Genetics in Medicine最新文献

{"title":"Genomics-informed neuropsychiatric care for neurodevelopmental disorders: Results from a multidisciplinary clinic.","authors":"Aaron D Besterman, David J Adams, Nicole R Wong, Benjamin N Schneider, Sunil Mehta, Charlotte DiStefano, Rujuta B Wilson, Julian A Martinez-Agosto, Shafali S Jeste","doi":"10.1016/j.gim.2024.101333","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101333","url":null,"abstract":"<p><strong>Purpose: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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%).</p><p><strong>Conclusions: </strong>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.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101333"},"PeriodicalIF":6.6,"publicationDate":"2024-12-16","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolving knowledge of \"red flag\" clinical features associated with TTR p.(Val142Ile) in a diverse electronic health record-linked biobank.","authors":"Amy R Kontorovich, Connor B Benson, Alexandra McClellan, Gillian M Belbin, Eimear E Kenny, Noura S Abul-Husn","doi":"10.1016/j.gim.2024.101346","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101346","url":null,"abstract":"<p><strong>Purpose: </strong>Previous studies have established \"red flags\" that raise clinical suspicion for the hereditary form of transthyretin amyloidosis (ATTRv). However, these have not been specifically evaluated for the most common associated variant, TTR p.(Val142Ile).</p><p><strong>Methods: </strong>Using an ancestrally diverse electronic health record-linked biobank with exome sequence data from 27,630 unrelated adults, we evaluated nine ATTRv-related clinical features among TTR p.(Val142Ile) positive and negative individuals.</p><p><strong>Results: </strong>Among 337 variant positive individuals (median age 63, 60% female), ten (3.0%) were diagnosed with amyloidosis. TTR p.(Val142Ile) was associated with increased odds of cardiomyopathy/heart failure (CM/HF), atrial fibrillation, polyneuropathy, carpal tunnel syndrome, and proteinuria, but only in individuals ≥ 60 years. These features were evident 1.7 to 7.7 years earlier in variant positive vs. negative individuals (HR 1.37, P = 3.99 x 10^-2; HR 1.78, P = 2.52 x 10^-3; HR 1.78, P = 1.70 x 10^-3; HR 1.81, P = 5.14 x 10^-3; HR 1.60, P = 1.94 x 10^-2, respectively). By age 50, the cumulative incidence of CM/HF was 3.5-fold higher, and by age 60, the incidences of CM/HF, polyneuropathy, and proteinuria were 2-fold higher in variant positive individuals.</p><p><strong>Conclusions: </strong>This study clarifies red flags that are associated with TTR p.(Val142Ile) in an age-dependent manner. With modifying therapies available, early diagnosis of ATTRv in variant positive individuals through recognition of key clinical features is paramount.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101346"},"PeriodicalIF":6.6,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142853477","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":"Evaluating Reproductive Carrier Screening using Biotinidase Deficiency as a Model: Variants Identified, Variant Rates and Management.","authors":"Peter Benn, Yang Wang, Josie Gray, Elizabeth Kramer Dugan, Mark Hajjar, Brittany Prigmore, Vivienne Souter, Barry Wolf","doi":"10.1016/j.gim.2024.101345","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101345","url":null,"abstract":"<p><strong>Purpose: </strong>To review biotinidase gene (BTD) variants identified in a large, diverse, reproductive carrier screening (RCS) cohort and outline management of heterozygotes with pathogenic or likely pathogenic (P/LP) variants.</p><p><strong>Methods: </strong>This retrospective observational study included samples tested from January 2020 to September 2022 in a 274-gene panel. The study involved females aged 18 to 55 years. Screening was performed using next generation sequencing covering exons and 10 base-pair flanking introns. The heterozygote frequency was calculated for P/LP variants for the entire population and individual racial/ethnic groups.</p><p><strong>Results: </strong>Of the 91,637 women tested, 5,625 (6.1%) had a P/LP variant in BTD. NM_000060.4:c.1330G>C p.(Asp444His) (referred to as D444H or D424H) alone, or in combination with another variant, accounted for 5,193 (92.3%) of the positive tests. P/LP heterozygote rates differed between racial and ethnic groups. We ascertained seven novel P/LP variants not previously recorded in databases.</p><p><strong>Conclusions: </strong>The BTD P/LP variants identified through RCS were substantially compatible with those found through positive newborn screening. Therefore, RCS provides a potential for earlier diagnosis. We observed significant differences in P/LP heterozygote rates for biotinidase deficiency among different racial and ethnic groups. Most reported variants can be interpreted without requiring determination of serum biotinidase activity.