Thursday, March 23, 2023
| Patient 1 (P1) | Patient 2 (P2) | Patient 3 (P3) | |
|---|---|---|---|
| Sex | Male | Female | Male |
| Consanguinity | No | Yes | No |
| Ethnicity | French Caucasian | Portuguese | Argentinian |
| Developmental features | |||
| IUGR | No | Yes, < 3rd percentile | No |
| Prematurity | No | Yes (36 WG) | No |
| Microcephaly | Yes (< 2.5 SD) | Yes (< 2 SD) | No |
| Dysmorphy | Yes (hypotelorism) | Yes | No |
| Hypocellular bone marrow failure | Yes, at 4 months | Yes, at birth | Yes, at 3 months |
| Immunodeficiency | Yes | Yes | Yes |
| Neurological features | |||
| Developmental delay | Speech delay | Mild learning difficulties | No |
| Cerebellar atrophy | No | No | No |
| Gastrointestinal features | Esophageal strictures | Esophageal strictures | Inflammatory colitis |
| Mucocutaneous features | None | Oral leukoplakia | None |
| Nail dystrophy | |||
| Skin hyperpigmentation | |||
| Increased DEB-induced chromosome breaks in blood cells | No | No | No |
| Outcome | HSCT at 15 months, alive | HSCT at 8 months, alive | Alive, under transfusion support and Ig replacement |
| HSCT conditioning regimens | Fludarabine, busulfan, ATG | Fludarabine, cyclophosphamide, ATG | NA |
| Toxicity | No | Cutaneous GVHD | NA |
Table 1. Clinical features of patients
IUGR, intrauterine growth retardation; SD, standard deviation; DEB, diepoxybutane; HSCT, hematopoietic stem cell transplantation; ATG, anti-thymocyte globulin; GVHD, graft-versus-host disease; WG, weeks of gestation; NA, not applicable.
Physicians - maximum of 1.00 AMA PRA Category 1 Credit(s)™
ABIM Diplomates - maximum of 1.00 ABIM MOC points
This activity is intended for hematologists, oncologists, pediatricians, geneticists, pathologists, internal medicine, and other clinicians caring for patients with inherited bone marrow failure syndromes (IBMFS) caused by Apollo variants.
The goal of this activity is to describe biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B (Apollo) in 3 unrelated patients with a dyskeratosis congenita (DC) Høyeraal-Hreidarsson (HH) phenotype, including early onset hypocellular BMF, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation.
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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.
Inherited bone marrow failure syndromes (IBMFSs) represent heterogeneous Mendelian diseases having in common an impaired production of 1 or several blood cell lineages.[1] Growth delay, mucocutaneous abnormalities, developmental defects, and cancer predisposition are other clinical outcomes that can manifest in IBMFS.[1] Dyskeratosis congenita (DC) and its severe variant Høyeraal-Hreidarsson (HH) syndrome are rare IBMFSs. DC is mainly characterized by progressive bone marrow failure, premature aging manifestations, and increased cancer predisposition, whereas HH can associate with early-onset bone marrow failure, intrauterine growth retardation (IUGR), microcephaly, and/or cerebellar hypoplasia, and immunodeficiency.[2,3] Because DC and HH are caused by genetic defects that affect the integrity and/or the length of telomeres, they belong to a heterogeneous group of conditions termed either telomere biology disorders (TBDs), telomeropathies, or short telomere syndromes.[2–5] Telomeres are constituted by double-stranded TTAGGG repeats terminated by a 3' single-stranded sequence called G-overhang. Telomeres are decorated by a complex named shelterin[6] composed of 6 proteins (TRF1, TRF2, TIN2, RAP1, TPP1, and POT1) among which TRF1 and TRF2 bind directly to the duplex telomeric DNA and POT1 binds to the single-strand G-overhang.[6] Shelterin is essential for the protection of chromosomes from degradation and/or fusion and for maintaining telomere length.[7] To date, variants in 11 factors (TERT, TERC, dyskerin, NOP10, NHP2, TCAB1, TIN2, TPP1, CTC1, RTEL1, and PARN) that participate in telomere biology have been found to cause DC and HH.[2,3,8] In DC and HH, the severity and onset of symptoms are generally correlated to the degree of telomere length reduction.[9,10] Thus, telomere length determination is an effective approach to diagnose DC/HH in patients with IBMFS.[2,10,11]
Apollo (SNM1B), encoded by the DNA cross-link repair 1B (DCLRE1B/Apollo; NC_000001.11) gene, is a 5'-to-3' DNA exo-nuclease that functions within the Fanconi anemia (FA) pathway and is involved in the repair of both mitomycin C (MMC)-induced DNA interstrand crosslinks (ICL) and DNA double-strand breaks (DSB)[12] as well as the stabilization of stalled replication forks and S-phase checkpoint activation.[13–17] Moreover, the identification of single nucleotide polymorphisms in the DCLRE1B/Apollo locus associated with breast cancers and cutaneous melanoma supported a protective role of Apollo in genome integrity.[18,19]
Apollo also participates in telomere protection via an interaction between its telomeric repeat factors homology (TRFH)–binding motif (TBM) and the TRFH domain of TRF2.[20–23] Apollo KO mouse embryonic fibroblasts (MEFs) exhibited impaired production of G-overhangs and frequent telomere fusions at the newly-replicated leading-end telomeres. This observation suggested that the nuclease activity of Apollo is involved in the generation of G-overhang that avoids fusion of leading telomeres.[24–26] In human cells, the role of Apollo at telomeres is less clear since its depletion induces telomere fragility causing multiple telomeric signals (MTS), that is however not associated with impaired G-overhang, increased telomere fusion or telomere shortening.[20,21] Nonetheless, it has been demonstrated that human Apollo together with TRF2 and the topoisomerase Topo-IIafunction in DNA replication of telomeric sequences by alleviating topological stress.[23]
We previously described a HH patient expressing an aberrantly spliced Apollo transcript leading to the production of a truncated Apollo that exerted a dominant negative effect on the stability of telomeres without affecting their global length.[27] Nonetheless, because we failed to identify the origin of the splice anomaly, we were unable to demonstrate a causal link between the truncated form of Apollo and the patient's clinical features.[27] Thus, although Apollo appears to be important for telomere stability and DNA repair, its relative contribution to telomere maintenance and genome integrity remains elusive, especially in humans.
Here, we identified biallelic Apollo/DCLRE1B variants in children exhibiting clinical features akin to DC/HH that are, however, not associated with decreased telomere length. Our study defines human Apollo as a genome caretaker.
