Genetics in Medicine最新文献

{"title":"Efficacy of Transitioning from Alglucosidase Alfa to Avalglucosidase Alfa in Infantile-Onset Pompe Disease: A Single-Center Cohort Analysis.","authors":"Yin-Hsuan Chien, Hui-An Chen, Rai-Hseng Hsu, Chien-Hua Yeh, Ching-Ya Fang, Ni-Chung Lee, Wuh-Liang Hwu, Yin-Hsiu Chien","doi":"10.1016/j.gim.2025.101373","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101373","url":null,"abstract":"<p><strong>Background: </strong>Although alglucosidase alfa (AGL) has been the standard treatment for Pompe disease, its efficacy is limited, partially because of its low mannose-6-phosphate content. Avalglucosidase alfa (AVA), a glycoengineered recombinant human acid α-glucosidase, has shown improved receptor-mediated uptake compared with AGL. Herein, we report the long-term efficacy and safety of AVA in patients with infantile-onset Pompe disease (IOPD) previously treated with AGL.</p><p><strong>Materials and methods: </strong>This retrospective cohort study included nine patients with IOPD who transitioned from AGL to AVA; these patients were diagnosed and treated after being detected with IOPD via newborn screening. We analyzed the clinical status, biomarker levels (serum creatine kinase [CK] and urine glucose tetrasaccharide ([Glc4]), and functional assessments before and after AVA treatment of these patients. Statistical analyses were performed using the Wilcoxon matched-pair signed-rank test.</p><p><strong>Results: </strong>All nine patients received AGL at dosages exceeding the label recommendations owing to inadequate responses. After transitioning to AVA at a dosage of 40 mg/kg every other week for a median duration of 4.9 years, the patients experienced significant reductions in biomarker levels (CK levels decreased by 63% and Glc4 levels decreased by 69%). Functional assessments, including pulmonary function and 6-min walk tests, showed improvement in young patients but remained stable in older patients. Safety analyses revealed manageable infusion-associated reactions (IARs). Immune modulation therapy for antidrug antibodies (ADA) was administered to one IOPD patient.</p><p><strong>Conclusion: </strong>The transition from a high dose of AGL to AVA demonstrated sustained improvements in biomarker levels and motor function in patients with IOPD. Early initiation of AVA is crucial for patients with IOPD.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101373"},"PeriodicalIF":6.6,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Feasibility of Using Patient Navigation to Improve Identification of Hereditary Cancer Syndromes in Newly Diagnosed Colorectal Cancer Patients.","authors":"Emma Sears, Jacky Dahlquist, Sarah Stayman, Cynthia Ko, Eric Q Konnick, Allison Cole, Ying Zhang, Marlana Kohn, Vida Henderson, Sarah Knerr","doi":"10.1016/j.gim.2025.101372","DOIUrl":"https://doi.org/10.1016/j.gim.2025.101372","url":null,"abstract":"<p><strong>Purpose: </strong>Using germline genetic testing to identify hereditary cancer syndromes in patients newly diagnosed with colorectal cancer (CRC) carries substantial benefits. We examined the feasibility of using patient navigation, an evidence-based approach to reducing structural barriers to recommended care, to improve test completion by increasing pre-test counseling attendance.</p><p><strong>Methods: </strong>We conducted key informant interviews with representatives from organizations providing cancer care to CRC patients. Interviews included questions derived from the Consolidated Framework for Implementation Research, which delineates barriers and facilitators to implementing evidence-based practices. We used an inductive-deductive coding approach to identify themes related to program feasibility.</p><p><strong>Results: </strong>We interviewed nineteen participants across thirteen organizations. Key feasibility barriers included: funding to implement and sustain a navigation program; staffing and supervising the navigator role; health information technology needs; gaining administrators' buy-in; and evolving genetic service delivery models. Participants suggested multiple strategies to address implementation barriers, but most would prefer other approaches to improve genetic test completion over implementing a genomics-focused patient navigation program.</p><p><strong>Conclusion: </strong>Stakeholders across a range of health care organizations saw limited value in improving identification of hereditary CRC syndromes by implementing a program designed to increase pre-test genetic counseling attendance. The need to scale up genetic testing has shifted interest towards delivery models better integrated in established care pathways, requiring fewer resources, and providing broader reach.