Surfactant Protein C Deficiency via the SFTPC Gene

Surfactant Protein C (SP-C) deficiency is a respiratory disorder due to dysfunction of surfactant composition. Surfactant is a lipid and protein mixture lining the lung tissue that lowers alveolar surface tension and prevents atelectasis during expiration. Loss of surfactant function results in alveoli collapse following expiration leading to shortness of breath and impaired oxygen delivery in the lung. Patients with SP-C deficiency have variable clinical presentation from lethal disease via respiratory failure in infancy to asymptomatic (Thomas et al. 2002; Hamvas 2006). Adult forms present with idiopathic interstitial pneumonias and pulmonary fibrosis (van Moorsel et al. 2010; Gower and Nogee 2011). Genetic testing is helpful in the differential diagnosis of SP-B deficiency from other surfactant deficiencies, non-bacterial pneumonitis, chemical/inhalant pneumonitis, chronic aspiration, and immunologically mediated lung disease (Hamvas 2006).

SP-C deficiency in inherited in an autosomal dominant manner through pathogenic variants in the SFTPC gene. Surfactant dysfunction may also be inherited in an autosomal dominant manner through pathogenic variants in NKX2-1 or an autosomal recessive manner through pathogenic variants in the SFTPB and ABCA3 genes (Hamvas 2006; Weaver and Conkright 2001). SP-C deficiency onset and clinical features are variable within families even when presenting with the same pathogenic variant. This is thought to be due to environmental and other genetic modifiers that influence presentation of SP-C Deficiency (Thomas et al. 2002). Nearly 50% of cases of SP-C deficiency have de novo pathogenic variants in the SFTPC gene. Missense variants account for the majority of pathogenic variants, occur within the linker and BRIOCHOS domains and disrupt intracellular trafficking of the SFTPC protein (Thurm et al. 2013; Willander et al. 2012; Sáenz et al. 2015). The c.218T>C (p.Ile73Thr) variant is the most common pathogenic variant and is found in about a quarter of cases of SP-C deficiency. Splice site and small insertions/deletions have also been reported in patients with SP-C deficiency (Hamvas 2006). The SFTPC gene encodes surfactant protein C, an integral membrane protein. Surfactant protein C is initially produced as a pro-peptide requiring proteolytic processing prior to insertion in the cell membrane. Surfactant protein C aids in lowering alveolar surface tension to prevent atelectasis (Weaver and Conkright 2001).

Clinical sensitivity is currently unknown as only a small number of patients have been reported with SP-C deficiency. Analytical sensitivity is high as all reported pathogenic variants to date are detectable by sequencing.

This test provides full coverage of all coding exons of the SFTPC gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).