Genetic variant characterization in intron 4 of the surfactant protein B gene

Hamvas, Aaron; Wegner, Daniel; Trusgnich, Michelle; Madden, Kenneth P.; Heins, Hillary B.; Liu, Ying; Rice, Treva; An, Ping; Watkins-Torry, Julie; Cole, F. Sessions

doi:10.1002/humu.9378

Cited by 12 publications

(5 citation statements)

References 15 publications

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“…We did not have sufficient power to pursue the contribution of these more rare mutations to the disease-based risk for RDS in our neonatal intensive care unit cohort that was not enriched for lethal RDS. Common variants in SFTPB and SFTPC with minor allele frequencies Ն0.2 have also been associated with the risk for RDS, but the mechanisms by which these variants and combinations thereof impart risk are undetermined (27)(28)(29)(30). To our knowledge, the contribution of common variants in ABCA3 to the risk of RDS has not been evaluated.…”

Section: Discussionmentioning

confidence: 99%

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

et al. 2008

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ABSTRACT:The prevalence of the common mutations in the surfactant protein-B (121ins2), surfactant protein-C (I73T), and ATP-binding cassette member A3 (E292V) genes in populationbased or case-control cohorts of newborn respiratory distress syndrome (RDS) is unknown. We determined the frequencies of these mutations in ethnically diverse population and disease-based cohorts using restriction enzyme analysis (121ins2 and E292V) and a 5Ј nuclease assay (I73T) in DNA samples from population-based cohorts in Missouri, Norway, South Korea, and South Africa, and from a case-control cohort of newborns with and without RDS (n ϭ 420). We resequenced the ATP-binding cassette member A3 gene (ABCA3) in E292V carriers and computationally inferred ABCA3 haplotypes. The population-based frequencies of 121ins2, E292V, and I73T were rare (Ͻ0.4%). E292V was present in 3.8% of newborns with RDS, a 10-fold greater prevalence than in the Missouri cohort (p Ͻ 0.001). We did not identify other loss of function mutations in ABCA3 among patients with E292V that would account for their RDS. E292V occurred on a unique haplotype that was derived from a recombination of two common ABCA3 haplotypes. E292V was over-represented in newborns with RDS suggesting that E292V or its unique haplotype impart increased genetic risk for RDS. (Pediatr Res 63: 645-649, 2008)

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Section: Discussionmentioning

confidence: 99%

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

et al. 2008

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“…Several studies have shown that intronic variant is very important for genetic diseases clinical diagnosis and sometimes as a cause of monogenic disorders and hereditary cancer syndromes [ 9 , 23 ]. Hamvas et al found that Genetic variants in intron 4 of the surfactant protein B gene SFTPB is associate with pulmonary morbidity in newborn infants and adults [ 24 ]. Weisschuh et al assigned pathogenicity to POC1B novel deep Intronic and non-canonical splice site variants [ 25 ].…”

Section: Discussionmentioning

confidence: 99%

Intronic position +9 and −9 are potentially splicing sites boundary from intronic variants analysis of whole exome sequencing data

et al. 2023

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Whole exome sequencing (WES) can also detect some intronic variants, which may affect splicing and gene expression, but how to use these intronic variants, and the characteristics about them has not been reported. This study aims to reveal the characteristics of intronic variant in WES data, to further improve the clinical diagnostic value of WES. A total of 269 WES data was analyzed, 688,778 raw variants were called, among these 367,469 intronic variants were in intronic regions flanking exons which was upstream/downstream region of the exon (default is 200 bps). Contrary to expectation, the number of intronic variants with quality control (QC) passed was the lowest at the +2 and −2 positions but not at the +1 and −1 positions. The plausible explanation was that the former had the worst effect on trans-splicing, whereas the latter did not completely abolish splicing. And surprisingly, the number of intronic variants that passed QC was the highest at the +9 and −9 positions, indicating a potential splicing site boundary. The proportion of variants which could not pass QC filtering (false variants) in the intronic regions flanking exons generally accord with “S”-shaped curve. At +5 and −5 positions, the number of variants predicted damaging by software was most. This was also the position at which many pathogenic variants had been reported in recent years. Our study revealed the characteristics of intronic variant in WES data for the first time, we found the +9 and −9 positions might be a potentially splicing sites boundary and +5 and −5 positions were potentially important sites affecting splicing or gene expression, the +2 and −2 positions seem more important splicing site than +1 and −1 positions, and we found variants in intronic regions flanking exons over ± 50 bps may be unreliable. This result can help researchers find more useful variants and demonstrate that WES data is valuable for intronic variants analysis.

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“…We omitted 380 bps in intron 4 due to inability of BigDye terminator sequencing chemistry to resolve multiple CA dinucleotide repeats in this region [26] as well as intron 10, untranslated exon 11, and the 3′ untranslated region.…”

Section: Methodsmentioning

confidence: 99%

Developmental and Genetic Regulation of Human Surfactant Protein B in vivo

et al. 2008

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Background: Genetic and developmental disruption of surfactant protein B (SP-B) expression causes neonatal respiratory distress syndrome (RDS). Objectives: To assess developmental and genetic regulation of SP-B expression in vivo. Methods: To evaluate in vivo developmental regulation of SP-B, we used immunoblotting to compare frequency of detection of mature and pro-SP-B peptides in developmentally distinct cohorts: 24 amniotic fluid samples, unfractionated tracheal aspirates from 101 infants ≥34 weeks’ gestation with (75) and without (26) neonatal RDS, and 6 nonsmoking adults. To examine genetic regulation, we used univariate and logistic regression analyses to detect associations between common SP-B (SFTPB) genotypes and SP-B peptides in the neonatal RDS cohort. Results: We found pro-SP-B peptides in 24/24 amniotic fluid samples and in 100/101 tracheal aspirates from newborn infants but none in bronchoalveolar lavage from normal adults (0/6) (p < 0.001). We detected an association (p = 0.0011) between pro-SP-B peptides (M_r 40 and 42 kDa) and genotype of a nonsynonymous single nucleotide polymorphism at genomic position 1580 that regulates amino-terminus glycosylation. Conclusions: Pro-SP-B peptides are more common in developmentally less mature humans. Association of genotype at genomic position 1580 with pro-SP-B peptides (M_r 40 and 42 kDa) suggests genetic regulation of amino terminus glycosylation in vivo.

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Genetic variant characterization in intron 4 of the surfactant protein B gene

Cited by 12 publications

References 15 publications

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

Population and Disease-Based Prevalence of the Common Mutations Associated With Surfactant Deficiency

Intronic position +9 and −9 are potentially splicing sites boundary from intronic variants analysis of whole exome sequencing data

Developmental and Genetic Regulation of Human Surfactant Protein B in vivo

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