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101372"},"PeriodicalIF":6.6,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating the clinical and genetic spectrum of inositol polyphosphate phosphatase INPP4A-related neurodevelopmental disorder","authors":"Lettie E. Rawlins ,&nbsp;Reza Maroofian ,&nbsp;Stuart J. Cannon ,&nbsp;Muhannad Daana ,&nbsp;Mina Zamani ,&nbsp;Shamsul Ghani ,&nbsp;Joseph S. Leslie ,&nbsp;Nishanka Ubeyratna ,&nbsp;Nasar Khan ,&nbsp;Hamid Khan ,&nbsp;Annarita Scardamaglia ,&nbsp;Robin Cloarec ,&nbsp;Shujaat Ali Khan ,&nbsp;Muhammad Umair ,&nbsp;Saeid Sadeghian ,&nbsp;Hamid Galehdari ,&nbsp;Almundher Al-Maawali ,&nbsp;Adila Al-Kindi ,&nbsp;Reza Azizimalamiri ,&nbsp;Gholamreza Shariati ,&nbsp;Andrew H. Crosby","doi":"10.1016/j.gim.2024.101278","DOIUrl":"10.1016/j.gim.2024.101278","url":null,"abstract":"<div><h3>Purpose</h3><div>Biallelic <em>INPP4A</em> variants have recently been associated with severe neurodevelopmental disease in single-case reports. Here, we expand and elucidate the clinical-genetic spectrum and provide a pathomechanistic explanation for genotype-phenotype correlations.</div></div><div><h3>Methods</h3><div>Clinical and genomic investigations of 30 individuals were undertaken alongside molecular and in silico modelling and translation reinitiation studies.</div></div><div><h3>Results</h3><div>We characterize a clinically variable disorder with cardinal features, including global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic <em>INPP4A</em> variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Our studies identify the likely pathomechanism of this genotype-phenotype correlation entailing translational reinitiation in exon 4 resulting in an N-terminal truncated INPP4A protein retaining partial functionality, associated with less severe disease. We also identified identical reinitiation site conservation in <em>Inpp4a</em>^{<em>−/−</em>} mouse models displaying similar genotype-phenotype correlation. Additionally, we show fibroblasts from a single affected individual exhibit disrupted endocytic trafficking pathways, indicating the potential biological basis of the condition.</div></div><div><h3>Conclusion</h3><div>Our studies comprehensively characterize <em>INPP4A</em>-related neurodevelopmental disorder and suggest genotype-specific clinical assessment guidelines. We propose that the potential mechanistic basis of observed genotype-phenotype correlations entails exon 4 translation reinitiation.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101278"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142307516","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes","authors":"Melissa Martyn ,&nbsp;Ling Lee ,&nbsp;Alli Jan ,&nbsp;Rigan Tytherleigh ,&nbsp;Fiona Lynch ,&nbsp;Chloe Mighton ,&nbsp;Sophie E. Bouffler ,&nbsp;Elly Lynch ,&nbsp;Ivan Macciocca ,&nbsp;Lisette Curnow ,&nbsp;Giulia McCorkell ,&nbsp;Sebastian Lunke ,&nbsp;Belinda Chong ,&nbsp;Martin B. Delatycki ,&nbsp;Lilian Downie ,&nbsp;Danya Vears ,&nbsp;Stephanie Best ,&nbsp;Marc Clausen ,&nbsp;Yvonne Bombard ,&nbsp;Zornitza Stark ,&nbsp;Clara Gaff","doi":"10.1016/j.gim.2024.101327","DOIUrl":"10.1016/j.gim.2024.101327","url":null,"abstract":"<div><h3>Purpose</h3><div>Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences.</div></div><div><h3>Methods</h3><div>A cohort of 235 families who had completed ultrarapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to 3 screens on their genomic data: pediatric-onset, adult-onset, and expanded couple carrier screening. We investigated decision making, understanding, and service delivery preferences using surveys at 3 time points (pre counseling, post counseling, and post result) and performed inductive content analysis of pretest genetic counseling transcripts.</div></div><div><h3>Results</h3><div>A total of 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening easy (87%) compared with adult (68%; <em>P</em> = .002) or pediatric (71%; <em>P</em> = .01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this 1 month later. A delayed offer of screening was acceptable to most respondents (78%).</div></div><div><h3>Conclusion</h3><div>Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101327"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142643814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microcosting genomics: Challenges and opportunities","authors":"Francisco Santos Gonzalez ,&nbsp;Wendy J. Ungar ,&nbsp;James Buchanan ,&nbsp;John Christodoulou ,&nbsp;Zornitza Stark ,&nbsp;Ilias Goranitis","doi":"10.1016/j.gim.2024.101310","DOIUrl":"10.1016/j.gim.2024.101310","url":null,"abstract":"","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101310"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A germline PDGFRB splice site variant associated with infantile myofibromatosis and resistance to imatinib","authors":"Boutaina Boulouadnine ,&nbsp;Mathilde Filser ,&nbsp;Camille