical overlap was supported by DeepGestalt analysis (www.face2gene.com). The system identified 6 chromatin disorders out of 30 possible diagnoses. The remaining 24 included 9 miscellaneous cryptic chromosomal abnormalities (excluded due to normal microarray study). To the best of our knowledge, this is the first description of likely distinctive facial features in a patient with Usmani-Riazuddin syndrome. Further multicentric analyses are needed for a better definition of this aspect.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140655420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Pediatric acute promyelocytic leukemia and Fanconi anemia: Case report and literature review 小儿急性早幼粒细胞白血病和范可尼贫血:病例报告和文献综述。
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-24 DOI: 10.1111/cge.14537
Claire Freycon, Edith Sepulchre, Vincent-Philippe Lavallée, David Mitchell, Margaret L. MacMillan, Catherine Vezina, Catherine Goudie
{"title":"Pediatric acute promyelocytic leukemia and Fanconi anemia: Case report and literature review","authors":"Claire Freycon,&nbsp;Edith Sepulchre,&nbsp;Vincent-Philippe Lavallée,&nbsp;David Mitchell,&nbsp;Margaret L. MacMillan,&nbsp;Catherine Vezina,&nbsp;Catherine Goudie","doi":"10.1111/cge.14537","DOIUrl":"10.1111/cge.14537","url":null,"abstract":"<p>Acute promyelocytic leukemia (APL) represents 5%–10% of childhood acute myeloid leukemia (AML) and is the most curable subtype of AML. Fanconi anemia (FA) is one of the most common inherited bone marrow failure syndromes caused by biallelic pathogenic variants (PV) in specific DNA-repair genes. Biallelic PVs in <i>FANCD1/BRCA2</i> (FA-D1) account for 3% of FA and are associated with early-onset leukemia and a high risk of solid tumors. We report a 4 year-old boy from non-consanguineous parents diagnosed with standard risk APL. This child had café-au-lait spots and an extra thumb remnant. Genomic sequencing revealed two PV in <i>FANCD1/BRCA2</i> confirming a diagnosis of FA-D1. Chromosomal breakage studies were compatible with FA. Each parent carried one variant and had no personal history of cancer. Morphological then molecular remissions were achieved with all-trans retinoic acid and Arsenic trioxide. This patient underwent haploidentical stem cell transplant. In addition to our patient, a literature search revealed four additional patients with APL/FA, with a total of three patients with FA-D1. This raises the possibility of an association between such rare disorders. Practical management of APL in the setting of FA-D1 is discussed with an overview of current evidence and knowledge gaps.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140659801","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC 通过两个携带 ZCCHC8 和 TERC 变异基因的家庭的报告,拓展对端粒生物学紊乱的认识
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-12 DOI: 10.1111/cge.14534
Nikolaj Juul Nitschke, Anne Marie Jelsig, Charlotte Lautrup, Malene Lundsgaard, Marianne Tang Severinsen, Jack Bernard Cowland, Lisa Leth Maroun, Mette Klarskov Andersen, Kirsten Grønbæk
{"title":"Expanding the understanding of telomere biology disorder with reports from two families harboring variants in ZCCHC8 and TERC","authors":"Nikolaj Juul Nitschke,&nbsp;Anne Marie Jelsig,&nbsp;Charlotte Lautrup,&nbsp;Malene Lundsgaard,&nbsp;Marianne Tang Severinsen,&nbsp;Jack Bernard Cowland,&nbsp;Lisa Leth Maroun,&nbsp;Mette Klarskov Andersen,&nbsp;Kirsten Grønbæk","doi":"10.1111/cge.14534","DOIUrl":"10.1111/cge.14534","url":null,"abstract":"<p>Telomere biology disorder (TBD) can present within a wide spectrum of symptoms ranging from severe congenital malformations to isolated organ dysfunction in adulthood. Diagnosing TBD can be challenging given the substantial variation in symptoms and age of onset across generations. In this report, we present two families, one with a pathogenic variant in <i>ZCCHC8</i> and another with a novel variant in <i>TERC</i>. In the literature, only one family has previously been reported with a <i>ZCCHC8</i> variant and TBD symptoms. This family had multiple occurrences of pulmonary fibrosis and one case of bone marrow failure. In this paper, we present a second family with the same <i>ZCCHC8</i> variant (p.Pro186Leu) and symptoms of TBD including pulmonary fibrosis, hematological disease, and elevated liver enzymes. The suspicion of TBD was confirmed with the measurement of short telomeres in the proband. In another family, we report a novel likely pathogenic variant in <i>TERC</i>. Our comprehensive description encompasses hematological manifestations, as well as pulmonary and hepatic fibrosis. Notably, there are no other reports which associate this variant to disease. The families expand our understanding of the clinical implications and genetic causes of TBD.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140580392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2 与 CTNND2 双重复缺失相关的劳赫-阿扎雷洛综合征的严重表现
