Clinical Genetics最新文献

{"title":"Functional studies in yeast confirm the pathogenicity of a new GINS3 Meier–Gorlin syndrome variant","authors":"Yosra Mehrjoo,&nbsp;Philippe M. Campeau,&nbsp;Lama Al Abdi,&nbsp;Abdullah Aldowaish,&nbsp;Omar Abouyousef,&nbsp;Fowzan S. Alkuraya,&nbsp;Marta Codina-Solà,&nbsp;Anna M. Cueto-González,&nbsp;Hugo Wurtele","doi":"10.1111/cge.14545","DOIUrl":"10.1111/cge.14545","url":null,"abstract":"<p>Meier–Gorlin syndrome (MGORS) is an autosomal recessive disorder characterized by short stature, microtia, and patellar hypoplasia, and is caused by pathogenic variants of cellular factors involved in the initiation of DNA replication. We previously reported that biallelic variants in <i>GINS3</i> leading to amino acid changes at position 24 (p.Asp24) cause MGORS. Here, we describe the phenotype of a new individual homozygous for the Asp24Asn variant. We also report the clinical characteristics of an individual harboring a novel homozygous <i>GINS3</i> variant (Ile25Phe) and features suggestive of MGORS. Modification of the corresponding residue in yeast Psf3 (Val9Phe) compromised S phase progression compared to a humanized Psf3 Val9Ile variant. Expression of Psf3 Val9Phe in yeast also caused sensitivity to elevated temperature and the replicative stress-inducing drug hydroxyurea, confirming partial loss of function of this variant in vivo and allowing us to upgrade the classification of this variant. Taken together, these data validate the critical importance of the GINS DNA replication complex in the molecular etiology of MGORS.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"342-346"},"PeriodicalIF":2.9,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14545","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075641","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}

{"title":"Inherited thrombocytopenia associated with a variant in the FLI1 binding site in the 5′ UTR of ANKRD26","authors":"Caitlin Dunstan-Harrison,&nbsp;Ian M. Morison,&nbsp;Elizabeth C. Ledgerwood","doi":"10.1111/cge.14547","DOIUrl":"10.1111/cge.14547","url":null,"abstract":"<p>Variants in the 5′ UTR of <i>ANKRD26</i> are a common cause of inherited thrombocytopenia (<i>ANKRD26</i>-RT), and are associated with sustained <i>ANKRD26</i> expression, which inhibits megakaryocyte maturation and proplatelet formation. <i>ANKRD26</i> expression is controlled by the binding of a RUNX1/FLI1 complex to the 5′ UTR. To date, all reported <i>ANKRD26</i>-RD associated variants have been within the RUNX1 binding site and a 22 base pair flanking region. Here, we report a novel variant in the 5′ UTR of <i>ANKRD26</i>, c.-107C&gt;T. This variant is in the FLI1 binding site, and is predicted to disrupt FLI1 binding due to loss of a hydrogen bond with FLI1. Differentiated PBMCs from affected family members showed impaired megakaryocyte maturation and proplatelet formation and sustained expression of <i>ANKRD26</i>, and platelets from affected family members had higher <i>ANKRD26</i> expression than control platelets. The variant increased activity of the <i>ANKRD26</i> promotor in a reporter assay. We also provide evidence that the previously reported c.-140C&gt;G <i>ANKRD26</i> 5′ UTR variant is benign and not associated with thrombocytopenia. Identification of the c.-107C&gt;T variant extends the range of the regulatory region in the 5′ UTR of <i>ANKRD26</i> that is associated with <i>ANKRD26</i>-RT.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"315-320"},"PeriodicalIF":2.9,"publicationDate":"2024-05-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14547","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140956210","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}

{"title":"Genetic profile of Brazilian patients with LAMA2-related dystrophies","authors":"Clara Gontijo Camelo,&nbsp;Cristiane de Araujo Martins Moreno,&nbsp;Mariana da Cunha Artilheiro,&nbsp;Alulin Tácio Quadros Monteiro Fonseca,&nbsp;Juliana Gurgel Gianetti,&nbsp;André Vinícius Barbosa,&nbsp;Karina Carvalho Donis,&nbsp;Jonas Alex Morales Saute,&nbsp;André Pessoa,&nbsp;Hélio Van der Linden Jr,&nbsp;Ana Rita Alcântara Gonçalves,&nbsp;Leslie Domenici Kulikowski,&nbsp;Fernando Kok,&nbsp;Edmar Zanoteli","doi":"10.1111/cge.14538","DOIUrl":"10.1111/cge.14538","url":null,"abstract":"<p>LAMA2-related dystrophies (LAMA2-RD) constitute a rare neuromuscular disorder with a broad spectrum of phenotypic severity. Our understanding of the genotype–phenotype correlations in this condition remains incomplete, and reliable clinical data for clinical trial readiness is limited. In this retrospective study, we reviewed the genetic data and medical records of 114 LAMA2-RD patients enrolled at seven research centers in Brazil. We identified 58 different pathogenic variants, including 21 novel ones. Six variants were more prevalent and were present in 81.5% of the patients. Notably, the c.1255del, c.2049_2050del, c.3976 C&gt;T, c.5234+1G&gt;A, and c.4739dup variants were found in patients unable to walk and without cortical malformation. In contrast, the c.2461A&gt;C variant was present in patients who could walk unassisted. Among ambulatory patients, missense variants were more prevalent (<i>p</i> &lt; 0.0001). Although no specific hotspot regions existed in the <i>LAMA2</i>, 51% of point mutations were in the LN domain, and 88% of the missense variants were found within this domain. Functional analysis was performed in one intronic variant (c.4960-17C&gt;A) and revealed an out-of-frame transcript, indicating that the variant creates a cryptic splicing site (AG). Our study has shed light on crucial phenotype–genotype correlations and provided valuable insights, particularly regarding the Latin American population.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"305-314"},"PeriodicalIF":2.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921602","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}

