Shwachman-Diamond syndrome due to biallelic EFL1 variants with complex and fatal clinical course in early infancy

Holger Cario; Alexis Bertrand; Shengjiang Tan; Bernd Auber; Miriam Erlacher; Eva-Maria Mair; Sandra von Hardenberg; Dirk Lebrecht; Patrick Revy; Alan J Warren

doi:10.1111/bjh.19793

Shwachman-Diamond syndrome due to biallelic EFL1 variants with complex and fatal clinical course in early infancy

Br J Haematol. 2024 Oct 8. doi: 10.1111/bjh.19793. Online ahead of print.

Authors

Holger Cario^{1

2}, Alexis Bertrand^{3

4

5}, Shengjiang Tan^{6

7

8}, Bernd Auber⁹, Miriam Erlacher^{1

10}, Eva-Maria Mair¹¹, Sandra von Hardenberg⁹, Dirk Lebrecht¹⁰, Patrick Revy^{3

4}, Alan J Warren^{6

7

8}

Affiliations

¹ Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.
² Center for Rare Hematopoietic Disorders and Immunodeficiencies (ZSHI), Rare Disease Center, University Medical Center Ulm, Ulm, Germany.
³ Laboratory of Genome Dynamics in the Immune System, INSERM UMR 1163, Imagine Institute, Paris, France.
⁴ Université Paris Cité, Imagine Institute, Paris, France.
⁵ Université Paris-Saclay, Paris, France.
⁶ Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Wellcome Trust-Medical Research Council Stem Cell Institute, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Cambridge Biomedical Campus, Cambridge, UK.
⁸ Department of Haematology, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, UK.
⁹ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
¹⁰ Center for Pediatrics and Adolescent Medicine, Pediatric Hematology and Oncology, University Medical Center Freiburg, Freiburg, Germany.
¹¹ Division of Neonatology and Pediatric Intensive Care Medicine, Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Ulm, Germany.

PMID: 39379149
DOI: 10.1111/bjh.19793

Abstract

Shwachman-Diamond syndrome represents a clinically and genetically heterogeneous disorder. We report on an infant with a very severe, fatal clinical course caused by biallelic EFL1 variants: c.89A>G, p.(His30Arg), and c.2599A>G, p.(Asn867Asp). Functional analysis of patient-derived B-lymphoblastoid and SV40-transformed fibroblast cell lines suggests that the compound heterozygous EFL1 variants impaired mature ribosome formation leading to compromised protein synthesis, ultimately resulting in a severe form of Shwachman-Diamond syndrome.

Keywords: EFL1; Shwachman–Diamond syndrome; bone marrow failure; infancy.

Abstract

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