Table 1.

Predisposition to Pulmonary Fibrosis: Genes and Distinguishing Clinical Features

Gene 1% of all FPFMOIAge of Onset of Pulmonary FibrosisDistinguishing Features
Genes associated w/telomere maintenance 2 DKC1 ~1% 3XL 4AdultShort telomere syndrome features
NAF1 ~1% 5, 6ADAdultCombined PF & emphysema; short telomere syndrome features
PARN 4%-5% 5, 7AD
AR		Mean: 64 yrs
RTEL1 4%-9% 5, 8ADMean: 60 yrs
TERC 2%-5% 9ADMean: 51 yrsShort telomere syndrome features
TERT 15%-20% 5, 10, 11AD>40 yrs (mean: 58 yrs; PF in >60% of those age >60 yrs)Some persons have combined PF & emphysema
TINF2 ~1% 12ADAdultShort telomere syndrome features
ZCCHC8 <1%ADAdult± bone marrow failure
Genes associated w/surfactant metabolism ABCA3 <1% 13ARRare in adults, more common in childhood-onset PFLung radiographs show ground glass opacities, reticulations, & cysts of variable size, predominantly involving upper lobes
SFTPA1 <1% 14, 15ADAdultLung adenocarcinoma
SFTPA2 <1% 14, 16ADAdultLung adenocarcinoma
SFTPC 1%-5% 14, 17ADInfancy to late adulthoodWide array of radiographic abnormalities, incl combined PF & emphysema, & atypical upper lobe involvement 18

AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; PF = pulmonary fibrosis

1.

Genes are listed alphabetically.

2.

Persons w/predisposition to PF associated with a gene involved in telomere maintenance may have additional features within the spectrum of telomere biology disorders (of which classic dyskeratosis congenita is the most severe phenotype; see Table 2).

3.
4.

Heterozygous females can be variably affected [Alder et al 2013].

5.

Loss-of-function variants in NAF1, PARN, RTEL1, and TERT are typically pathogenic.

6.
7.

OMIM 616371; rarely associated with AR inheritance [Zhang et al 2019]

8.

OMIM 616373

9.

OMIM 614743

10.

OMIM 614742

11.

Individuals with germline pathogenic variants in genes associated with short telomere syndrome, especially those older than age 60 years, may acquire somatic TERT promoter pathogenic variants in circulating leukocytes [Maryoung et al 2017, Gutierrez-Rodrigues et al 2019].

12.
13.
14.

Pathogenic variants in the surfactant metabolism genes (SFTPA1, SFTPA2, SFTPC) are typically missense variants that lead to increased endoplasmic reticulum stress.

15.
16.

OMIM 178642

17.

OMIM 610913

18.

From: Pulmonary Fibrosis Predisposition Overview

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