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Genetic disorders of the surfactant system: focus on adult disease

Coline H.M. van Moorsel, Joanne J. van der Vis, Jan C. Grutters
European Respiratory Review 2021 30: 200085; DOI: 10.1183/16000617.0085-2020
Coline H.M. van Moorsel
1Dept of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands
2Division of Hearts and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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Joanne J. van der Vis
1Dept of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands
3Dept of Clinical Chemistry, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands
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Jan C. Grutters
1Dept of Pulmonology, St Antonius ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands
2Division of Hearts and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands
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  • FIGURE 1
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    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
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    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
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    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
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    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

  • Figures
  • TABLE 1

    Characteristics of genes involved in monogenic parenchymal lung disease

    CharacteristicSFTPA1SFTPA2SFTPBSFTPCABCA3NKX2-1
    Genomic
     Genomic location10q22.310q22.32p11.28p21.316p13.314q13.3
     Size kb4.54.59.59.8653.8
     Number of exons (coding)6 (4)6 (4)11 (10)6 (5)33 (30)3 (3)
     Exons encoding mature protein3–63–66–724–331–3
     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 kDa35358419139
    Disease
     InheritanceAutosomal dominantAutosomal dominantAutosomal recessiveAutosomal dominantAutosomal recessiveAutosomal dominant
     Children at diagnosisRare (one infant)Not reportedNeonatal RDS
    Rarely ILD in childhood
    ILD in childhood
    Some neonatal RDS
    Neonatal RDS
    ILD in childhood
    Neonatal RDS
    ILD in childhood
     Adults at diagnosisInterstitial pneumonitis/pulmonary fibrosis
    Lung cancer
    Interstitial pneumonitis/pulmonary fibrosis
    Lung cancer
    Not reportedInterstitial pneumonitis/pulmonary fibrosisRarely
    Interstitial pneumonitis/pulmonary fibrosis
    Rarely
    Interstitial pneumonitis/pulmonary fibrosis
     Mutation sitesCRDCRDCoding sequenceMature peptide
    C-terminal linker
    BRICHOS domain
    Coding sequenceGene deletion
    Exon 2–3
    Most frequent mutation
     Known asNANA121ins2I73TE292VNA
     DNA notationc.361delCinsGAA#c.218T>Cc.875A>T
     Proteinp.(Pro121GlufsTer95)#p.(Ile73Thr)p.(Glu292Val)
     TranscriptNM_000542.5NM_003018.3NM_001089.3
     RS numberrs35328240rs121917834rs149989682
     ClassificationPathogenicPathogenicPathogenic
     Mutation frequency>60% of mutated alleles>25% of mutated alleles<10% of mutated alleles
     OriginHaplotype of NW European descentMutation hotspotUnique haplotype associated with European descent
     GnomAD allele frequency¶0.0004+0.0000.004

    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.

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    Genetic disorders of the surfactant system: focus on adult disease
    Coline H.M. van Moorsel, Joanne J. van der Vis, Jan C. Grutters
    European Respiratory Review Mar 2021, 30 (159) 200085; DOI: 10.1183/16000617.0085-2020

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    Genetic disorders of the surfactant system: focus on adult disease
    Coline H.M. van Moorsel, Joanne J. van der Vis, Jan C. Grutters
    European Respiratory Review Mar 2021, 30 (159) 200085; DOI: 10.1183/16000617.0085-2020
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    • 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
    • Info & Metrics
    • PDF

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    • Genetics
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