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101345"},"PeriodicalIF":6.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142835201","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":"The characterization of new de novo CACNA1G variants affecting the intracellular gate of Cav3.1 channel broadens the spectrum of neurodevelopmental phenotypes in SCA42ND.","authors":"Leila Qebibo, Amaël Davakan, Mathilde Nesson-Dauphin, Najlae Boulali, Karine Siquier-Pernet, Alexandra Afenjar, Jeanne Amiel, Deborah Bartholdi, Magalie Barth, Eléonore Blondiaux, Ingrid Cristian, Zoe Frazier, Alice Goldenberg, Jean-Marc Good, Catherine Lourdes Salussolia, Mustafa Sahin, Helen McCullagh, Kimberly McDonald, Anne McRae, Jennifer Morrison, Jason Pinner, Marwan Shinawi, Annick Toutain, Emílie Vyhnálková, Patricia G Wheeler, Yael Wilnai, Moran Hausman-Kedem, Marion Coolen, Vincent Cantagrel, Lydie Burglen, Philippe Lory","doi":"10.1016/j.gim.2024.101337","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101337","url":null,"abstract":"<p><strong>Purpose: </strong>Missense de novo variants in CACNA1G, which encodes the Cav3.1 T-type calcium channel, have been associated with a severe, early-onset form of cerebellar disorder with neurodevelopmental deficits (SCA42ND). We explored a large series of pediatric cases carrying heterozygous variants in CACNA1G to further characterize genotype-phenotype correlations in SCA42ND.</p><p><strong>Methods: </strong>We describe 19 patients with congenital CACNA1G-variants including 6 new heterozygotes of the recurrent SCA42ND variants, p.(Ala961Thr) and p.(Met1531Val), and 8 unreported variants including 7 missense variants, mainly de novo. We carried out genetic and structural analyses of all variants. Patch-clamp recordings were performed to measure their channel activity.</p><p><strong>Results: </strong>We provide a consolidated clinical description for the patients carrying p.(Ala961Thr) and p.(Met1531Val). The new variants associated with the more severe phenotypes are found in the Cav3.1 channel intracellular gate. Calcium currents of these Cav3.1 variants showed slow inactivation and deactivation kinetics, and increase in window current, supporting a gain of channel activity. On the contrary, the p.(Met197Arg) variant (IS4-S5 loop) resulted in a loss of channel activity.</p><p><strong>Conclusion: </strong>This detailed description of several de novo missense pathogenic variants in CACNA1G, including 13 previously reported cases, supports a clinical spectrum of congenital CACNA1G syndrome beyond spinocerebellar ataxia.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101337"},"PeriodicalIF":6.6,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142828198","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":"Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing datasets.","authors":"Ben Weisburd, Rakshya Sharma, Villem Pata, Tiia Reimand, Vijay S Ganesh, Christina Austin-Tse, Ikeoluwa Osei-Owusu, Emily O'Heir, Melanie O'Leary, Lynn Pais, Seth A Stafki, Audrey L Daugherty, Chiara Folland, Stojan Perić, Nagia Fahmy, Bjarne Udd, Magda Horakova, Anna Łusakowska, Rajanna Manoj, Atchayaram Nalini, Veronika Karcagi, Kiran Polavarapu, Hanns Lochmüller, Rita Horvath, Carsten G Bönnemann, Sandra Donkervoort, Göknur Haliloğlu, Ozlem Herguner, Peter B Kang, Gianina Ravenscroft, Nigel Laing, Hamish S Scott, Ana Töpf, Volker Straub, Sander Pajusalu, Katrin Õunap, Grace Tiao, Heidi L Rehm, Anne O'Donnell-Luria","doi":"10.1016/j.gim.2024.101336","DOIUrl":"10.1016/j.gim.2024.101336","url":null,"abstract":"<p><strong>Purpose: </strong>We set out to develop a publicly available tool that could accurately diagnose spinal muscular atrophy (SMA) in exome, genome or panel sequencing datasets aligned to a GRCh37, GRCh38, or T2T reference genome.</p><p><strong>Methods: </strong>The SMA Finder algorithm detects the most common genetic causes of SMA by evaluating reads that overlap the c.840 position of the SMN1 and SMN2 paralogs. It uses these reads to determine whether an individual most likely has zero functional copies of SMN1.</p><p><strong>Results: </strong>We developed SMA Finder and evaluated it on 16,626 exomes and 3,911 genomes from the Broad Institute Center for Mendelian Genomics, 1,157 exomes and 8,762 panel samples from Tartu University Hospital, and 198,868 exomes and 198,868 genomes from the UK Biobank. SMA Finder's false positive rate was below 1 in 200,000 samples, its positive predictive value was greater than 96%, and its true positive rate was 29 out of 29. Most of these SMA diagnoses had initially been clinically misdiagnosed as Limb-girdle muscular dystrophy (LGMD).