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

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

Research output: Contribution to journalArticle

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1042-1048
Number of pages7
JournalAmerican Journal of Medical Genetics, Part A
Volume146
Issue number8
DOIs
StatePublished - Apr 15 2008

Keywords

  • Array-CGH
  • Dosage effect
  • Dosage sensitive gene
  • Dup(12)(q24.11 → q24.23)
  • Duplication 12q24
  • Noonan syndrome
  • PTPN11
  • TBX3
  • TBX5
  • Trisomy 12q24
  • aCGH

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Shchelochkov, O. A., Patel, A., Weissenberger, G. M., Chinault, A. C., Wiszniewska, J., Fernandes, P. H., Eng, C., Kukolich, M. K., & Sutton, V. R. (2008). Duplication of chromosome band 12q24.11q24.23 results in apparent Noonan syndrome. American Journal of Medical Genetics, Part A, 146(8), 1042-1048. https://doi.org/10.1002/ajmg.a.32215