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Frontal view of patients with deleted NRAS. Patients present features of Noonan Syndrome 6, including macrocephaly, short/webbed neck, low hairline, skin abnormalities, triangular face with age, low-set ears, arched eyebrows, hypertelorism, ptosis, downslating palpebral fissures and epicanthal folds. Considering the patients with NRAS deletion, we did not have a picture of patient 253793 and 258063.
Source publication
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 Noon...
Contexts in source publication
Context 1
... was evaluated by a geneticist at 20 years of age, when his weight was 68.5 kg (25-50th centile), height 161 cm (< 3rd percentile) and OFC 53 cm (< 3rd percentile). Besides the short stature, his phenotype had several fea- tures reminiscent of Noonan Syndrome, including intellec- tual disability, ptosis, low hairline at the nape, broad neck, excess of pigmented nevi resembling lentigines, pectus excavatum and scoliosis (see Figure 1). Complementary examinations showed patellar chondromalacia, osteoporo- sis, asymmetry of the lower limbs, nephrolithiasis with in- creased loss of K + and Ca + in urine, hypercholesterolemia and primary hypothyroidism. ...
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... order to perform a genotype-phenotype correlation study of chromosome 1p13.2 microdeletions, we compared the clinical characteristics of our patient to those of previ- ously described cases (Table 1 and Figure 1). Isolated chro- mosome 1p13.2 microdeletions are not common; we could find only three individuals reported in the literature (Mattia et al., 1992;Bisgaard et al., 2007;Fitzgibbon et al., 2009). ...
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... phenotype of our patient and also of other pa- tients with the 1p13.2 deletion includes several features of Noonan Syndrome (Table 1 and Figure 1); 2. Variants of NRAS have been described as causing Noonan Syndrome, Type 6 (OMIM #613224), an auto- somal dominant disorder (Cirstea et al., 2010). However, these have been shown to be gain-of-function mutations; ...
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... Haploinsufficiency Index predictions (HI) shown in the DECIPHER database for all the genes deleted in our patient, revealed that the NRAS gene was the one with higher rank of HI (which suggested that this gene is more likely to exhibit haploinsufficiency) (Huang et al., 2010); 4. The region surrounding NRAS is rarely seen in polymorphic CNVs (Figure 4). ...
Context 5
... the other hand, our patient and other cases with pure chromosome 1p13.2 microdeletions and hemizygosity for NRAS reviewed by us from the literature or from the DECIPHER database all seemed to present several clinical features of Noonan Syndrome (Table 1 and Figure 1). The presence of such features related to Noonan Syndrome in pa- tients with deletion of NRAS and presumably haplo- insufficiency of the gene product appears prima facie paradoxical. ...
Citations
... 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, intellectual disability, and autism (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 ). ...
The RAS/RAF/MEK/ERK1/2 intracellular signaling pathway is activated by numerous cues during brain development and dysregulated in neurodevelopmental syndromes, particularly the RASopathies and certain forms of autism. Cortical excitatory/inhibitory imbalance is thought to be critical in the neuropathogenesis of these conditions. However, the developmental functions of ERK1/2 signaling in cortical inhibitory neurons (CINs) and other medial ganglionic eminence (MGE)-derived non-neuronal cells are poorly understood. Here, we genetically modulated ERK1/2 signaling in mouse MGE neural progenitors or GABAergic neurons in vivo. We find that MEK-ERK1/2 signaling is essential for regulating MGE-derived oligodendrocyte number in the anterior commissure. While Erk1/2 inactivation does not alter CIN number, we discovered a significant and persistent reduction in somatostatin, but not parvalbumin, expression in a subset of CINs. ERK1/2 signaling is also necessary for chemogenetic activity-dependent FOSB expression in CINs in vivo. Interestingly, one week of chronic chemogenetic stimulation in juvenile or adult animals partially rescues the decrease in somatostatin expression in Erk1/2 mutant CINs. Our data demonstrate ERK1/2 signaling is required for the establishment of MGE-derived glia, whereas in CINs, ERK1/2 drives activity dependent-responses and the expression of somatostatin in a subset of neurons.
... To the best of our understanding, isolated deletions on chromosome 1p13.2 are uncommon; thus far, only five published pieces of literature have reported that patients with 1p13.2 deletions displayed NDDs [11][12][13][14][15]. But few patients have a family history, and the definite evidence of the association between 1p13.2 deletion and NDDs still needs further functional studies. ...
... deletion and NDDs. To the best of our knowledge, only five articles have reported 1p13.2 deletions in five patients [11][12][13][14][15] (Table 2). As shown, a total of 9 out of 10 (90%) patients were described with intellectual disability, 8 (80%) with language impairments, and 8 (80%) with gross motor developmental delay. ...
... Besides, 50-60% of cases were observed with short stature, facial appearance and neck abnormality. Such features have occurred in Noonan Syndrome, which is also characterized by developmental delay, intellectual impairment, short stature, and distinctive facial features, such as low-set ears, hypertelorism and ptosis [14]. The deletion region of all the 10 preceding cases encompassed the NRAS gene. ...
Background
A multitude of studies have highlighted that copy number variants (CNVs) are associated with neurodevelopmental disorders (NDDs) characterized by a wide range of clinical characteristics. Benefiting from CNV calling from WES data, WES has emerged as a more powerful and cost-effective molecular diagnostic tool, which has been widely used for the diagnosis of genetic diseases, especially NDDs. To our knowledge, isolated deletions on chromosome 1p13.2 are rare. To date, only a few patients were reported with 1p13.2 deletions and most of them were sporadic. Besides, the correlation between 1p13.2 deletions and NDDs remained unclear.
Case presentation
Here, we first reported five members in a three-generation Chinese family who presented with NDDs and carried a novel 1.41 Mb heterozygous 1p13.2 deletion with precise breakpoints. The diagnostic deletion contained 12 protein-coding genes and was observed to segregate with NDDs among the members of our reported family. Whether those genes contribute to the patient’s phenotypes is still inconclusive.
Conclusions
We hypothesized that the NDD phenotype of our patients was caused by the diagnostic 1p13.2 deletion. However, further in-depth functional experiments are still needed to establish a 1p13.2 deletion-NDDs relationship. Our study might supplement the spectrum of 1p13.2 deletion-NDDs.
... 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. ...
BACKGROUND Squamosal sutures are minor sutures of the human skull. Early isolated fusion of the sutures (squamosal synostosis) is rarely found.
OBSERVATIONS The authors report a case of a girl who presented with an abnormal head shape and bilateral squamosal synostosis. Genetic testing revealed a chromosome 1p12–1p13.3 deletion. She has been managed with conservative treatment of the synostosis. She has global developmental delay and multiple anomalies due to the chromosome abnormality.
LESSONS Isolated squamosal suture synostosis could be an uncommon feature of chromosome 1p12–1p13.3 deletion.
