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

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.

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

“…[37][38][39][40] Patients with whole or partial chromosome 12q duplications (including the 12q24.21 region and TBX5 gene) have been described to have some of the cardiac features of HOS (mainly septal defects), other congenital anomalies and dysmorphism, but hardly any of the skeletal features. [41][42][43][44][45][46][47][48][49] This partially conforms to the prominent cardiac defects and milder limb defects seen in this family with the TBX5 duplication, therefore it seems expression of TBX5 must be finely regulated for normal cardiac and limb development. Postma et al 50 described a HOS family with predominantly cardiac defects and mild limb defects, with a novel gain-of-function missense mutation (Gly125Arg) in TBX5.…”

Cardio-Facio-Cutaneous Syndrome: Clinical Features, Diagnosis, and Management Guidelines

“…If these are negative, the geneticist may consider a chromosome microarray analysis to screen for microdeletions/microduplications that can be associated with phenotypes that partially overlap with CFC. [23][24][25][26] If all of the above are negative, the geneticist/genetics provider can consider whole exome or genome sequencing for diagnosis.…”

Noonan Syndrome: Clinical Aspects and Molecular Pathogenesis

“…It should be mentioned that de novo duplications of the chromosomal region encompassing PTPN11 (12q24) have been documented in 2 subjects with clinical features suggestive of NS without mutations in any known NS genes [Shchelochkov et al, 2008;Graham et al, 2009]. While these consistent observations suggest that increased dosage of SHP2 may have dysregulating effects on intracellular signaling and consequences on developmental processes, the screening of a relatively large cohort of NS cases negative for mutations in previously identified genes indicate that PTPN11 gene duplication represents an uncommon cause of NS.…”