A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is caused by heterozygous mutation in the RPA1 gene (179835) on chromosome 17p13.

Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-6 (PFBMFT6) is characterized by highly variable symptoms mainly affecting the hematopoietic or pulmonary systems. The age of symptom onset is also highly variable, ranging from infancy to adulthood. Some affected individuals develop early-onset pancytopenia, immunodeficiency, or myelodysplasia, whereas others manifest late-onset pulmonary fibrosis. Skin, nail, or hair features resembling dyskeratosis congenita (DKC; see, e.g., DKCA1, 127550) may also be observed. Both PFBMFT6 and DKCA are associated with shortened telomeres, thus sharing a pathogenetic mechanism (summary by Sharma et al., 2022).

For a discussion of genetic heterogeneity of telomere-related pulmonary fibrosis and/or bone marrow failure, see PFBMFT1 (614742).

Sharma et al. (2022) reported 4 unrelated probands with variable hematologic, pulmonary, and skin manifestations associated with short telomeres. Patient 1 was a 28-year-old woman who presented at 10 years of age with pancytopenia, hypoplastic bone marrow, and a history of congenital eye anomaly requiring enucleation as an infant. She developed a classic dyskeratosis congenita-associated mucocutaneous triad during adolescence, including leukoplakia, nail dystrophy, and reticular skin pigmentation, but did not require treatment. Her blood counts stabilized over time due to somatic reversion (see MOLECULAR GENETICS). Patient 2 presented at age 13 years with myelodysplastic syndrome (MDS) with excess blasts and a somatic NRAS mutation (G12D; 164790.0007) at 37% allelic frequency. She also had facial dysmorphism and mildly restricted pulmonary function. After undergoing hematopoietic stem cell transplant, she developed significant complications with graft-versus-host disease, necrotizing pneumonitis, recurrent infections, and pulmonary fibrosis. She died of multiorgan failure 11 months post-transplant. The unaffected father and sister of P2 also carried a RPA1 mutation, suggesting incomplete disease penetrance. Patient 3 had early hair graying and onset of progressive pulmonary fibrosis at age 58 years. Two sisters of P3 were also diagnosed with pulmonary fibrosis and died of the disease; no DNA was available. P4 was a 3-year-old girl who presented at birth with prematurity, failure to thrive, lymphopenia, and hypogammaglobulinemia. At age 3, she was stable on IgG replacement therapy. Telomere length, assessed by different methods, was decreased in the blood cells of all patients.

The transmission pattern of PFBMFT6 in 2 unrelated families (families 2 and 3) reported by Sharma et al. (2022) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity. The heterozygous mutations in the RPA1 gene that were identified in 2 patients (patients 1 and 4) with PFBMFT6 by Sharma et al. (2022) occurred de novo.

In 4 unrelated probands with PFBMFT6, Sharma et al. (2022) identified heterozygous missense mutations in the RPA1 gene affecting residues in the DNA-binding domain-A (DBD-A) (E240K, 179835.0001; V227A, 179835.0002, and T270A, 179835.0003). The mutations, which were found by exome sequencing, were either absent from the gnomAD database or present at a very low frequency. Two mutations occurred de novo and 1 was inherited from an unaffected parent; familial segregation studies for patient 3 could not be determined. In vitro functional expression studies showed that the E240K and V227A variants had increased binding to ssDNA and telomeric DNA compared to controls, consistent with a gain-of-function effect. In contrast, T270A had binding properties similar to wildtype, but was postulated to have other detrimental effects. Expression of the E240K mutation into iPSC-derived hematopoietic cells resulted in shortened telomeres and impaired differentiation of hematopoietic progenitor cells, particularly of the erythroid and myeloid lineages, but also affecting CD34+ cells. Of note, patient 1 had an atypical disease course with stabilization of blood counts and mucocutaneous features without intervention over 18 years. Her bone marrow analysis at age 13 showed reduced expression of the mutant E240K variant (27%) compared to fibroblasts (50%). Two somatic events were identified in the bone marrow that interfered with expression and proliferation of the mutant E240K allele: an RPA1 truncating (K579X) mutation at 10% allelic frequency and in cis with E240K, causing degradation of germline mutant RNA, and uniparental isodisomy of chromosome 17p, resulting in replacement of the germline variant with a wildtype allele. These allelic patterns were maintained over time and likely caused a rescue effect that coincided with the lack of progressive symptoms in the patient.