Autosomal recessive agammaglobulinemia due to compound heterozygous IGHM alterations identified: a case report

Abstract

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. 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>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. 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.