Objective To review the pathophysiology, evaluation, management, and outcomes of children with inherited disorders of surfactant metabolism due to mutations in the genes encoding surfactant proteins-B or -C（SFTPB, SF...Objective To review the pathophysiology, evaluation, management, and outcomes of children with inherited disorders of surfactant metabolism due to mutations in the genes encoding surfactant proteins-B or -C（SFTPB, SFTPC）, ATP binding cassette member A3 （ABCA3）, and thyroid transcription factor （NKX2.1）.Data sources Review of the literature, previous work from the author＇s and collaborators＇ laboratories, St. Louis Children＇s Hospital Lung Transplant Database.Study selection Key articles in the field, author＇s work.Results Inherited disorders of surfactant metabolism present as acute, severe respiratory dysfunction in the neonatal period （SFTPB, ABCA3, NKX2.1） or as chronic respiratory insufficiency in later infancy and childhood which is of variable onset, severity, and course （SFTPC, ABCA3, NKX2.1）. Diagnosis is established with sequencing the relevant genes; lung biopsy with electron microscopy is a useful adjunct. For surfactant protein-B and ABCA3 deficiency presenting with acute neonatal disease, treatment options are limited to lung transplantation or compassionate care. For the more chronic presentations of surfactant protein-C, ABCA3, and NKX2.1 associated disease, the natural history is variable and therefore individualized, supportive care is appropriate,Conclusions Inherited disorders of surfactant metabolism are rare, but informative diseases that provide unique opportunities for understanding mechanisms of respiratory disease in newborns and children.展开更多
Background: Rare mutations in surfactant-associatedgenes contribute to neonatal respiratory distress syndrome.The frequency of mutations in these genes in the Chinesepopulation is unknown.Methods: We obtained blood sp...Background: Rare mutations in surfactant-associatedgenes contribute to neonatal respiratory distress syndrome.The frequency of mutations in these genes in the Chinesepopulation is unknown.Methods: We obtained blood spots from the GuangxiNeonatal Screening Center in Nanning, China thatincluded Han (n=443) and Zhuang (n=313) ethnic groups.We resequenced all exons of the surfactant proteins-B(SFTPB), -C (SFTPC), and the ATP-binding cassettemember A3 (ABCA3) genes and compared the frequenciesof 5 common and all rare variants.Results: We found minor differences in thefrequencies of the common variants in the Han andZhuang cohorts. We did not find any rare mutations inSFTPB or SFTPC, but we found three ABCA3 mutationsin the Han [minor allele frequency (MAF)=0.003] and 7 inthe Zhuang (MAF=0.011) cohorts (P=0.10). The ABCA3mutations were unique to each cohort;five were novel.The collapsed carrier rate of rare ABCA3 mutations inthe Han and Zhuang populations combined was 1.3%,which is signifi cantly lower than that in the United States(P<0.001).Conclusions: The population-based frequency ofmutations in ABCA3 in south China newborns is signifi cantlylower than that in United States. The contribution of theserare ABCA3 mutations to disease burden in the south Chinapopulation is still unknown.展开更多
Background To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. Methods We used bloodspots from 2010 ...Background To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. Methods We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants. Results We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang popula-tions (0.0045 vs. 0.0064, respectively,P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous vari-ants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB;F341L was also not previously reported in exome sequencing project. Conclusions The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1,CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research.展开更多
文摘Objective To review the pathophysiology, evaluation, management, and outcomes of children with inherited disorders of surfactant metabolism due to mutations in the genes encoding surfactant proteins-B or -C（SFTPB, SFTPC）, ATP binding cassette member A3 （ABCA3）, and thyroid transcription factor （NKX2.1）.Data sources Review of the literature, previous work from the author＇s and collaborators＇ laboratories, St. Louis Children＇s Hospital Lung Transplant Database.Study selection Key articles in the field, author＇s work.Results Inherited disorders of surfactant metabolism present as acute, severe respiratory dysfunction in the neonatal period （SFTPB, ABCA3, NKX2.1） or as chronic respiratory insufficiency in later infancy and childhood which is of variable onset, severity, and course （SFTPC, ABCA3, NKX2.1）. Diagnosis is established with sequencing the relevant genes; lung biopsy with electron microscopy is a useful adjunct. For surfactant protein-B and ABCA3 deficiency presenting with acute neonatal disease, treatment options are limited to lung transplantation or compassionate care. For the more chronic presentations of surfactant protein-C, ABCA3, and NKX2.1 associated disease, the natural history is variable and therefore individualized, supportive care is appropriate,Conclusions Inherited disorders of surfactant metabolism are rare, but informative diseases that provide unique opportunities for understanding mechanisms of respiratory disease in newborns and children.
