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染色体带12q24.11q24.23的重复导致明显的努南综合征。

Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome.

作者信息

Shchelochkov Oleg A, Patel Ankita, Weissenberger George M, Chinault A Craig, Wiszniewska Joanna, Fernandes Priscilla H, Eng Christine, Kukolich Mary K, Sutton V Reid

机构信息

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

出版信息

Am J Med Genet A. 2008 Apr 15;146A(8):1042-8. doi: 10.1002/ajmg.a.32215.

Abstract

Noonan syndrome is an autosomal dominant disorder with an estimated incidence of 1 in 1,000 to 1 in 2,500 live births. It is characterized by postnatal-onset short stature, characteristic facial changes, webbed neck, pectus carinatum, or excavatum, congenital heart defects, and bleeding abnormalities. Gain-of-function mutations in the PTPN11, KRAS, SOS1, and RAF1 genes that are components of the RAS/MEPK signaling pathway are identified in about 70-85% of individuals with Noonan syndrome. We report here a case of duplication of chromosome region 12q24.11q24.23 identified by array comparative genomic hybridization (aCGH) that includes the PTPN11 gene in a 3-year-old girl with apparent Noonan syndrome. The patient presented with postnatal-onset failure-to-thrive, developmental delay, microcephaly, velopalatal incompetence, pectus excavatum, coarctation of aorta, atrial and ventricular septal defects, decreased muscle tone, and minor facial anomalies consistent with Noonan syndrome. At 3 years of age her speech, gross and fine motor development were at the level of a 12-18 month old child. This degree of developmental delay was atypical for an individual with Noonan syndrome, raising concerns for a chromosomal abnormality. Array-CGH showed an interstitial duplication of 10 Mb including the PTPN11 gene. Sequencing of PTPN11, KRAS, SOS1 and the coding region of RAF1 did not identify mutations. The increased gene dosage of the PTPN11 gene in the form of duplication is expected to have the same consequence as gain-of-function mutations seen in Noonan syndrome. We propose that at least some of the 15-30% of individuals with Noonan syndrome who do not have a mutation by sequencing may have a gain in copy number of PTPN11 and recommend that comprehensive testing for Noonan syndrome should include analysis for copy number changes of PTPN11.

摘要

努南综合征是一种常染色体显性疾病,估计发病率为1000至2500例活产中有1例。其特征为出生后身材矮小、典型面部改变、蹼颈、鸡胸或漏斗胸、先天性心脏缺陷以及出血异常。约70 - 85%的努南综合征患者中可发现RAS/MEPK信号通路组成部分PTPN11、KRAS、SOS1和RAF1基因的功能获得性突变。我们在此报告一例通过阵列比较基因组杂交(aCGH)鉴定出的12q24.11q24.23染色体区域重复的病例,该区域包含PTPN11基因,患者为一名3岁明显患有努南综合征的女童。该患者表现为出生后生长发育迟缓、发育延迟、小头畸形、腭咽功能不全、漏斗胸、主动脉缩窄、房间隔和室间隔缺损、肌张力降低以及与努南综合征相符的轻微面部异常。3岁时,她的语言、粗大和精细运动发育水平相当于12 - 18个月大的儿童。这种程度的发育延迟在努南综合征患者中并不典型,引发了对染色体异常的担忧。阵列比较基因组杂交显示存在一个10 Mb的间质性重复,包括PTPN11基因。对PTPN11、KRAS、SOS1和RAF1编码区进行测序未发现突变。以重复形式增加的PTPN11基因剂量预计会产生与努南综合征中功能获得性突变相同的后果。我们提出,在通过测序未发现突变的15 - 30%的努南综合征患者中,至少有一部分可能存在PTPN11拷贝数增加的情况,并建议对努南综合征进行全面检测时应包括对PTPN11拷贝数变化的分析。

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