RAF1-associated Noonan syndrome presenting antenatally with an abnormality of skull shape, subdural haematoma and associated with novel cerebral malformations

Hartill, Verity; Dillon, Mitchell W.; Warren, Daniel; Blyth, Moira

doi:10.1097/mcd.0000000000000153

Cited by 6 publications

(5 citation statements)

References 15 publications

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“…A total of 79.2% of pathogenic RAF1 alleles affect residues within the 14‐3‐3ζ recognition site of CR2, such as Arg256, Ser257, Ser259, Thr260, Pro261, Asn262, and Val263 (Kobayashi et al, ; Pandit et al, ; Razzaque et al, ; Sana et al, ); binding of RAF1 to 14‐3‐3ζ is critical for its autoinhibition (Kubicek et al, ; Light, Paterson, & Marais, ). The second group of mutations (8.1%) affects the adjacent residues Ser612 and Leu613 located C‐terminally to the CR3 domain, and the third group (7.9%) affects the two amino acid residues Asp486 and Thr491 within the activation segment of the kinase domain (Croonen et al, ; Hartill, Dillon, Warren, & Blyth, ; Hopper, Feinstein, Manning, Benitz, & Hudgins, ; Ko, Kim, Kim, & Yoo, ; Kobayashi et al, ; Pandit et al, ; Ratola et al, ; Razzaque et al, ; Sana et al, ; Schulz, Frober, Kraus, & Schneider, ). Only two amino acid substitutions in CR3 have been described so far (4%): p.(Ser427Gly) was found in mother and son with NS as well as in an unrelated patient (Kobayashi et al, ; Zebisch et al, ), and p.(Glu478Lys) was found in one patient (Ezquieta et al, ).…”

Section: Introductionmentioning

confidence: 99%

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Harms

Alawi

Amor

et al. 2017

American J of Med Genetics Pt A

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Noonan syndrome is characterized by typical craniofacial dysmorphism, postnatal growth retardation, congenital heart defect, and learning difficulties and belongs to the RASopathies, a group of neurodevelopmental disorders caused by germline mutations in genes encoding components of the RAS-MAPK pathway. Mutations in the RAF1 gene are associated with Noonan syndrome, with a high prevalence of hypertrophic cardiomyopathy (HCM). RAF1 mutations cluster in exons encoding the conserved region 2 (CR2), the kinase activation segment of the CR3 domain, and the C-terminus. We present two boys with Noonan syndrome and the identical de novo RAF1 missense variant c.1082G>C/p.(Gly361Ala) affecting the CR3, but located outside the kinase activation segment. The p.(Gly361Ala) mutation has been identified as a RAF1 allele conferring resistance to RAF inhibitors. This amino acid change favors a RAF1 conformation that allows for enhanced RAF dimerization and increased intrinsic kinase activity. Both patients with Noonan syndrome showed typical craniofacial dysmorphism, macrocephaly, and short stature. One individual developed HCM and was diagnosed with a disseminated oligodendroglial-like leptomeningeal tumor (DOLT) of childhood at the age of 9 years. While there is a well-established association of NS with malignant tumors, especially childhood hemato-oncological diseases, brain tumors have rarely been reported in Noonan syndrome. Our data demonstrate that mutation scanning of the entire coding region of genes associated with Noonan syndrome is mandatory not to miss rare variants located outside the known mutational hotspots.

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Section: Introductionmentioning

confidence: 99%

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Harms

Alawi

Amor

et al. 2017

American J of Med Genetics Pt A

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“…Of note, the mutation p.(Leu603Pro), adjacent to p.(Ser604Cys), observed in a Noonan patient, showed impaired kinase activity and reduced ERK activation as did a truncated RAF1 protein p.(Arg254fs) (Dhandapany et al 2014 ). Pathogenic RAF1 mutations in the Cr2 domain causing Noonan syndrome are mainly associated to the onset of cardiovascular malformations, although sporadic cases of cerebrovascular abnormalities have been reported (Zarate et al 2014 ; Hartill et al 2017 ). The state of knowledge of its role in vasculopathy brain changes is less consolidated but there are evidences in Raf1 homozygous knock out mouse endothelial cells (Wimmer et al 2012 ) of the direct critical role of Raf1 in angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes

Tritto,

Bettinaglio,

Mangano

et al. 2024

Hum. Genet.

