Submission Details

NOP10 was first reported in relation to semidominant pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9 in 2020 (Kannengiesser C et al., PMID:32139460). Some patients present with pulmonary fibrosis, in the heterozygous state typically later in life; some patients present with extrapulmonary phenotype earlier in life. Individuals with dyskeratosis congenita are also included in this curation. Dyskeratosis congenita is a multisystem disorder that variably includes nail, skin and mucosal findings, bone marrow failure, cancer predisposition, interstitial lung disease and hepatic fibrosis, among other manifestations. In the index family reported by Kannengiesser C et al., two individuals are deceased from leukemia (death age 26 and 61) and one individual had long term leukopenia (age 43 at report). These findings are relevant to the possible association between NOP10 and childhood, adolescent and young adult cancer predisposition. At least 2 unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.

Variants in NOP10 have been reported in individuals with the following disease entities: Cataracts, hearing impairment, nephrotic syndrome, and enterocolitis 2; Dyskeratosis congenita, autosomal recessive 1; and Pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 9. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or phenotypic variability between the pulmonary fibrosis and dyskeratosis congenita phenotypes. Therefore, those entities have been lumped into one disease entity (OMIM:620400) and split from the cataracts phenotype.

This gene-disease relationship is supported by a cell model showing that the knockdown of NOP10 using siRNAs results in reduced TERC expression, which is consistent with patient cell assays (PMID:17507419) and coimmunoprecipitation that shows the physical association of NOP10 protein with DKC1 protein, DKC1 has been implicated in the same disease by this expert panel (PMID:11074001).

Variants in this gene have been reported in at least 2 probands in 2 publications (PMID:32139460, 17507419). Variants in this gene segregated with disease in five additional family members with more having been tested.

In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Interstitial Lung Disease Gene Curation Expert Panel on the meeting date 18 March 2025 (SOP Version 11).

The Childhood, Adolescent and Young Adult Cancer Predisposition GCEP participated in discussion and contributed to our classification of this gene as a secondary contributor.