Copy number variants including RAS pathway genes—How much RASopathy is in the phenotype?

Abstract

The RASopathies comprise a group of clinically overlapping developmental syndromes the common pathogenetic basis of which is dysregulated signal flow through the RAS-MAPK pathway. Mutations in several components or modifiers of the pathway have been identified in Noonan syndrome and related disorders. Over the past years copy number variants (CNVs) encompassing RAS pathway genes (PTPN11, RAF1, MEK2, or SHOC2) have been reported in children with developmental syndromes. These observations raised speculations that the associated phenotypes represent RASopathies, implying that the increased or reduced expression of the respective RAS pathway component and a consecutive dysregulation of RAS pathway signalling is responsible for the clinical picture. Herein, we present two individuals and three of their relatives harboring duplications of either 3p25.2 including the RAF1 locus or 19p13.3 including the MEK2 locus. Duplication carriers exhibited variable clinical phenotypes including non-specific facial dysmorphism, short stature, and learning difficulties. A careful review of the literature supported the impression that phenotypes associated with CNVs including RAS pathway genes commonly share non-specific symptoms with RASopathies, while the characteristic "gestalt" is lacking. Considering the known molecular pathogenesis of RASopathies, it is questionable that a modest increase in the expression of a functionally normal signaling component can mimic the effects of a qualitatively abnormal (hyperactive) mutant protein. We thus argue that current empirical and biological evidence is still insufficient to allow the conclusion that an altered copy number of a RAS pathway component is indeed the mechanism that is critical for the phenotype associated with CNVs including RASopathy genes.

Expansion of the RASopathies

“…In each of these cases, gene duplication is thought to result in increased dosage of SHP2 which has the equivalent effect as the common gain of function mutation in PTPN11 associated with NS. In addition, rare chromosomal duplications associated with SHOC2 in a NS patient [56], and RAF1 and MAP2K2 in patients with mild RASopathy spectrum phenotypes have been reported [57, 58]. Chromosomal deletions have also been reported to be associated with a RASopathy phenotype.…”

“…Chromosomal deletions have also been reported to be associated with a RASopathy phenotype. A chromosomal deletion encompassing the BRAF locus at 7q34 was reported in two individuals with phenotypes overlapping several RASopathies [58, 59]. In addition, two studies reported interstitial deletion of 19p13.3 encompassing the MEK2 gene [60, 61].…”

The RAS-Effector Interface: Isoform-Specific Differences in the Effector Binding Regions

“…g ., pancreatic cancer [16]) and developmental disorders, including Noonan syndrome [17,18,19]. Whereas the latter is thought to be commonly caused by dysregulation of mainly one pathway, the RAS-MAPK pathway [19], RAS-mediated cancer progression involves activation of several pathways, e . g ., PI3K-AKT [3,20], RALGDS-RAL [9,13], PLCε-second messengers [14] or Hippo-YAP [21] as well as RAS-MAPK [22].…”

Differentiating between copy‐number‐variation and gain‐of‐function mutation

“…Lissewski et al [] took on the difficult task of arguing the absence of the variable Noonan syndrome or rasopathy phenotype in individuals with a copy number variation (CNV) affecting RAS/MAPK pathway genes. This is an important report because it challenges the assumption that gene duplication results in similar phenotypic findings as missense mutations associated with a gain‐of‐function of the abnormal protein product.…”

“…While Lissewski et al [] report on individuals with CNVs encompassing genes of the RAS/MAPK pathway, their message is relevant for other genetic disorders. In contrast to loss‐of‐function mutations acting through haploinsufficiency for the functional gene product, in which a whole gene deletion has the same effect as a nonsense mutation, it is not possible to conclude that a gene duplication has an effect comparable to constitutive activation of a gene product.…”