Inherited bone marrow failure syndromes (IBMFSs) are a set of illnesses characterized by a reduction in the generation of one or more blood cell types. Dyskeratosis congenita (DC) and its severe variation, Hyeraal-Hreidarsson (HH) syndrome, are uncommon IBMFSs characterized by bone marrow failure, developmental abnormalities, and a variety of premature aging consequences caused by dangerously short telomeres. In three unrelated patients with a DC/HH phenotype that consisted of early-onset hypocellular bone marrow failure, B & NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation, researchers found biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B. All three patients had a homozygous or compound heterozygous (with a null allele) missense mutation affecting the identical residue L142 (L142F or L142S) in Apollo’s catalytic domain.
Patients’ Apollo-deficient cells had spontaneous chromosomal instability and poor DNA repair, which was augmented by CRISPR/Cas9-mediated gene correction. Furthermore, the cells of the patients displayed symptoms of telomere fragility that were not related to a drop in telomere length overall. Human Apollo KO HT1080 cell lines, in contrast to patients’ cells, displayed severe telomere dysfunction and significant telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. The findings characterized human Apollo as a genome caregiver and uncovered biallelic Apollo variations as a genetic etiology of a previously unknown severe IBMFS with clinical features of DC/HH but normal telomere length.