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## Acknowledgements

The authors would like to especially thank all the family members who participated in this study and gave permission to use genetic and clinical information. We thank Stephanie Moon for guidance on the mRNA stability assay, Sumin Kim for reagents and protocols for oligo-dT FISH, and the University of Michigan Advanced Genomics, Transgenic Animal Model, and Microscopy Cores for sequencing and equipment. This research was supported by NSF Doctoral Dissertation Research Improvement Grant 1919671: F055138, Wenner-Gren Foundation for Anthropological Research N02820: 9967, Leakey Foundation Dissertation Fieldwork Grant, the University of Michigan Rackham Candidate Research Grant, the Joan B. Kessler Award, and the University of Michigan Pandemic Research Recovery Award to E.A.W, as well as the National Institutes of Health award numbers R01AWD010411 to S.L.B, A.Sh., and K.M.G, R00HD099403 to A.E.S, F31NS122207 and T32NS077888 to G.R.L, and T32GM008056 to K.J, and Indian Council of Medical Research (2020-5840) and the Ramalingaswami Fellow (D.O. NO.BT/HRD/35/02/2006) to A.Sr.

## Author contributions

A.E.S. generated the mouse model and human cell lines. E.A.W. performed human cell culture and organoid experiments and all bioinformatics analyzes. G.R.L., K.J., B.B., S.L.R, C.D.P., and A.E.S. performed mouse experiments. D.P., S.L.R., and C.D.P. contributed to immunohistochemistry analyzes. E.A.W., G.R.L., and S.L. performed the molecular biology experiments. E.A.W. created the figures. E.A.W., G.L., S.L.B, and A.E.S. wrote the manuscript. A.E.S., S.L.B, A.Sr., S.B., S.M., R.P., M.H, R.J.H, E.K, A.O, J.D., A.K., K.C., E.J.P., R.J.L., R.R.L., T-L.L., J.A., C.T.G., K.M.G., K.B., and A.Sh. contributed to the clinical work or variant identification.

## Competing interests

The authors declare no competing interests.
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111. Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. *Bioinformatics* **29**, 15-21 (2013).

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116. Veiga, D. F. T. maser: Mapping Alternative Splicing Events to pRoteins. *R package 1.20.0*, 1-22 (2022).

117. Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. *Proc. Natl Acad. Sci. USA* **102**, 15545-15550 (2005).

118. Zhou, Y. et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. *Nat. Commun.* **10**, 1523 (2019).

119. Keenan, A. B. et al. ChEA3: transcription factor enrichment analysis by orthogonal omics integration. *Nucleic Acids Res.* **47**, W212-W224 (2019).

## Acknowledgements

The authors would like to especially thank all the family members who participated in this study and gave permission to use genetic and clinical information. We thank Stephanie Moon for guidance on the mRNA stability assay, Sumin Kim for reagents and protocols for oligo-dT FISH, and the University of Michigan Advanced Genomics, Transgenic Animal Model, and Microscopy Cores for sequencing and equipment. This research was supported by NSF Doctoral Dissertation Research Improvement Grant 1919671: F055138, Wenner-Gren Foundation for Anthropological Research N02820: 9967, Leakey Foundation Dissertation Fieldwork Grant, the University of Michigan Rackham Candidate Research Grant, the Joan B. Kessler Award, and the University of Michigan Pandemic Research Recovery Award to E.A.W, as well as the National Institutes of Health award numbers R01AWD010411 to S.L.B, A.Sh., and K.M.G, R00HD099403 to A.E.S, F31NS122207 and T32NS077888 to G.R.L, and T32GM008056 to K.J, and Indian Council of Medical Research (2020-5840) and the Ramalingaswami Fellow (D.O. NO.BT/HRD/35/02/2006) to A.Sr.

