A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-9 (PFBMFT9) is caused by heterozygous mutation in the NOP10 gene (606471) on chromosome 15q14. One such family has been reported.

Telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-9 (PFBMFT9) is an autosomal dominant short telomere syndrome characterized by the development of pulmonary fibrosis or hematologic abnormalities, including leukopenia and leukemia, in adulthood. Liver disease may also be present. There is incomplete penetrance and evidence of genetic anticipation. Affected individuals have shortened telomeres, but do not show mucocutaneous manifestations (Kannengiesser et al., 2020).

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

Kannengiesser et al. (2020) reported a large 3-generation family with variable pulmonary and hematologic abnormalities associated with short telomeres. The proband was a woman diagnosed with pulmonary fibrosis at 66 years of age. Three of her sibs, 2 of whom were deceased, also developed pulmonary fibrosis between 62 and 78 years of age; all were nonsmokers. Another sib and his son died of leukemia at ages 61 and 26, respectively. One of the sons of the proband had long-term leukopenia. The father of the proband, who died at age 80, had nonalcoholic liver cirrhosis. Mucocutaneous manifestations were not observed in this family. Five of the patients carried a heterozygous mutation in the NOP10 gene; 3 had pulmonary fibrosis and 1 had long-term leukopenia. The fifth individual with the mutation had no lung or blood disease at age 50.

The transmission pattern of PFBMFT9 in the family reported by Kannengiesser et al. (2020) was consistent with autosomal dominant inheritance with incomplete penetrance. Genetic anticipation was also observed.

In 4 affected individuals from a large family with PFBMFT9, Kannengiesser et al. (2020) identified a heterozygous missense mutation in the NOP10 gene (Y6C; 606471.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not present in 140,000 individuals in the gnomAD database. One unaffected family member also carried the mutation, suggesting incomplete penetrance. Functional studies of the mutation and studies of patient cells were not performed, but molecular modeling demonstrated that the affected residue is in a region in close contact with DKC1 (300126) and likely disrupts stability of the domain and the NOP10 complex. Patients with the mutation showed short telomeres, although 1 noncarrier also had short telomeres, suggesting that epigenetic factors may play a role in telomere length.