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| Pulmonary Fibrosis_Interstitial Lung Disease v0.90 | NHP2 |
Chirag Patel gene: NHP2 was added gene: NHP2 was added to Pulmonary Fibrosis_Interstitial Lung Disease. Sources: Expert Review Mode of inheritance for gene: NHP2 was set to BIALLELIC, autosomal or pseudoautosomal Phenotypes for gene: NHP2 were set to Dyskeratosis congenita, autosomal recessive 2 MONDO:0013519 Review for gene: NHP2 was set to RED Added comment: ClinGen 'limited' classification. NHP2 ribonucleoprotein (NHP2) was first reported in relation to autosomal recessive dyskeratosis congenita in 2008 (Vulliamy et al., PMID 18523010). NHP2 biallelic variant carriers present with features common to other monogenic telomere biology disorders (TBD) like: oral leukoplakia, reticular skin pigmentation, nail dystrophy, bone marrow failure, intellectual disability, and short telomeres. Variation in other telomere related genes like TERT and TERC have been shown to be related to interstitial lung disease (ILD), but to date ILD has not been observed for this gene-disease entity (PMID 38718684). Seven variants (6 missense, and 1 stop-loss extension) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data from 3 different publications describing a total of 4 probands with ages of onset being reported in both childhood and adulthood. Additionally, 4 families have been reported with heterozygous variant carriers that have presented with features consistent with TBD. The ClinGen Interstitial Lung Disease GCEP has decided to exclude heterozygous cases from this curation due to high population frequencies and/or lack of sufficient detail regarding genotyping. If, however, more convincing data of autosomal dominant inheritance becomes available, the curated entity and classification will be revisited. This gene-disease relationship is supported by protein interaction data, a yeast model and functional alteration in non-patient cells; PMID 11160879, 11074001, 37440454). Experimental data demonstrated that variant NHP2 is related to a decrease in the expression of TERC, and that expression of variant NHP2 and interaction with NOP10 and DKC1 were reduced. The mechanism is unclear but thought to be LOF. 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 GCEP on the meeting date April 15, 2025 (SOP 11). This gene-disease pair was originally evaluated by the General GCEP on June 1, 2017. It was reevaluated on August 1, 2025. Although additional case and experimental evidence (PMIDs: 37440454, 31985013) was published, the classification did not change. Sources: Expert Review |
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