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-11 DOI: 10.1111/cge.14532
Melissa Pauly, Mandy Krumbiegel, Sandra Trumpp, Sonja Braig, Thomas Rupprecht, Cornelia Kraus, Steffen Uebe, André Reis, Georgia Vasileiou
{"title":"Severe manifestation of Rauch-Azzarello syndrome associated with biallelic deletion of CTNND2","authors":"Melissa Pauly,&nbsp;Mandy Krumbiegel,&nbsp;Sandra Trumpp,&nbsp;Sonja Braig,&nbsp;Thomas Rupprecht,&nbsp;Cornelia Kraus,&nbsp;Steffen Uebe,&nbsp;André Reis,&nbsp;Georgia Vasileiou","doi":"10.1111/cge.14532","DOIUrl":"10.1111/cge.14532","url":null,"abstract":"<p><i>CTNND2</i> encodes δ-catenin, a component of an adherens junction complex, and plays an important role in neuronal structure and function. To date, only heterozygous loss-of-function <i>CTNND2</i> variants have been associated with mild neurodevelopmental delay and behavioral anomalies, a condition, which we named Rauch-Azzarello syndrome. Here, we report three siblings of a consanguineous family of Syrian descent with a homozygous deletion encompassing the last 19 exons of <i>CTNND2</i> predicted to disrupt the transcript. All presented with severe neurodevelopmental delay with absent speech, profound motor delay, stereotypic behavior, microcephaly, short stature, muscular hypotonia with lower limb hypertonia, and variable eye anomalies. The parents and the fourth sibling were heterozygous carriers of the deletion and exhibited mild neurodevelopmental impairment resembling that of the previously described heterozygous individuals. The present study unveils a severe manifestation of <i>CTNND2</i>-associated Rauch-Azzarello syndrome attributed to biallelic loss-of-function aberrations, clinically distinct from the already described mild presentation of heterozygous individuals. Furthermore, we demonstrate novel clinical features in homozygous individuals that have not been reported in heterozygous cases to date.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14532","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140580308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Genotypic and phenotypic features of 39 Chinese patients with glycogen storage diseases type I, VI, and IX 39 名中国糖原贮积病 I、VI 和 IX 型患者的基因型和表型特征
IF 2.9 3区 医学
Clinical Genetics Pub Date : 2024-04-05 DOI: 10.1111/cge.14530
Jindan Yu, Xiuxin Ling, Lingli Chen, Youhong Fang, Haihua Lin, Jingan Lou, Yanqi Ren, Jie Chen
{"title":"Genotypic and phenotypic features of 39 Chinese patients with glycogen storage diseases type I, VI, and IX","authors":"Jindan Yu,&nbsp;Xiuxin Ling,&nbsp;Lingli Chen,&nbsp;Youhong Fang,&nbsp;Haihua Lin,&nbsp;Jingan Lou,&nbsp;Yanqi Ren,&nbsp;Jie Chen","doi":"10.1111/cge.14530","DOIUrl":"10.1111/cge.14530","url":null,"abstract":"<p>Glycogen storage diseases (GSDs) are abnormally inherited glycogen metabolism mainly affecting the liver, muscles, and heart. Deficiency of proteins involved in glycogen metabolism caused by genetic mutations are responsible for different subtype of GSDs. However, there are still some challenges in diagnosing GSD. This study includes 39 suspected GSDs patients from unrelated families in China. Next-generation sequencing (NGS) was used to investigate the reason for their diseases at the genetic level. Finally, all 39 patients were diagnosed with GSDs, including 20 GSD-Ia, 4 GSD-VI, and 15 GSD IX (12 GSD-IXa patients and 3 GSD-IXb patients). Thirty-two mutations in <i>G6PC1</i>, <i>PYGL</i>, <i>PHKA2</i>, and <i>PHKB</i> genes were identified, with 14 of them being novel variants. The pathogenicity of novel variants was classified according to ACMG guildlines and predicted by <i>in slico</i> algorithms. Mutations p.L216L and p.R83H in <i>G6PC1</i> gene may be the hot spot mutation in Chinese. Hearing impairment is a rare clinical feature of GSD Ia, which has also been observed in our cohort. The severity of GSD VI and IX was indicated by our patients. Close follow-up should be applied to GSD VI and IX patients. Our findings provided evidence for building the phenotype–genotype of GSDs and expanded the mutation spectrum of related genes.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140580615","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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