基金supported by the National Natural Science Foundation of China 81260094(Chen YJ)National Institutes of Health R01 HL065174(Cole FS,Hamvas A),R01 HL082747(Cole FS,Hamvas A),K12 HL089968(Wambach JA,Cole FS),K08 HL105891(Wambach JA)Foundation of Health Department of Guangxi Zhuang Autonomous Region 2012059(Chen YJ).
文摘Background: Rare mutations in surfactant-associatedgenes contribute to neonatal respiratory distress syndrome.The frequency of mutations in these genes in the Chinesepopulation is unknown.Methods: We obtained blood spots from the GuangxiNeonatal Screening Center in Nanning, China thatincluded Han (n=443) and Zhuang (n=313) ethnic groups.We resequenced all exons of the surfactant proteins-B(SFTPB), -C (SFTPC), and the ATP-binding cassettemember A3 (ABCA3) genes and compared the frequenciesof 5 common and all rare variants.Results: We found minor differences in thefrequencies of the common variants in the Han andZhuang cohorts. We did not find any rare mutations inSFTPB or SFTPC, but we found three ABCA3 mutationsin the Han [minor allele frequency (MAF)=0.003] and 7 inthe Zhuang (MAF=0.011) cohorts (P=0.10). The ABCA3mutations were unique to each cohort;five were novel.The collapsed carrier rate of rare ABCA3 mutations inthe Han and Zhuang populations combined was 1.3%,which is signifi cantly lower than that in the United States(P<0.001).Conclusions: The population-based frequency ofmutations in ABCA3 in south China newborns is signifi cantlylower than that in United States. The contribution of theserare ABCA3 mutations to disease burden in the south Chinapopulation is still unknown.
基金the National Natural Science Foundation of China 81260094National Institutes of Health R01 HL065174+3 种基金R01 HL082747K12 HL089968K08 HL105891Foundation of Health Department of Guangxi Zhuang Autonomous Region 2012059.
文摘Background To determine population-based prevalence and disease contribution of phosphatidylcholine synthetic pathway-associated gene variants in a native southern Chinese cohort. Methods We used bloodspots from 2010 that were obtained from the Guangxi Neonatal Screening Center in Nannning China and included the Han (n = 443) and Zhuang (n = 313) ethnic groups. We sequenced the exons of cholinephosphate cytidylyltransferase (PCYT1B) lysophospholipid acyltransferase 1 (LPCAT1), and cholinephosphotransferase (CHPT1) genes, and analyzed both rare and common exonic variants. Results We obtained five mutations (G199D, A299V, G434C, Y490C, L312S) with eight alleles in the three candidate genes. The collapsed minor allele frequency for candidate genes was not significantly different between the Han and Zhuang popula-tions (0.0045 vs. 0.0064, respectively,P = 0.725). The combined Han and Zhuang pool collapsed carrier frequency of rare mutation allele was found to be 1.06%, which is much higher than previously reported for the Missouri population (0.1%). Further, we detected six exonic common variants (three in LPCAT1 and three in CHPT1), with three non-synonymous vari-ants (F162S, F341L, M427K) among them. Two of the non-synonymous exonic variants (F341L, M427K) were not found in CHB;F341L was also not previously reported in exome sequencing project. Conclusions The population-based frequency of mutations in the phosphatidylcholine synthesis pathway-associated genes PCYT1B LPCAT1,CHPT1 is low in southern Chinese newborns and there is no evidence of contribution to population-based disease burden of respiratory distress syndrome. As a population-based study of rare mutations and common variants, this work is valuable in directing future research.