</p><p><strong>Conclusion: </strong>Our extensive evaluation of SMA Finder on exome, genome and panel sequencing samples found it to have nearly 100% accuracy and demonstrated its ability to reduce diagnostic delays, particularly in individuals with milder subtypes of SMA. Given this accuracy, the common misdiagnoses identified here, the widespread availability of clinical confirmatory testing for SMA, as well as the existence of treatment options, we propose that it is time to add SMN1 to the ACMG list of genes with reportable secondary findings after genome and exome sequencing.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101336"},"PeriodicalIF":6.6,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817779","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":"Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).","authors":"Tuya Pal, Katherine R Schon, Esteban Astiazaran-Symonds, Judith Balmaña, William D Foulkes, Paul James, Susan Klugman, Alicia A Livinski, Julie S Mak, Joanne Ngeow, Nicoleta Voian, Myra J Wick, Helen Hanson, Douglas R Stewart, Marc Tischkowitz","doi":"10.1016/j.gim.2024.101243","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101243","url":null,"abstract":"<p><strong>Purpose: </strong>ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer. Resources for managing ATM heterozygotes in clinical practice are limited.</p><p><strong>Methods: </strong>An international workgroup developed a clinical practice resource to guide management of ATM heterozygotes using peer-reviewed publications and expert opinion.</p><p><strong>Results: </strong>Although ATM is a moderate (intermediate) penetrance gene, cancer risks may be considered as a continuous variable, influenced by family history and other modifiers. ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history, ideally as part of a clinical trial, with existence of country-specific guidelines. For ATM GPV heterozygotes who develop cancer, radiation therapy decisions should not be influenced by the genetic result. Although poly-adenosine diphosphate ribose polymerase inhibitors are licensed for use in metastatic castration-resistant prostate cancer and ATM GPVs, the evidence-base is currently weak.</p><p><strong>Conclusion: </strong>Systematic prospective data collection is needed to establish the spectrum of ATM-associated cancer and determine the outlines of surveillance, response to cancer treatment, and survival.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101243"},"PeriodicalIF":6.6,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142785032","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":"Phenylalanine hydroxylase deficiency diagnosis and management: A 2023 evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG).","authors":"Wendy E Smith, Susan A Berry, Kaitlyn Bloom, Christine Brown, Barbara K Burton, Olivia M Demarest, Gabrielle P Jenkins, Jennifer Malinowski, Kim L McBride, H Joel Mroczkowski, Curt Scharfe, Jerry Vockley","doi":"10.1016/j.gim.2024.101289","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101289","url":null,"abstract":"<p><strong>Purpose: </strong>To replace an existing clinical practice guideline for the diagnosis and management of phenylalanine hydroxylase (PAH) deficiency.</p><p><strong>Methods: </strong>The PAH Deficiency Guideline Workgroup used the Grading of Recommendations Assessment, Development, and Evaluation evidence-to-decision framework to develop evidence summaries and practice recommendations based on the recent American College of Medical Genetics and Genomics systematic review.</p><p><strong>Results: </strong>Many recommendations from the 2014 PAH practice guideline are recognized as standard of care in this evidence-based guideline. Key recommendations from the previous guideline that were not supported by strong evidence are now strongly supported; (1) treatment for PAH deficiency should be lifelong for individuals with untreated phenylalanine (Phe) levels >360 μmol/L, (2) individuals with lifelong Phe levels ≤360 μmol/L have better intellectual outcomes than those who do not, (3) achieving Phe levels ≤360 μmol/L before conception is strongly recommended to prevent pregnancy complications and negative outcomes for the offspring, and (4) genetic testing for PAH variants is recommended at birth to confirm diagnosis and guide therapy.</p><p><strong>Conclusion: </strong>We strongly recommend lifelong maintenance of Phe ≤360 μmol/L (using plasma or whole blood) for optimal intellectual outcomes and for reduced teratogenicity, utilizing all available and necessary dietary, pharmaceutical, and patient-educational modalities.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101289"},"PeriodicalIF":6.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142768140","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, Mathilde Filser, Camille Leducq, Taylor Losole, Joshua Bies, Stephanie Smetsers, Dorus Kouwenberg, Iris de Lange, Arjen Mensenkamp, Uwe Richard Kordes, Véronique Minard-Colin, Daniel Orbach, Bénédicte Brichard, Ronald de Krijger, Julien Masliah-Planchon, Jean-Baptiste Demoulin","doi":"10.1016/j.gim.2024.101334","DOIUrl":"10.1016/j.gim.2024.101334","url":null,"abstract":"<p><strong>Purpose: </strong>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 (PDGFRB). Here, we reported a novel germline intronic PDGFRB variant, c.2905-8G>A, in 6 unrelated infants with multifocal myofibromatosis and their relatives.