{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T05:25:09Z","timestamp":1787117109352,"version":"build-2736575974"},"reference-count":6,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"\n Background<\/jats:title>\n Agammaglobulinemia type 1 (AGM1) is a rare autosomal recessive inborn error of immunity caused by biallelic defects in the immunoglobulin heavy constant mu gene (IGHM), resulting in arrested B-cell development, profound antibody deficiency, and recurrent bacterial infections. Owing to its rarity and genetic heterogeneity, establishing a molecular diagnosis may remain challenging despite extensive genetic evaluation.<\/jats:p>\n <\/jats:sec>\n \n Case presentation<\/jats:title>\n An 11-year-old girl presented with recurrent respiratory infections, profound hypogammaglobulinemia, and absent circulating B cells since infancy. Intravenous immunoglobulin replacement therapy was initiated early in life, resulting in marked clinical improvement. Previous targeted next-generation sequencing using a 407-gene panel for inborn errors of immunity did not establish a molecular diagnosis. Because of the persistent clinical suspicion of a monogenic disorder, trio whole-exome sequencing combined with copy number variant analysis was subsequently performed. This identified compound heterozygous alterations in IGHM, consisting of a paternally inherited missense variant (c.1763C&gt;G; p.His417Asp) and a maternally inherited 169.1-kb deletion encompassing the entire IGHM gene. Segregation analysis confirmed that both alterations were located in trans. Although both variants remain classified as variants of uncertain significance according to American College of Medical Genetics and Genomics (ACMG) criteria, the characteristic clinical phenotype, longitudinal immunological findings, segregation pattern, and biological plausibility strongly support their clinical relevance.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n This case expands the molecular spectrum of IGHM-associated agammaglobulinemia and highlights the diagnostic value of integrating whole-exome sequencing with copy number variant analysis in patients with unresolved primary antibody deficiencies, particularly when targeted genetic testing is inconclusive.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fmed.2026.1901229","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:38:18Z","timestamp":1787114298000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Autosomal recessive agammaglobulinemia due to compound heterozygous IGHM alterations identified: a case report"],"prefix":"10.3389","volume":"13","author":[{"given":"Cristhel","family":"Puente","sequence":"first","affiliation":[{"name":"Edgardo Rebagliati Martins Hospital","place":["Lima, Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan Carlos","family":"Aldave Becerra","sequence":"additional","affiliation":[{"name":"Edgardo Rebagliati Martins Hospital","place":["Lima, Peru"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1038\/gene.2017.14","article-title":"Autosomal recessive agammaglobulinemia due to defect in \u03bc heavy chain caused by a novel mutation in the IGHM gene","volume":"18","author":"Silva","year":"2017","journal-title":"Genes Immun"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1007\/s12016-021-08870-5","article-title":"Agammaglobulinemia: from X-linked to autosomal forms of disease","volume":"63","author":"Cardenas-Morales","year":"2022","journal-title":"Clin Rev Allergy Immunol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"320","DOI":"10.1016\/j.ajhg.2007.10.011","article-title":"Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements","volume":"82","author":"van Zelm","year":"2008","journal-title":"Am J Hum Genet"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1172\/JCI15658","article-title":"Clinical and molecular analysis of patients with defects in micro heavy chain gene","volume":"110","author":"Lopez Granados","year":"2002","journal-title":"J Clin Invest"},{"key":"ref5","year":"2023"},{"key":"ref6","first-page":"73","article-title":"Novel variant in IGHM gene in a patient with agammaglobulinemia: a case report of a preschool child presenting with recurrent pneumonia","volume-title":"LymphoSign J","author":"Heifetz","year":"2024"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1901229\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T04:38:28Z","timestamp":1787114308000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1901229\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":6,"alternative-id":["10.3389\/fmed.2026.1901229"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1901229","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"article-number":"1901229"}}