Leducq ,&nbsp;Taylor Losole ,&nbsp;Joshua Bies ,&nbsp;Stephanie Smetsers ,&nbsp;Dorus Kouwenberg ,&nbsp;Iris de Lange ,&nbsp;Arjen Mensenkamp ,&nbsp;Uwe Richard Kordes ,&nbsp;Véronique Minard-Colin ,&nbsp;Daniel Orbach ,&nbsp;Bénédicte Brichard ,&nbsp;Ronald de Krijger ,&nbsp;Julien Masliah-Planchon ,&nbsp;Jean-Baptiste Demoulin","doi":"10.1016/j.gim.2024.101334","DOIUrl":"10.1016/j.gim.2024.101334","url":null,"abstract":"<div><h3>Purpose</h3><div>Infantile myofibromatosis is characterized by the development of myofibroblastic tumors in young children. In most cases, the disease is caused by somatic gain-of-function variants in platelet-derived growth factor (PDGF) receptor beta <em>(PDGFRB)</em>. Here, we reported a novel germline intronic <em>PDGFRB</em> variant, c.2905-8G&gt;A, in 6 unrelated infants with multifocal myofibromatosis and their relatives.</div></div><div><h3>Methods</h3><div>We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays.</div></div><div><h3>Results</h3><div>All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G&gt;A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the <em>PDGFRB</em> transcript. Functional studies revealed that the splice change induced a partial loss of function, contrasting with previously described variants. In 4 tumor samples, we identified a second somatic hit at position Asp850 in <em>PDGFRB</em> exon 18, triggering constitutive receptor activation and resistance to imatinib. In addition to vinblastine and methotrexate, 2 patients received imatinib without objective response. One of them switched to dasatinib with concomitant improvement.</div></div><div><h3>Conclusion</h3><div>This splice-site <em>PDGFRB</em> variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101334"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomics-informed neuropsychiatric care for neurodevelopmental disorders: Results from a multidisciplinary clinic","authors":"Aaron D. Besterman ,&nbsp;David J. Adams ,&nbsp;Nicole R. Wong ,&nbsp;Benjamin N. Schneider ,&nbsp;Sunil Mehta ,&nbsp;Charlotte DiStefano ,&nbsp;Rujuta B. Wilson ,&nbsp;Julian A. Martinez-Agosto ,&nbsp;Shafali S. Jeste","doi":"10.1016/j.gim.2024.101333","DOIUrl":"10.1016/j.gim.2024.101333","url":null,"abstract":"<div><h3>Purpose</h3><div>Patients with neurodevelopmental disorders (NDDs) have high rates of neuropsychiatric comorbidities. Genomic medicine may help guide care because pathogenic variants are identified in up to 50% of patients with NDDs. We evaluate the impact of a genomics-informed, multidisciplinary, neuropsychiatric specialty clinic on the diagnosis and management of patients with NDDs.</div></div><div><h3>Methods</h3><div>We performed a retrospective study of 316 patients from the University of California, Los Angeles Care and Research in Neurogenetics Clinic, a genomics-informed multidisciplinary clinic.</div></div><div><h3>Results</h3><div>Among the 246 patients who underwent genetic testing, 41.8% had a pathogenic or likely pathogenic variant. Patients had 62 different genetic diagnoses, with 12 diagnoses shared by 2 or more patients, whereas 50 diagnoses were found in only single patients. Genetic diagnosis resulted in direct changes to clinical management in all patients with a pathogenic or likely pathogenic variant, including cascade testing (30.6%), family counseling (22.2%), medication changes (13.9%), clinical trial referral (2.8%), medical surveillance (30.6%), and specialty referrals (69.4%).</div></div><div><h3>Conclusions</h3><div>A genomics-informed model can provide significant clinical benefits to patients with NDDs, directly affecting management across multiple domains for most diagnosed patients. As precision treatments advance, establishing a genetic diagnosis will be critical for proper management. With the growing number of rare neurogenetic disorders, clinician training should emphasize core principles of genomic medicine over individual syndromes.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101333"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK)","authors":"Alice Garrett ,&nbsp;Sophie Allen ,&nbsp;Miranda Durkie ,&nbsp;George J. Burghel ,&nbsp;Rachel Robinson ,&nbsp;Alison Callaway ,&nbsp;Joanne Field ,&nbsp;Bethan Frugtniet ,&nbsp;Sheila Palmer-Smith ,&nbsp;Jonathan Grant ,&nbsp;Judith Pagan ,&nbsp;Trudi McDevitt ,&nbsp;Charlie F. Rowlands ,&nbsp;Terri McVeigh ,&nbsp;Helen Hanson ,&nbsp;Clare Turnbull","doi":"10.1016/j.gim.2024.101305","DOIUrl":"10.1016/j.gim.2024.101305","url":null,"abstract":"<div><h3>Purpose</h3><div>Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network.</div></div><div><h3>Methods</h3><div>A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group working group.</div></div><div><h3>Results</h3><div>CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data.