Figures
- FIGURE 1
Mutation spectrum, age and sex of patients with surfactant-related mutations in comparison with telomere-related mutations. a) Mutation spectrum of adult Dutch probands with familial pulmonary fibrosis (mutation spectrum of the St. Antonius cohort, consisting of the probands (>18 years) of families with pulmonary fibrosis screened with whole exome sequencing. b) Age distribution of patients with a surfactant- or telomere-related gene mutation (age distribution of probands and family members with pulmonary fibrosis). Telomere-related mutation data is from the St. Antonius cohort. Surfactant mutation data is from the St. Antonius cohort and all adult cases reported in the literature. Age is the patient's age at disease diagnosis or the age reported in the literature. c) Male-to-female ratio of adult patients with monogenic pulmonary fibrosis (cohort composition is similar to that of b).
- FIGURE 2
Age at disease onset spectrum for genes associated with monogenic surfactant-related parenchymal lung disease. a) Distribution of age and sex in patients with adult-onset disease, including all cases reported in the literature and from the St. Antonius cohort (columns represent age categories for subjects with an age ±2.5 years around the column label). Age is the patient's age at disease diagnosis or the age in the original report. b) Model for monogenic surfactant-related disease, showing the relative contribution of each gene to monogenic parenchymal lung disease (the break at age 18 years represents the lack of knowledge of how paediatric data relates to adult data, while the dashed line for SFTPB is representative for US patients of North-Western origin, the frequency being much lower in other cohorts). SFTPC, SFTPA1 and SFTPA2 are heterozygous cases except for two brothers included in SFTPA1 (*).
- FIGURE 3
Radiology of patients heterozygous for a surfactant protein mutation. High-resolution computed tomography (HRCT) of patient 1 (SFTPC M71V) at diagnosis (a) and after 14 years (b) (the arrow points to a clearly walled cyst at diagnosis that collapses during disease evolution. HRCT of patient 2 (SFTPC Y113C) at diagnosis (c) and after 2 years (d) (cysts are evident at diagnosis that develop into a bullae-like structure over 2 years. HRCT of patient 3 (SFTPA2 N171Y) at 1 month prior to bilateral lung transplantation (e) with pre- and post-transplantation pulmonary function tests (f). Blue line: maximal vital capacity; red line: forced expiratory volume in 1 s; green line: diffusing capacity of the lung for carbon monoxide; dotted vertical line: time of lung transplantation (LTX).
- FIGURE 4
Pulmonary phenotype in patients with SFTPA1 or SFTPA2 mutations at diagnosis. The cohort consists of all cases reported in the literature combined with cases from the St. Antonius cohort. a) Frequency of pulmonary phenotype in the total cohort. b) Number of patients with pulmonary fibrosis, lung cancer or other lung disease grouped by age (where age is the patient's age at disease diagnosis or the age in the original report).
Tables
- TABLE 1
Characteristics of genes involved in monogenic parenchymal lung disease
Characteristic SFTPA1 SFTPA2 SFTPB SFTPC ABCA3 NKX2-1 Genomic Genomic location 10q22.3 10q22.3 2p11.2 8p21.3 16p13.3 14q13.3 Size kb 4.5 4.5 9.5 9.8 65 3.8 Number of exons (coding) 6 (4) 6 (4) 11 (10) 6 (5) 33 (30) 3 (3) Exons encoding mature protein 3–6 3–6 6–7 2 4–33 1–3 Number of amino acids in mature protein (numbering) 227 (21–248) 227 (21–248) 79 (201–279) 35 (24–58) 1704 (1–1704) 401 (1–401) Molecular weight of mature protein kDa 35 35 8 4 191 39 Disease Inheritance Autosomal dominant Autosomal dominant Autosomal recessive Autosomal dominant Autosomal recessive Autosomal dominant Children at diagnosis Rare (one infant) Not reported Neonatal RDS
Rarely ILD in childhoodILD in childhood
Some neonatal RDSNeonatal RDS
ILD in childhoodNeonatal RDS
ILD in childhoodAdults at diagnosis Interstitial pneumonitis/pulmonary fibrosis
Lung cancerInterstitial pneumonitis/pulmonary fibrosis
Lung cancerNot reported Interstitial pneumonitis/pulmonary fibrosis Rarely
Interstitial pneumonitis/pulmonary fibrosisRarely
Interstitial pneumonitis/pulmonary fibrosisMutation sites CRD CRD Coding sequence Mature peptide
C-terminal linker
BRICHOS domainCoding sequence Gene deletion
Exon 2–3Most frequent mutation Known as NA NA 121ins2 I73T E292V NA DNA notation c.361delCinsGAA# c.218T>C c.875A>T Protein p.(Pro121GlufsTer95)# p.(Ile73Thr) p.(Glu292Val) Transcript NM_000542.5 NM_003018.3 NM_001089.3 RS number rs35328240 rs121917834 rs149989682 Classification Pathogenic Pathogenic Pathogenic Mutation frequency >60% of mutated alleles >25% of mutated alleles <10% of mutated alleles Origin Haplotype of NW European descent Mutation hotspot Unique haplotype associated with European descent GnomAD allele frequency¶ 0.0004+ 0.000 0.004 RDS: respiratory distress syndrome; ILD: interstitial lung disease; CRD: carbohydrate recognition domain; NA: not applicable; NW: North-Western. #: depending on the transcript referred to as c.397delCinsGAA and p.Pro133GlnfsTer95; ¶: GnomAD frequency for European non-Finnish; +: frequency of rs779795233, the read data shows this concerns rs35328240.
Jump To
- Article
- Abstract
- Abstract
- Surfactant-related genes
- Surfactant proteins B and C
- SFTPB gene mutations
- SFTPC gene mutations
- Lamellar body protein gene ABCA3
- Surfactant proteins A and D
- SFTPA2 gene mutations
- SFTPA1 gene mutations
- Pathogenesis
- Mutation spectrum
- Age
- Sex in adult-onset disease
- Radiological and histological findings
- Lung cancer
- Genetic testing
- Therapy
- Conclusion
- Footnotes
- References
- Figures & Data
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