{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T14:59:53Z","timestamp":1751468393835,"version":"3.37.3"},"reference-count":64,"publisher":"American Society of Hematology","issue":"20","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,10,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Inherited bone marrow failure (IBMF) syndromes are rare blood disorders characterized by hematopoietic cell dysfunction and predisposition to hematologic malignancies. Despite advances in the understanding of molecular pathogenesis of these heterogeneous diseases, genetic variant interpretation, genotype\u2013phenotype correlation, and outcome prognostication remain difficult. As new IBMF and other myelodysplastic syndrome (MDS) predisposition genes continue to be discovered (frequently in small kindred studies), there is an increasing need for a systematic framework to evaluate penetrance and prevalence of mutations in genes associated with IBMF phenotypes. To address this need, we analyzed population-based genomic data from &amp;gt;125\u2009000 individuals in the Genome Aggregation Database for loss-of-function (LoF) variants in 100 genes associated with IBMF. LoF variants in genes associated with IBMF\/MDS were present in 0.426% of individuals. Heterozygous LoF variants in genes in which haploinsufficiency is associated with IBMF\/MDS were identified in 0.422% of the population; homozygous LoF variants associated with autosomal recessive IBMF\/MDS diseases were identified in only .004% of the cohort. Using age distribution of LoF variants and 2 measures of mutational constraint, LOEUF (\u201closs-of-function observed\/expected upper bound fraction\u201d) and pLI (\u201cprobability of being loss-of-function intolerance\u201d), we evaluated the pathogenicity, tolerance, and age-related penetrance of LoF mutations in specific genes associated with IBMF syndromes. This analysis led to insights into rare IBMF diseases, including syndromes associated with DHX34, MDM4, RAD51, SRP54, and WIPF1. Our results provide an important population-based framework for the interpretation of LoF variant pathogenicity in rare and emerging IBMF syndromes.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002687","type":"journal-article","created":{"date-parts":[[2020,10,26]],"date-time":"2020-10-26T15:37:32Z","timestamp":1603726652000},"page":"5232-5245","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes"],"prefix":"10.1182","volume":"4","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1129-5129","authenticated-orcid":false,"given":"Joseph H.","family":"Oved","sequence":"first","affiliation":[{"name":"Division of Hematology, Department of Pediatrics,"},{"name":"Comprehensive Bone Marrow Failure Center, Division of Hematology, and"},{"name":"Cell Therapy & Transplant Section, Division of Oncology, Children\u2019s Hospital of Philadelphia, Philadelphia, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daria V.","family":"Babushok","sequence":"additional","affiliation":[{"name":"Comprehensive Bone Marrow Failure Center, Division of Hematology, and"},{"name":"Division of Hematology-Oncology, Hospital of University of Pennsylvania, Philadelphia, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0439-402X","authenticated-orcid":false,"given":"Michele P.","family":"Lambert","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics,"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Wolfset","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Nemours\/Alfred I. duPont Hospital for Children, Wilmington, DE;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Anna","family":"Kowalska","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mortimer","family":"Poncz","sequence":"additional","affiliation":[{"name":"Division of Hematology, Department of Pediatrics,"},{"name":"Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Konrad J.","family":"Karczewski","sequence":"additional","affiliation":[{"name":"Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA; and"},{"name":"Program in Medical and Population Genetics, Broad Institute, Cambridge, MA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy S.","family":"Olson","sequence":"additional","affiliation":[{"name":"Comprehensive Bone Marrow Failure Center, Division of Hematology, and"},{"name":"Cell Therapy & 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