{"title":"Identification of seven variants in the col4a1 gene that alter RNA splicing by minigene assay","authors":"Zhi Wang,&nbsp;Yan Sun,&nbsp;Yiyin Zhang,&nbsp;Yan Zhang,&nbsp;Ran Zhang,&nbsp;Changying Li,&nbsp;Xuyan Liu,&nbsp;Fengjiao Pan,&nbsp;Dan Qiao,&nbsp;Xiaomeng Shi,&nbsp;Bingying Zhang,&nbsp;Ning Xu,&nbsp;Irene Bottillo,&nbsp;Leping Shao","doi":"10.1111/cge.14546","DOIUrl":"10.1111/cge.14546","url":null,"abstract":"<p>Type IV collagen is an integral component of basement membranes. Mutations in COL4A1, one of the key genes encoding Type IV collagen, can result in a variety of diseases. It is clear that a significant proportion of mutations that affect splicing can cause disease directly or contribute to the susceptibility or severity of disease. Here, we analyzed exonic mutations and intronic mutations described in the COL4A1 gene using bioinformatics programs and identified candidate mutations that may alter the normal splicing pattern through a minigene system. We identified seven variants that induce splicing alterations by disrupting normal splice sites, creating new ones, or altering splice regulatory elements. These mutations are predicted to impact protein function. Our results help in the correct molecular characterization of variants in COL4A1 and may help develop more personalized treatment options.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"336-341"},"PeriodicalIF":2.9,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140921603","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}

{"title":"High prevalence of copy number variations in the Japanese participants with suspected MODY","authors":"Satoshi Tanaka,&nbsp;Hiroyuki Akagawa,&nbsp;Kenkou Azuma,&nbsp;Sayaka Higuchi,&nbsp;Atsushi Ujiie,&nbsp;Koshi Hashimoto,&nbsp;Naoko Iwasaki","doi":"10.1111/cge.14544","DOIUrl":"10.1111/cge.14544","url":null,"abstract":"<p>Maturity-Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation-dependent Probe Amplification (MLPA) and functional analyses. Twenty-one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in <i>HNF4A</i> and 1 in <i>HNF1B</i>. Pathogenic variants were identified in 12 participants (12/21, 57.1%) – relatively high rate reported to date. Notably, one-third of the participants had CNVs in <i>HNF4A</i> or <i>HNF1B</i>, indicating a limitation of WES-only screening.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"293-304"},"PeriodicalIF":2.9,"publicationDate":"2024-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140908167","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}

{"title":"FGF12 copy number variant associated with epileptic encephalopathy","authors":"Anna Abraham,&nbsp;Keri Ramsey,&nbsp;Newell Belnap,&nbsp;Szabolcs Szelinger,&nbsp;Wayne Jepsen,&nbsp;Chris Balak,&nbsp;Meredith Sanchez-Castillo,&nbsp;Marcus Naymik,&nbsp;Anna Bonfitto,&nbsp;Sampathkumar Rangasamy,&nbsp;Semyon Kruglyak,&nbsp;Matthew Huentelman,&nbsp;Vinodh Narayanan","doi":"10.1111/cge.14542","DOIUrl":"10.1111/cge.14542","url":null,"abstract":"<p><i>FGF12</i> related epilepsy presents with variable phenotypes. We report another patient with a duplication involving the <i>FGF12</i> gene who presented similar to other published cases having normal early development and responded to phenytoin.\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 1","pages":"114-115"},"PeriodicalIF":3.5,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140876031","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}

{"title":"A fine-scale genetic map of the Japanese population","authors":"Jun Takayama,&nbsp;Satoshi Makino,&nbsp;Takamitsu Funayama,&nbsp;Masao Ueki,&nbsp;Akira Narita,&nbsp;Keiko Murakami,&nbsp;Masatsugu Orui,&nbsp;Mami Ishikuro,&nbsp;Taku Obara,&nbsp;the Tohoku Medical Megabank Project Study Group,&nbsp;Shinichi Kuriyama,&nbsp;Masayuki Yamamoto,&nbsp;Gen Tamiya","doi":"10.1111/cge.14536","DOIUrl":"10.1111/cge.14536","url":null,"abstract":"<p>Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium—a non-random association of alleles among loci—by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10 092 551 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals whose genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents' and offspring's genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.</p>","PeriodicalId":10354,"journal":{"name":"Clinical Genetics","volume":"106 3","pages":"284-292"},"PeriodicalIF":2.9,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cge.14536","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891574","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}

{"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":"106 3","pages":"277-283"},"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}

{"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>^−/− 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":"106 2","pages":"209-213"},"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}

{"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>²) 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>² = 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":"106 2","pages":"204-208"},"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}