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NF1 microdeletion syndrome, accounting for 5–11% of NF1 patients, is caused by a deletion in the NF1 region and it is generally characterized by a severe phenotype. Although 70% of NF1 microdeletion patients presents the same 1.4 Mb type-I deletion, some patients may show additional clinical features. Therefore, the contribution of several pathogenic mechanisms, besides haploinsufficiency of some genes within the deletion interval, is expected and needs to be defined. We investigated an altered expression of deletion flanking genes by qPCR in patients with type-1 NF1 deletion, compared to healthy donors, possibly contributing to the clinical traits of NF1 microdeletion syndrome. In addition, the 1.4-Mb deletion leads to changes in the 3D chromatin structure in the 17q11.2 region. Specifically, this deletion alters DNA-DNA interactions in the regions flanking the breakpoints, as demonstrated by our 4C-seq analysis. This alteration likely causes position effect on the expression of deletion flanking genes.Interestingly, 4C-seq analysis revealed that in microdeletion patients, an interaction was established between the RHOT1 promoter and the SLC6A4 gene, which showed increased expression. We performed NGS on putative modifier genes, and identified two “likely pathogenic” rare variants in RAS pathway, possibly contributing to incidental phenotypic features.This study provides new insights into understanding the pathogenesis of NF1 microdeletion syndrome and suggests a novel pathomechanism that contributes to the expression phenotype in addition to haploinsufficiency of genes located within the deletion.This is a pivotal approach that can be applied to unravel microdeletion syndromes, improving precision medicine, prognosis and patients’ follow-up.

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Section: Discussionmentioning

confidence: 99%

“…When patients with NS require surgery, few authors also suggest that thorough neurological examination and imaging be performed in the context of neurological symptoms or an abnormality of cranial vault shape in suspected cases of RASopathy. 67 In CCD, an autosomal dominant developmental abnormality, patients can present with delayed closure of the cranial sutures, midface hypoplasia, moderately short stature, aplastic clavicles, and other abnormalities. 68 Because of the fragility of the skull in CCD, the mechanical and rotational forces produced during vaginal delivery may cause excessive distortion and lead to PFH.…”

Section: Comprehensive Clinical and Neuroimaging Review Of Posterior ...mentioning

confidence: 99%

Comprehensive Clinical and Neuroimaging Review of Posterior Fossa Hemorrhage in Preterm and Term Newborns

Hsu,

Zhu,

Islam

et al. 2023

Journal of Pediatric Neurology

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Posterior fossa hemorrhage (PFH) is a highly morbid condition in preterm and term infants. In this article, we aim to first describe a case of PFH, and using this example, provide a comprehensive narrative review of the pathophysiology, risk factors, diagnosis, and management of PFH. Management may differ depending on the etiology and based on careful consideration of the risks and benefits of surgical versus conservative management.

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RAF1-associated Noonan syndrome presenting antenatally with an abnormality of skull shape, subdural haematoma and associated with novel cerebral malformations

Cited by 6 publications

References 15 publications

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

The novel RAF1 mutation p.(Gly361Ala) located outside the kinase domain of the CR3 region in two patients with Noonan syndrome, including one with a rare brain tumor

Genetic/epigenetic effects in NF1 microdeletion syndrome: beyond the haploinsufficiency, looking at the contribution of not deleted genes

Comprehensive Clinical and Neuroimaging Review of Posterior Fossa Hemorrhage in Preterm and Term Newborns

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