2例Cornelia de Lange综合征病例报告并NIPBL基因突变研究
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摘要
目的:对2例生长发育迟缓伴有特殊面容及肢体发育异常的患儿进行基因检测,实现罕见病的精准诊断,为遗传咨询提供指导。方法:应用单基因检测及全外显子组高通量测序技术对临床疑似CdLS患儿进行致病基因突变筛查,并行一代测序验证以及患儿父母的验证。结果:本研究中的2例患儿均检测到国内外尚未报道的NIPBL基因突变,c.2252 dupA、p.Asn751Lysfs以及NM-015384.4:c.6179dupA,父母均无携带,为新生变异。结论:对于发育迟缓伴特殊面容及肢体异常的患儿要考虑到Cornelia de Lang综合征可能,采用基因检测手段实现精准诊断,为患者及家属遗传咨询提供依据。
Objective:To perform genetic testing on two children with growth retardation,unusual facies,and limb abnormalities,and to achieve precise diagnosis of a rare disease and provide guidance for genetic counseling. Methods:Single-gene sequencing and highthroughput whole-exome sequencing were used to detect mutations in children with clinically suspected Cornelia de Lang syndrome(CdLS),which were also confirmed by Sanger sequencing and the sequencing results from the parents. Results:Two children were found to have NIPBL gene mutations:c.2252 dupA,p.Asn751 Lysfs and NM-015384.4:c.6179 dupA,which had not been reported before.These were also de novo mutations,not detected in their parents. Conclusion:CdLS needs to be considered in children with growth retardation,unusual facies,and limb abnormalities. Genetic testing can be used to achieve precise diagnosis and provide genetic counseling for patients and their families.
Objective:To perform genetic testing on two children with growth retardation,unusual facies,and limb abnormalities,and to achieve precise diagnosis of a rare disease and provide guidance for genetic counseling. Methods:Single-gene sequencing and highthroughput whole-exome sequencing were used to detect mutations in children with clinically suspected Cornelia de Lang syndrome(CdLS),which were also confirmed by Sanger sequencing and the sequencing results from the parents. Results:Two children were found to have NIPBL gene mutations:c.2252 dupA,p.Asn751 Lysfs and NM-015384.4:c.6179 dupA,which had not been reported before.These were also de novo mutations,not detected in their parents. Conclusion:CdLS needs to be considered in children with growth retardation,unusual facies,and limb abnormalities. Genetic testing can be used to achieve precise diagnosis and provide genetic counseling for patients and their families.
引文
[1] Barisic I,Tokic VM,Bianchi F,et al. Descriptive epidemiology of Cornelia de Lange syndrome in Europe[J]. Am J Med Genet A,2008,146A(1):51-59.
[2] Selicorni A,Russo S,Gervasini C,et al. Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation[J]. Clinical Genetics,2007,72(2):98-108.
[3] Kline AD,Krantz ID,Sommer A,et al. Cornelia de Lange syndrome:clinical review,diagnostic and scoring systems,and anticipatory guidance[J]. Am J Med Genet A,2007,143A(12):1287-1296.
[4] Krantz ID,Mccallum J,Descipio C,et al. Cornelia de Lange syndrome is caused by mutations in NIPBL,the human homolog of Drosophila melanogaster Nipped-B[J]. Nature Genetics,2004,36(6):631-635.
[5] Tonkin ET,Wang TJ,Lisgo S,et al. NIPBL,encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B,is mutated in Cornelia de Lange syndrome[J]. Nature Genetics,2004,36(6):636-641.
[6] Dorsett D. Cohesin,gene expression and development:lessons from Drosophila[J]. Chromosome Res,2009,17(2):185-200.
[7] Hulinsky R,Byrne J L,Lowichik A,et al. Fetus with interstitial del(5)(p13.1p14.2)diagnosed postnatally with Cornelia de Lange syndrome[J]. Am J Med Genet A,2005,137A(3):336-338.
[8] Richards S,Aziz N,Bale S,et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med,2015,17(5):405-424.
[9] Mehta D,Vergano S A,Deardorff M,et al. Characterization of limb differences in children with Cornelia de Lange syndrome[J]. Am J Med Genet C Semin Med Genet,2016,172(2):155-162.
[10] Marchisio P,Selicorni A,Bianchini S,et al. Audiological findings,genotype and clinical severity score in Cornelia de Lange syndrome[J].Int J Pediatr Otorhinolaryngol,2014,78(7):1045-1048.
[11] Mundlos S,Horn D. Limb Malformations[M]. Berlin:Springer Berlin Heidelberg,2014.
[12] Jackson L,Kline AD,Barr MA,et al. de Lange syndrome:a clinical review of 310 individuals[J]. American Journal of Medical Genetics,1993,47(7):940-946.
[13]赵云静,麻宏伟. 2例Cornelia de Lange综合征患儿NIPBL基因突变研究[J].中国当代儿科杂志,2018,20(5):387-391.
[2] Selicorni A,Russo S,Gervasini C,et al. Clinical score of 62 Italian patients with Cornelia de Lange syndrome and correlations with the presence and type of NIPBL mutation[J]. Clinical Genetics,2007,72(2):98-108.
[3] Kline AD,Krantz ID,Sommer A,et al. Cornelia de Lange syndrome:clinical review,diagnostic and scoring systems,and anticipatory guidance[J]. Am J Med Genet A,2007,143A(12):1287-1296.
[4] Krantz ID,Mccallum J,Descipio C,et al. Cornelia de Lange syndrome is caused by mutations in NIPBL,the human homolog of Drosophila melanogaster Nipped-B[J]. Nature Genetics,2004,36(6):631-635.
[5] Tonkin ET,Wang TJ,Lisgo S,et al. NIPBL,encoding a homolog of fungal Scc2-type sister chromatid cohesion proteins and fly Nipped-B,is mutated in Cornelia de Lange syndrome[J]. Nature Genetics,2004,36(6):636-641.
[6] Dorsett D. Cohesin,gene expression and development:lessons from Drosophila[J]. Chromosome Res,2009,17(2):185-200.
[7] Hulinsky R,Byrne J L,Lowichik A,et al. Fetus with interstitial del(5)(p13.1p14.2)diagnosed postnatally with Cornelia de Lange syndrome[J]. Am J Med Genet A,2005,137A(3):336-338.
[8] Richards S,Aziz N,Bale S,et al. Standards and guidelines for the interpretation of sequence variants:a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med,2015,17(5):405-424.
[9] Mehta D,Vergano S A,Deardorff M,et al. Characterization of limb differences in children with Cornelia de Lange syndrome[J]. Am J Med Genet C Semin Med Genet,2016,172(2):155-162.
[10] Marchisio P,Selicorni A,Bianchini S,et al. Audiological findings,genotype and clinical severity score in Cornelia de Lange syndrome[J].Int J Pediatr Otorhinolaryngol,2014,78(7):1045-1048.
[11] Mundlos S,Horn D. Limb Malformations[M]. Berlin:Springer Berlin Heidelberg,2014.
[12] Jackson L,Kline AD,Barr MA,et al. de Lange syndrome:a clinical review of 310 individuals[J]. American Journal of Medical Genetics,1993,47(7):940-946.
[13]赵云静,麻宏伟. 2例Cornelia de Lange综合征患儿NIPBL基因突变研究[J].中国当代儿科杂志,2018,20(5):387-391.