Autosomal-Recessive HOXA3 Deficiency Causes Congenital Athymia and Laryngeal Malformation

Authors

• Sarah S Dinges
• Marita Bosticardo
• Anke Hirschfelder
• Francesca Pala
• Johannes Kopp
• Viktor Glaser
• Johannes Grünhagen
• Giuseppe Sangiorgio
• Lisa Ehlers
• Pawel Durek
• Olga Staudacher
• Mirjam Völler
• Austen Worth
• Uwe Kölsch
• Zainab M Golwala
• Nadine Unterwalder
• Erwin Lankes
• Karl-Ulrich Schunck
• Frederik Heinrich
• Kayla Amini
• Stavros Loukogeorgakis
• Evey Howley
• Heather Kenney
• Hendrik S Fischer
• Sven C Weber
• Oliver Blankenstein
• Christian Meisel
• Anke Wendt
• Harald Stachelscheid
• Angela Kaindl
• Christoph Bührer
• Anita Balázs
• Mir-Farzin Mashreghi
• Julia K Polansky
• Dimitrios L Wagner
• E Graham Davies
• Marcus A Mall
• Alexandra Y Kreins
• Luigi D Notarangelo
• Horst von Bernuth

Language

English

Publication Date

9-28-2026

Journal

The Journal of Allergy and Clinical Immunology

DOI

10.1016/j.jaci.2026.09.010

PMID

42805310

Abstract

Background: Approximately 10% of patients with severe combined immunodeficiency phenotype lack a known genetic cause. In particular, the molecular basis of thymic defects is poorly understood. Homeobox (HOX) genes encode conserved transcription factors that control spatial body development. The function of human HOXA3 is undefined.

Objective: We characterized the first human with HOXA3 deficiency and investigated the role of HOXA3 in immune system development.

Methods: We performed clinical and immunologic phenotyping as well as genetic sequencing. A homozygous nonsense variant in HOXA3 was identified and functionally validated via reverse transcription polymerase chain reaction, Western blot analysis, assessment of transcriptional activity, and intracellular localization of HOXA3. We report clinical management and course.

Results: The homozygous HOXA3 nonsense variant generates a truncated protein with cytoplasmic retention and reduced transcriptional activity. The clinical phenotype includes craniofacial and cervical anomalies, severe laryngopharyngeal malformation with epiglottic hypoplasia causing dysphagia and aspiration, central breathing disorder, and thymus aplasia. T-cell maturation in artificial thymic organoids and recovery after thymus transplantation establish the T-cell defect as nonhematopoietic.

Conclusion: Human HOXA3 has nonredundant roles for the development of larynx and thymus. HOXA3 deficiency is a novel, life-threatening multisystem disorder. It is the first human homeobox-gene disease causing congenital athymia. These findings expand the diagnostic gene panel for patients with a severe combined immunodeficiency phenotype and indicate epiglottic hypoplasia as a new specific comorbidity of congenital athymia.

Keywords

HOXA3, SCID, TREC screening, athymia, epiglottic hypoplasia, homeobox genes, inborn error of immunity, laryngopharyngeal malformation, severe combined immunodeficiency, thymus transplantation

Published Open-Access

yes

Recommended Citation

Dinges, Sarah S; Bosticardo, Marita; Hirschfelder, Anke; et al., "Autosomal-Recessive HOXA3 Deficiency Causes Congenital Athymia and Laryngeal Malformation" (2026). Faculty, Staff and Students Publications. 8686.
https://digitalcommons.library.tmc.edu/baylor_docs/8686