</div></div><div><h3>Conclusion</h3><div>CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101305"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Opportunistic genomic screening has clinical utility: An interventional cohort study","authors":"Chloe Mighton ,&nbsp;Rita Kodida ,&nbsp;Salma Shickh ,&nbsp;Marc Clausen ,&nbsp;Emma Reble ,&nbsp;Jordan Sam ,&nbsp;Sonya Grewal ,&nbsp;Daena Hirjikaka ,&nbsp;Seema Panchal ,&nbsp;Carolyn Piccinin ,&nbsp;Melyssa Aronson ,&nbsp;Thomas Ward ,&nbsp;Susan Randall Armel ,&nbsp;Renee Hofstedter ,&nbsp;Tracy Graham ,&nbsp;Talia Mancuso ,&nbsp;Nicole Forster ,&nbsp;José-Mario Capo-Chichi ,&nbsp;Elena Greenfeld ,&nbsp;Abdul Noor ,&nbsp;Kevin E. Thorpe","doi":"10.1016/j.gim.2024.101323","DOIUrl":"10.1016/j.gim.2024.101323","url":null,"abstract":"<div><h3>Purpose</h3><div>Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking. We assessed the outcomes of opportunistic screening for a broad spectrum of SFs by evaluating the yield, impact on clinical management, and consistency between SFs and participants’ clinical features and family history.</div></div><div><h3>Methods</h3><div>Adult cancer patients had exome sequencing with the option to learn multiple categories of SFs. Outcomes data were collected through chart review and participant-reported measures up to one year after return of results.</div></div><div><h3>Results</h3><div>All participants (<em>n</em> = 139, 85.6% female, average 54.6 years old) who elected to learn SFs had ≥1 variant reported (100% [139/139]). The yield of reportable findings was highest for pharmacogenomic variants (97.8% [135/138] of participants), followed by common disease risk variants (89.4% [118/132]), carrier status (89.3% [117/131]), and variants related to Mendelian (27.2% [34/125]), medically actionable (15.2% [21/138]), and early-onset neurodegenerative (2.6% [3/117]) disease risks. SFs from the American College of Medical Genetics and Genomics list (v3.2, noncancer genes) were reported in 1.4% (2/138) of participants. SFs across all categories demonstrated clinical utility by prompting management changes in 28.1% (39/139) of participants. Moreover, a considerable proportion of participants had suggestive clinical features (49.0% (24/49)]) or family history (21.8% (27/124)) potentially related to their SFs.</div></div><div><h3>Conclusion</h3><div>Our findings indicate there are potential benefits from opportunistic screening for a broad range of SFs.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101323"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High yield of monogenic short stature in children from Kurdistan, Iraq: A genetic testing algorithm for consanguineous families","authors":"Shenali Anne Amaratunga ,&nbsp;Tara Hussein Tayeb ,&nbsp;Petra Dusatkova ,&nbsp;Lenka Elblova ,&nbsp;Jana Drabova ,&nbsp;Lukas Plachy ,&nbsp;Stepanka Pruhova ,&nbsp;Jan Lebl","doi":"10.1016/j.gim.2024.101332","DOIUrl":"10.1016/j.gim.2024.101332","url":null,"abstract":"<div><h3>Purpose</h3><div>Genetic testing in consanguineous families advances the general comprehension of pathophysiological pathways. However, short stature (SS) genetics remain unexplored in a defined consanguineous cohort. This study examines a unique pediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations.</div></div><div><h3>Methods</h3><div>Among 280 SS referrals from 2018-2020, 64 children met inclusion criteria (from consanguineous families; height ≤ −2.25 SD), 51 provided informed consent (30 females; 31 syndromic SS) and underwent investigation, primarily via exome sequencing. Prioritized variants were evaluated by the American College of Medical Genetics and Genomics standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS.</div></div><div><h3>Results</h3><div>A genetic cause of SS was elucidated in 31 of 51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (<em>GHR</em> and <em>SOX3</em>), thyroid axis (<em>TSHR</em>), growth plate (<em>CTSK</em>, <em>COL1A2</em>, <em>COL10A1</em>, <em>DYM</em>, <em>FN1</em>, <em>LTBP3</em>, <em>MMP13</em>, <em>NPR2</em>, and <em>SHOX</em>), signal transduction (<em>PTPN11</em>), DNA/RNA replication (<em>DNAJC21</em>, <em>GZF1</em>, and <em>LIG4)</em>, cytoskeletal structure (<em>CCDC8</em>, <em>FLNA</em>, and <em>PCNT</em>), transmembrane transport (<em>SLC34A3</em> and <em>SLC7A7</em>), enzyme coding (<em>CYP27B1</em>, <em>GALNS</em>, and <em>GNPTG</em>), and ciliogenesis (<em>CFAP410</em>). Two additional participants had Silver-Russell syndrome and 1 had del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10% to 33% of cases.</div></div><div><h3>Conclusion</h3><div>A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.</div></div>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":"27 2","pages":"Article 101332"},"PeriodicalIF":6.6,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}