A number sign (#) is used with this entry because of evidence that telomere-related pulmonary fibrosis and/or bone marrow failure syndrome-5 (PFBMFT5) is caused by heterozygous mutation in the ZCCHC8 gene (616381) on chromosome 12q24. One such family has been reported.

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

Individuals with PFBMFT5 have an age-dependent, rapidly progressive phenotype of pulmonary fibrosis and/or bone marrow failure with short telomeres and low levels of TERC (602322), a specialized noncoding RNA that provides the template for telomere repeat addition (Gable et al., 2019).

Gable et al. (2019) reported a large multigenerational family in which 4 individuals had pulmonary fibrosis and/or bone marrow failure. Three of the patients had died between 50 and 58 years of age. The surviving proband, who developed idiopathic pulmonary fibrosis at age 42 and bone marrow failure at age 48, had 2 sons who were asymptomatic. Laboratory studies of the proband and his 2 sons showed that all had shortened telomeres and low levels (about 50%) of TERC (602322) compared to controls.

The transmission pattern of PFBMFT5 in the family reported by Gable et al. (2019) was consistent with autosomal dominant inheritance.

In 3 members of a family with PFBMFT5, Gable et al. (2019) identified a heterozygous missense mutation in the ZCCHC8 gene (P186L; 616381.0001). The mutation, which was found by a combination of linkage analysis and whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two younger asymptomatic family members who had short telomeres also carried the mutation. The mutation was not found in the 1000 Genomes Project, Exome Sequencing Project, ExAC, or gnomAD databases. Analysis of patient cells showed a 50% decrease in ZCCHC8 protein levels compared to controls, suggesting that the mutation compromised protein stability. Patient cells also showed dysregulation of RNA processing, with abnormal accumulation of TERC precursors at the expense of mature TERC.

Gable et al. (2019) found that homozygous loss of Zcchc8 in mice resulted in postnatal lethality by 70 days. Zcchc8-null mice showed progressive neurodevelopmental defects, with small brain volume, defective neurogenesis, and hydrocephalus. Some of the features were consistent with a ciliopathy. These abnormalities were associated with defective turnover of low abundance RNA polymerase II (see 180660) transcripts and abnormal accumulation of other low abundance RNAs, including histones and RNAs that encode cilia protein components. The findings were consistent with dysregulation of RNA processing.