A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-7 (PFBMFT7) is caused by heterozygous mutation in the NAF1 gene (617868) on chromosome 4q32.

Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-7 (PFBMFT7) is an autosomal dominant disorder characterized by variable manifestations associated with shortened telomeres. Features can include pulmonary fibrosis, emphysema, anemia, lymphopenia, liver involvement with portal hypertension and hepatopulmonary syndrome, premature graying of the hair, nail dystrophy, and predisposition to squamous cell cancers or myelodysplasia (Stanley et al., 2016).

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

Stanley et al. (2016) reported a family (JH1) with variable manifestations of a short telomere syndrome. The proband was a 54-year-old woman diagnosed with pulmonary fibrosis and emphysema at age 44; she had a history of smoking. She also had extrapulmonary manifestations associated with short telomere syndromes, including premature graying of the hair (age 24), hepatopulmonary syndrome with noncirrhotic portal hypertension (age 53), squamous cell skin cancer (age 28), and myelodysplastic syndrome (age 54); she died at 54 years of age. Her mother and 2 sibs also had short telomeres with variable manifestations in each patient, including premature graying of the hair, nail dystrophy, lymphopenia, liver disease with portal hypertension, emphysema, and anemia. Genetic analysis identified a heterozygous frameshift mutation in the NAF1 gene that segregated with the disorder. Proband JH1 was identified from a cohort of 5 patients with pulmonary fibrosis and emphysema who underwent whole-genome sequencing. Subsequently, sequencing of the NAF1 gene among 25 patients with pulmonary fibrosis identified 1 patient (JH2) with a heterozygous frameshift mutation in the NAF1 gene. This patient was a woman with pulmonary fibrosis (age 56), bone marrow failure (age 56), chronic thrombocytopenia, and abnormal liver function who died at age 57. She had never smoked and underwent lung transplant, but developed sepsis afterwards. She did not have a family history of the disorder.

Schratz et al. (2023) identified 16 invasive solid tumors in 14 of 226 adults with short telomere syndromes due to mutations in several genes, including at least 1 patient with a NAF1 mutation. Nearly all (88%) of the tumors were derived from the squamous cell epithelium, most commonly of the head and neck, followed by anal squamous cell carcinoma and skin squamous cell carcinoma. In contrast, there was a lower than expected number of common age-related solid cancers among these patients. Most of the patients who developed squamous cell solid tumors were male. Development of the tumors was associated with CD4+ T-cell lymphopenia, suggesting impaired tumor surveillance by T cells and age-related T-cell exhaustion. Of note, all 3 anal cancers and 1 laryngeal cancer were associated with HPV infection, and 4 of 10 patients with T-cell lymphopenia had secondary causes for the lymphopenia (lung or liver transplant or iatrogenic immunosuppression).

The transmission pattern of PFBMFT7 in the family reported by Stanley et al. (2016) was consistent with autosomal dominant inheritance.

In 4 affected members of a 2-generation family (JH1) with PFBMFT7, Stanley et al. (2016) identified a heterozygous frameshift mutation in the NAF1 gene (617868.0001). The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. Subsequent direct sequencing of the NAF1 gene among another cohort of patients with pulmonary fibrosis identified 1 woman (JH2) who carried a different heterozygous frameshift mutation (617868.0002). The patients had short telomere length and low telomerase RNA levels (TERC; 602322). In vitro functional studies indicated that the mutations caused a partial or complete loss of NAF1 function and did not act in a dominant-negative manner. The authors concluded that NAF1 haploinsufficiency disturbs telomere length homeostasis by decreasing the levels of TERC. Altogether, NAF1 mutations were found in 2 (7%) of 30 patients with pulmonary fibrosis.