## Author contributions

A.E.S. generated the mouse model and human cell lines. E.A.W. performed human cell culture and organoid experiments and all bioinformatics analyzes. G.R.L., K.J., B.B., S.L.R, C.D.P., and A.E.S. performed mouse experiments. D.P., S.L.R., and C.D.P. contributed to immunohistochemistry analyzes. E.A.W., G.R.L., and S.L. performed the molecular biology experiments. E.A.W. created the figures. E.A.W., G.L., S.L.B, and A.E.S. wrote the manuscript. A.E.S., S.L.B, A.Sr., S.B., S.M., R.P., M.H, R.J.H, E.K, A.O, J.D., A.K., K.C., E.J.P., R.J.L., R.R.L., T-L.L., J.A., C.T.G., K.M.G., K.B., and A.Sh. contributed to the clinical work or variant identification.

## Competing interests

The authors declare no competing interests.
**Additional information**

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41467-024-45948-y.

**Correspondence** and requests for materials should be addressed to Stephanie L. Bielas or Ashleigh E. Schaffer.

**Peer review information** *Nature Communications* thanks Jozef Gecz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

**Reprints and permissions information** is available at http://www.nature.com/reprints

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2024

<footnote n="1">¹Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ²Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. ³Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. ⁴Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. ⁵Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, The Isil Berat Barlan Center for Translational Medicine, Istanbul 34722, Turkey. ⁶Department of Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen 6524, the Netherlands. ⁷Division of Genetic Medicine, Department of Pediatrics, University of Washington, 98195 Seattle, WA, USA. ⁸Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria. ⁹Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria. ¹⁰Greenwood Genetic Center, Greenwood, SC 29646, USA. ¹¹Section of Medical Genetics, SUNY Upstate Medical University, Syracuse, NY 13210, USA. ¹²Imagine Institute, INSERM U1163, Paris Cité University, Paris 75015, France. ¹³Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France. ¹⁴Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna 1090, Austria. ¹⁵St. Anna Children's Hospital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna 1090, Austria. ¹⁶Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India. ¹⁷Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ¹⁸These authors jointly supervised this work: Stephanie L. Bielas, Ashleigh E. Schaffer. e-mail: sbielas@umich.edu; ashleigh.schaffer@case.edu</footnote>
**Additional information**

**Supplementary information** The online version contains supplementary material available at https://doi.org/10.1038/s41467-024-45948-y.

**Correspondence** and requests for materials should be addressed to Stephanie L. Bielas or Ashleigh E. Schaffer.

**Peer review information** *Nature Communications* thanks Jozef Gecz and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

**Reprints and permissions information** is available at http://www.nature.com/reprints

**Publisher's note** Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Open Access** This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

© The Author(s) 2024

<footnote n="1">¹Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ²Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA. ³Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. ⁴Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India. ⁵Division of Pediatric Allergy and Immunology, School of Medicine, Marmara University, Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, The Isil Berat Barlan Center for Translational Medicine, Istanbul 34722, Turkey. ⁶Department of Human Genetics, Radboud University Medical Centre Nijmegen, Nijmegen 6524, the Netherlands. ⁷Division of Genetic Medicine, Department of Pediatrics, University of Washington, 98195 Seattle, WA, USA. ⁸Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna 1090, Austria. ⁹Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna 1090, Austria. ¹⁰Greenwood Genetic Center, Greenwood, SC 29646, USA. ¹¹Section of Medical Genetics, SUNY Upstate Medical University, Syracuse, NY 13210, USA. ¹²Imagine Institute, INSERM U1163, Paris Cité University, Paris 75015, France. ¹³Service de Médecine Génomique des Maladies Rares, Hôpital Necker-Enfants Malades, AP-HP, Paris 75015, France. ¹⁴Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna 1090, Austria. ¹⁵St. Anna Children's Hospital and Children's Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna 1090, Austria. ¹⁶Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576104, India. ¹⁷Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ¹⁸These authors jointly supervised this work: Stephanie L. Bielas, Ashleigh E. Schaffer. e-mail: sbielas@umich.edu; ashleigh.schaffer@case.edu</footnote>