Inherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length. Medscape Continuing Medical Education online: [Formula presented] In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and the American Society of Hematology. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 2575. Disclosures: Associate Editor Irene Roberts declares no competing financial interests. CME questions author Laurie Barclay owns stock, stock options, or bonds from the following ineligible company: AbbVie Inc (former).
Bibliographical noteFunding Information:
The authors thank the individuals P1, P2, and P3 and their families for their contribution to this study. P.R. thanks Yanick Crow for the kind gift of Bloom-deficient SV40-transformed fibroblasts. This work was supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellis?e La Ligue ?LIGUE 2020' to P.R. and ?LIGUE 2021' to V.G.), CEREDIH (Centre de R?f?rence D?ficits Immunitaires H?r?ditaires) and state funding from the Agence Nationale de la Recherche under ?Investissements d'avenir? program (ANR-10-IAHU-01) and (ANR-21-CE12-APOthesis). This work was supported by the Israel Science Foundation grant [2071/18] to Y.T. and the Israel Ministry of Science and Technology (Navon Fellowship) to A.A. This work was also supported by the STEP-GTP Fellowship to A.A. and by the Israel-UK-Palestine GROWTH Fellowship Scheme, the British Council, to R.S. This study contributes to the IdEx Universit? de Paris ANR-18-IDEX-0001PR. P.R. is a scientist from the Centre National de la Recherche Scientifique (CNRS).
This work was supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue ‘LIGUE 2020' to P.R. and ‘LIGUE 2021' to V.G.), CEREDIH (Centre de Référence Déficits Immunitaires Héréditaires) and state funding from the Agence Nationale de la Recherche under “Investissements d'avenir” program (ANR-10-IAHU-01) and (ANR-21-CE12-APOthesis). This work was supported by the Israel Science Foundation grant [2071/18] to Y.T. and the Israel Ministry of Science and Technology (Navon Fellowship) to A.A. This work was also supported by the STEP-GTP Fellowship to A.A. and by the Israel-UK-Palestine GROWTH Fellowship Scheme, the British Council, to R.S. This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001PR. P.R. is a scientist from the Centre National de la Recherche Scientifique (CNRS).
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