Pulmonary Fibrosis And/or Bone Marrow Failure, Telomere-Related, 4

A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure-4 (PFBMFT4) is caused by heterozygous mutation in the PARN gene (604212) on chromosome 16p13.

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

Clinical Features

Stuart et al. (2015) reported 6 unrelated families with pulmonary fibrosis and/or unspecified lung disease. Affected family members had shortened telomeres (less than 1-30% of control length). A few patients had premature graying of the hair, but none were noted to have features of bone marrow failure.

Inheritance

The transmission pattern of telomere-related pulmonary fibrosis in the families reported by Stuart et al. (2015) was consistent with autosomal dominant inheritance and incomplete penetrance. There was also evidence of environmental influences, e.g., smoking and occupational factors.

Molecular Genetics

In affected members of 6 unrelated families with telomere-related pulmonary fibrosis, Stuart et al. (2015) identified 6 different heterozygous mutations in the PARN gene (see, e.g., 604212.0005-604212.0008). Five of the mutations were truncating, consistent with haploinsufficiency; 1 was a missense mutation. The mutations were found by whole-exome sequencing of 99 probands with a family history of pulmonary fibrosis. Among all families, at least 9 clinically unaffected individuals carried a pathogenic mutation, consistent with incomplete penetrance. Cells from patients with truncating mutations showed reduced protein expression, but additional functional studies were not performed.