1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency

Abstract

Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.

Multifunctional requirements for ERK1/2 signaling in the development of ganglionic eminence derived glia and cortical inhibitory neurons

“…Individuals with RASopathies frequently exhibit craniofacial abnormalities, cardiac malformations, and increased cancer risk, in addition to neurological conditions such as epilepsy, developmental delay, intellectual disability, and autism (Tidyman & Rauen, 2016). Most RASopathy mutations increase ERK1/2 signaling, however, microdeletions that disrupt Erk1 or Erk2 expression have been linked to neurocognitive delay (Ben-Shachar et al, 2008; Fernandez et al, 2010; Linhares et al, 2016; Newbern et al, 2008; Nowaczyk et al, 2014; Pucilowska et al, 2015; Rauen, 2013; Saitta et al, 2004; Samuels et al, 2009; Sánchez et al, 2020). Moreover, ERK1/2 signaling is a point of functional convergence for several autism and schizophrenia-associated copy number variants (Blizinsky et al, 2016; Courchesne et al, 2020; Heavner & Smith, 2020; Lord et al, 2020; Moyses-Oliveira et al, 2020; Rosina et al, 2019).…”

Bilateral squamosal synostosis: unusual presentation of chromosome 1p12–1p13.3 deletion. Illustrative case

“…Linhares et al reviewed patients with deletion of chromosome 1p13.2 and adjacent regions and concluded that NRAS gene haploinsufficiency caused clinical features overlapping Noonan syndrome. 16 Our patient did not have facial features of Noonan syndrome, and her cardiac anomalies were not typical. Another possibility is a causative gene residing outside the deleted chromosome region.…”