</p><p><strong>Methods: </strong>We performed constitutional and tumor DNA and RNA sequencing to identify novel variants, which were subsequently characterized in cellular assays.</p><p><strong>Results: </strong>All patients had multiple skin nodules, 4 had bone lesions, and 2 had aggressive disease with bowel obstruction. The c.2905-8G>A substitution creates an alternative acceptor splice site in intron 21, inserting 2 codons in the PDGFRB 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 PDGFRB 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.</p><p><strong>Conclusion: </strong>This splice-site PDGFRB variant favors the development of myofibroma, featuring an acquired oncogenic variant in the same gene and resistance to targeted therapy.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101334"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","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":"Fetal fraction amplification within prenatal cfDNA screening enables detection of genome-wide copy-number variants at enhanced resolution.","authors":"Ashley Acevedo, Oyang Teng, Heather G LaBreche, Alison Nguyen, Luis Jazo, Sun Hae Hong, John Suk, Summer Pierson, Thomas Westover, Sarah Ratzel, Kevin R Haas, Dale Muzzey","doi":"10.1016/j.gim.2024.101269","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101269","url":null,"abstract":"<p><strong>Purpose: </strong>Clinically significant copy-number variants (CNVs) occur in 1% to 2% of pregnancies and are difficult to detect via prenatal cell-free DNA (cfDNA) screening because of the low fraction of fetal-derived cfDNA in maternal plasma. Here, we use fetal fraction amplification (FFA) and improved computational algorithms to enhance the resolution and sensitivity of CNV detection.</p><p><strong>Methods: </strong>We implemented and characterized the performance of a hidden Markov model that identifies fetal CNVs. This CNV caller was analytically validated on 117 FFA samples, including 57 fetal-CNV-containing samples, and applied retrospectively to a cohort of more than 300k patient samples.</p><p><strong>Results: </strong>Our assay was concordant with orthogonal testing and detected fetal CNVs ≥5 Mb with estimated aggregate sensitivity and specificity of >95.1% and >99.7%, respectively. The resolution of CNV detection was fetal fraction dependent, but 97.2% of samples reached ≥5-Mb resolution. Overall, CNVs ≥5 Mb were found in 1 in 500 pregnancies.</p><p><strong>Conclusion: </strong>FFA improves the sensitivity and resolution of CNV detection in prenatal cfDNA screening, allowing accurate detection of fetal CNVs as small as 1 Mb. Using our approach, we found that clinically significant fetal CNVs were detected more frequently than the common trisomies 13 and 18 that are recommended as part of guideline-based screening.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101269"},"PeriodicalIF":6.6,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142709909","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, Tara Hussein Tayeb, Petra Dusatkova, Lenka Elblova, Jana Drabova, Lukas Plachy, Stepanka Pruhova, Jan Lebl","doi":"10.1016/j.gim.2024.101332","DOIUrl":"https://doi.org/10.1016/j.gim.2024.101332","url":null,"abstract":"<p><strong>Introduction: </strong>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 paediatric cohort from Sulaimani, Iraq, aiming to inspire a genetic testing algorithm for similar populations.</p><p><strong>Methods: </strong>Among 280 SS referrals 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 ACMG standards. A comparative analysis was conducted by juxtaposing our findings against published gene panels for SS.</p><p><strong>Results: </strong>A genetic cause of SS was elucidated in 31/51 (61%) participants. Pathogenic variants were found in genes involved in the GH-IGF-1 axis (GHR, SOX3), thyroid axis (TSHR), growth plate (CTSK, COL1A2, COL10A1, DYM, FN1, LTBP3, MMP13, NPR2, SHOX), signal transduction (PTPN11), DNA/RNA replication (DNAJC21, GZF1, LIG4), cytoskeletal structure (CCDC8, FLNA, PCNT), transmembrane transport (SLC34A3, SLC7A7), enzyme coding (CYP27B1, GALNS, GNPTG) and ciliogenesis (CFAP410). Two additional participants had Silver-Russell syndrome and one del22q.11.21. Syndromic SS was predictive in identifying a monogenic condition. Using a gene panel would yield positive results in only 10-33% of cases.</p><p><strong>Conclusion: </strong>A tailored testing strategy is essential to increase diagnostic yield in children with SS from consanguineous populations.</p>","PeriodicalId":12717,"journal":{"name":"Genetics in Medicine","volume":" ","pages":"101332"},"PeriodicalIF":6.6,"publicationDate":"2024-11-20","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}