Recombination as a mechanism for sporadic mutation in the surfactant protein‐C gene

Abstract

SUMMARYObjective-To determine haplotype background of common mutations in the genes encoding surfactant proteins B and C (SFTPB and SFTPC) and to assess recombination in SFTPC.Study design-Using comprehensive resequencing of SFTPC and SFTPB, we assessed linkage disequilibrium (LD) (D'), and computationally inferred haplotypes. We computed average recombination rates and Bayes factors (BFs) within SFTPC in a population cohort and near SFTPC (±50kb) in HapMap cohorts. We then biochemically confirmed haplotypes in families with sporadic SFTPC mutations (n=11) and in individuals with the common SFTPB mutation (121ins2, n=34).Results-We detected strong evidence (weak LD and BFs > 1400) for an intragenic recombination hot spot in both genes. The 121ins2 SFTPB mutation occurred predominantly (89%) on 2 common haplotypes. In contrast, no consistent haplotypes were associated with mutated SFTPC alleles. Sporadic SFTPC mutations arose on the paternal allele in 4 of 5 families; the remaining child had evidence for somatic recombination on the mutated allele.Conclusions-In contrast to SFTPB, disease alleles at SFTPC do not share a common haplotype background. Most sporadic mutations in SFTPC occurred on the paternal allele, but somatic recombination may be an important mechanism of mutation in SFTPC.

Genotype alone does not predict the clinical course ofSFTPCdeficiency in paediatric patients

“…In patient 16, carrying p.A53T and p.L181V was likely disease-causing, as the leucine is highly conserved across species and the variation is predicted to be protein damaging or probably damaging by SIFT and PolyPhen-2. Additionally, p.L181V has been reported in one adult with idiopathic pulmonary fibrosis (IPF) [26] and in one child with ILD [27]. In an epidemiological study, p.A53T in contrast was associated with a two-fold increased risk of asthma [28], but not ILD or chronic obstructive pulmonary disease.…”

Surfactant Protein-C Promoter Variants Associated With Neonatal Respiratory Distress Syndrome Reduce Transcription

“…We bidirectionally sequenced all translated exons, introns, and promoter region of SFTPC (~6kb total) from 269 infants as previously described (22). We used Phred, Phrap, PolyPhred, and Consed (http://www.phrap.org/phredphrapconsed.html) to identify and annotate single nucleotide polymorphisms (SNPs) in sequencing chromatograms and Prettybase (http://pga.mbt.washington.edu) to extract a final file with genotypes.…”

An Official American Thoracic Society Clinical Practice Guideline: Classification, Evaluation, and Management of Childhood Interstitial Lung Disease in Infancy

“…The prevalence of mutations in SFTPC or ABCA3 are estimated from more than 20 case reports (169)(170)(171)(172) and case series (42,70,151,152,157,167,168,171,(173)(174)(175)(176)(177). Our confidence in the estimates is limited by the potential selection bias inherent in some of these studies, which could have biased the results toward a higher estimated prevalence.…”