Prenatal diagnosis of hypoplastic left heart syndrome associated with Noonan Syndrome and de novo <i>RAF1</i> mutation

Schulz, Stefan; Fröber, Rosemarie; Kraus, Cornelia; Schneider, Uwe

doi:10.1002/pd.3938

Cited by 12 publications

(8 citation statements)

References 7 publications

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“…Our patient’s mutation is localized at position Val263, adjacent to the most frequently mutated residues, in the same CR2 domain. Functional characterizations support that mutations which affect the 14–3-3 binding motif (such is in our case) cause an enhanced kinase activity in downstream RAS signaling ( MEK and ERK ) [ 10 , 29 , 34 ]. The exact mechanism of RAF1 activation in mutants remains unexplained.…”

Section: Discussionsupporting

confidence: 55%

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Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome

et al. 2018

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BackgroundNoonan syndrome (NS) is an autosomal dominant multisystem disorder caused by the dysregulation of several genes belonging to the RAS Mitogen Activated Protein Kinase (MAPK) signaling pathway. Incontinentia Pigmenti (IP) is an X-linked, dominantly inherited multisystem disorder.Case presentationThis study is the first report of the coexistence of Noonan (NS) and Incontinentia Pigmenti (IP) syndromes in the same patient. We report on the clinical phenotype and molecular characterization of this patient. The patient was examined by a pluridisciplinary staff of clinicians and geneticist. The clinical diagnosis of NS and IP was confirmed by molecular investigations. The newborn girl came to our clinics due to flagrant dysmorphia and dermatological manifestations. The clinical observations led to characterize the Incontinentia Pigmenti traits and a suspicion of a Noonan syndrome association. Molecular diagnosis was performed by Haloplex resequencing of 29 genes associated with RASopathies and confirmed the NS diagnosis. The common recurrent intragenic deletion mutation in IKBKG gene causing the IP was detected with an improved PCR protocol.ConclusionThis is the first report in the literature of comorbidity of NS and IP, two rare multisystem syndromes.

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Section: Discussionsupporting

confidence: 55%

“…2a ). This was retained since it was correlated to the phenotypic description of the patient and was already reported [ 29 ].We confirmed this alteration in the patient by Sanger Sequencing. The analysis of transmission in the patients’ parents confirmed that it occurred as de novo mutation (Fig.…”

Section: Resultsmentioning

confidence: 94%

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome

et al. 2018

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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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“…This is the first report of a RAF1 variant associated with craniosynostosis. The RAF1 substitution p.V263G, however, has been reported previously in a fetus with increased nuchal translucency associated with signs of hypoplastic left heart syndrome, which suggested a diagnosis of NS (Schulz, Frobers, Kraus, & Schneider, ), but this patient had no evidence of a cranial malformation. On the other hand, Razzaque reported a valine to alanine substitution at the same position (p.V263A) in a 1‐year male with moderate dysmorphic facial features, webbed neck, short stature, obstructive hypertrophic cardiomyopathy, and developmental delay.…”

Section: Discussionmentioning

confidence: 57%

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis

Rodrı́guez

Ponce

Berward

et al. 2019

American J of Med Genetics Pt A

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We report the case of a 14 years and 8 months girl, who is the first child of nonconsanguineous parents, with short stature, obstructive hypertrophic cardiomyopathy, multiple facial lentigines, high and wide forehead, downslanting palpebral fissures, lowset ears, short neck, and pectus excavatum; all features suggestive of Noonan syndrome with multiple lentigines (NSML). In addition, the patient exhibited craniosynostosis. Molecular analysis of rats sarcoma (RAS)/mitogen-activated protein kinase (MAPK) pathway genes with high-resolution melting curve analysis followed by sequencing showed a RAF1 amino acid substitution of valine to glycine at position 263 (p.V263G). The present report provides clinical data regarding the first association of a RAF1 variant and craniosynostosis in a patient with clinical diagnosis of NSML.

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Prenatal diagnosis of hypoplastic left heart syndrome associated with Noonan Syndrome and de novo RAF1 mutation

Cited by 12 publications

References 7 publications

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome

Clinical profile of comorbidity of rare diseases in a Tunisian patient: a case report associating incontinentia pigmenti and Noonan syndrome

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

RAF1 variant in a patient with Noonan syndrome with multiple lentigines and craniosynostosis

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