Pulmonary fibrosis familial

Gene: MUC5B

Green List (high evidence)

Comment on mode of inheritance: There are at least 3 unrelated families where individuals with bronchiectasis and recurrent pulmonary infections carried homozygous or compound heterozygous variants in MUCB5. In addition, a supportive mouse model showed that muc5b -/- knockout leads to airway obstruction and spontaneous pulmonary infections. Based on available evidence, the mode of inheritance should be changed to BOTH monoallelic and biallelic, autosomal or pseudoautosomal for Pulmonary fibrosis familial.

Created: 29 Dec 2025, 11:48 a.m. | Last Modified: 29 Dec 2025, 11:48 a.m.

Panel Version: 1.7

PMID: 35023825 Costain et al., 2022
Report of an adult proband with unexplained bronchiectasis, impaired pulmonary function, and repeated Staphylococcus aureus infection. WGS detected a homozygous MUC5B NM_002458.2: c.1938 + 1G>A variant. MUC5B protein absent from saliva, sputum, and nasal samples. Affected homozygous sibling presented with extensive sinus disease with nasal polyps, chronic nonproductive cough and a history of recurrent lung infections. 3 heterozygous siblings were asymptomatic.

PMID: 33526882 Alsamri et al., 2021
Two siblings with severe respiratory disease since birth. Both homozygous for NM_002458.2(MUC5B):c.16861G > T, p.Glu5621*. One of the siblings also carried a heterozygous variant SFTPA1:c.675C > G, resulting in more severe respiratory disease (SFTPA1 is associated with Interstitial lung disease). Lung biopsy of the sibling without the SFTPA1 variant showed 'alveolar simplification, interstitial fibrosis, intra-alveolar lipid-laden macrophages, and foci of foreign body giant cell reaction in distal airspaces'.

In addition, MUC5B:c.14936 T > C, p.Ile4979Thr (rs201287218) and MUC5B:c.16738G > A, p.Gly5580Arg (rs776709402) were found in compound heterozygous state in two siblings with severe respiratory disease from birth - posed to be causal, despite a Likely Benign classification in Varsome ACMG classification (rs201287218 has highest MAF = 0.001559 in African population, and rs776709402 MAF = 0.00004806 in Remaining population - neither has reported homozygotes in gnomAD v4.1.0).

https://acmcasereport.org/wp-content/uploads/2023/11/ACMCR-v11-2040.pdf (no PMID) - case report by Mukhtar et al., 2023
Report of an 8-year-old girl from Saudi Arabia with recurrent pulmonary exacerbation, bronchiectasis, and impaired mucociliary clearance. She had a homozygous MUC5B variant c.5145del p. (Thr1716Argf8*26) - detected by WES.

Functional evidence: PMID: 24317696 Roy et al., 2014: Muc5b−/− mice developed upper airway obstruction and spontaneous infection of upper and lower airways, followed by fatal bacteremia.

MUC5B is linked to {Pulmonary fibrosis, idiopathic, susceptibility to}, MIM:178500 in OMIM (accessed 29th Dec 2025).

Created: 29 Dec 2025, 11:42 a.m. | Last Modified: 29 Dec 2025, 11:42 a.m.

Panel Version: 1.7

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
{Pulmonary fibrosis, idiopathic, susceptibility to}, OMIM:178500; Pulmonary fibrosis, HP:0002206

Publications

• 24317696
• 33526882
• 35023825

Green List (high evidence)

NOTE: ONLY the MUC5B risk allele rs35705950 should be included in testing NOT the whole gene

Created: 26 Jun 2025, 2:33 p.m. | Last Modified: 26 Jun 2025, 2:33 p.m.

Panel Version: 1.7

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Risk allele for Pulmonary Fibrosis

Mode of pathogenicity
Other

Variants in this GENE are reported as part of current diagnostic practice

This gene has been added to the panel on the recommendation of the NHS Genomic Medicine Service and should be rated green.

Created: 22 Feb 2022, 3:45 p.m. | Last Modified: 22 Feb 2022, 3:45 p.m.

Panel Version: 0.4

Association of the minor allele (T) of a single common SNP in the promoter of MUC5B (rs35705950), conferring susceptibility to idiopathic pulmonary fibrosis.

Applicant review states, 'There are no known or published ethnic differences in detection rates, except for a low allele frequency of a MUC5B promotor SNP in Africans, which is known to be a risk allele for FPF. This SNP would be included in a gene panel for FPF'

Created: 16 Feb 2022, 4:02 p.m. | Last Modified: 22 Feb 2022, 3:41 p.m.

Panel Version: 0.2