Recurrent duplication mutation in<i>HRAS</i>causing mild Costello syndrome in a Chinese patient

Xu, Fengping; Wang, H. J.; Lin, Zhongxiao; Yu, Benjamin

doi:10.1111/ced.12571

Cited by 10 publications

(9 citation statements)

References 10 publications

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“…Among the less common mutations, HRAS p.E63_D69dup causes an attenuated phenotype with milder intellectual disability, fewer feeding issues, and a lower tumor risk (Lorenz et al, ; Xu, Wang, Lin, & Yu, ). Facial features tend to be less coarse in individuals with the rarer HRAS missense mutations p.T58I, p.K117R, p.A146V, and p.A146P (Chiu et al, ; Gripp et al, ; Kerr et al, ).…”

Section: Mutations and Genotype–phenotype Correlationssupporting

confidence: 91%

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Gripp

Morse

Axelrad

et al. 2019

American J of Med Genetics Pt A

102

111

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Costello syndrome (CS) is a RASopathy caused by activating germline mutations in HRAS. Due to ubiquitous HRAS gene expression, CS affects multiple organ systems and individuals are predisposed to cancer. Individuals with CS may have distinctive craniofacial features, cardiac anomalies, growth and developmental delays, as well as dermatological, orthopedic, ocular, and neurological issues;however, considerable overlap with other RASopathies exists. Medical evaluation requires an understanding of the multifaceted phenotype. Subspecialists may have limited experience in caring for these individuals because of the rarity of CS. Furthermore, the phenotypic presentation may vary with the underlying genotype. These guidelines were developed by an interdisciplinary team of experts in order to encourage timely health care practices and provide medical management guidelines for the primary and specialty care provider, as well as for the families and affected individuals across their lifespan. These guidelines are

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Section: Mutations and Genotype–phenotype Correlationssupporting

confidence: 91%

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Gripp

Morse

Axelrad

et al. 2019

American J of Med Genetics Pt A

102

111

View full text Add to dashboard Cite

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“…7A). One insertion is reported for two independent cases of Costello syndrome 23,24 and 6 different insertions are reported for 8 tumour samples 25–30 . Though these variants are similar to the VMOS RAS variants, it is possible that they have acquired a stronger signalling capability.…”

Section: Resultsmentioning

confidence: 99%

“…( A ) Sequence alignment as in Fig. 2A of a KRAS variant found in a Noonan patient (case 7; this study), a HRAS variant found in two patients with Costello (lit 1; 23,24 ) and of 6 variants of either KRAS or NRAS found in 8 different tumour samples (lit 2–7; 25–30 ). The number of independent observations of the variant and the context is indicated on the right of the alignment.…”

Section: Resultsmentioning

confidence: 99%

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Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS

Eijkelenboom

Schaik

et al. 2019

Sci Rep

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Mutations in the RAS genes are identified in a variety of clinical settings, ranging from somatic mutations in oncology to germline mutations in developmental disorders, also known as ‘RASopathies’, and vascular malformations/overgrowth syndromes. Generally single amino acid substitutions are identified, that result in an increase of the GTP bound fraction of the RAS proteins causing constitutive signalling. Here, a series of 7 in-frame insertions and duplications in HRAS (n = 5) and KRAS (n = 2) is presented, resulting in the insertion of 7–10 amino acids residues in the switch II region. These variants were identified in routine diagnostic screening of 299 samples for somatic mutations in vascular malformations/overgrowth syndromes (n = 6) and in germline analyses for RASopathies (n = 1). Biophysical characterization shows the inability of Guanine Nucleotide Exchange Factors to induce GTP loading and reduced intrinsic and GAP-stimulated GTP hydrolysis. As a consequence of these opposing effects, increased RAS signalling is detected in a cellular model system. Therefore these in-frame insertions represent a new class of weakly activating clinically relevant RAS variants.

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“…Activating mutations in the amino acid residues 12, 13, or 61 resulted in elevated levels of GTP‐bound RAS due to the impaired basal GAP‐stimulated hydrolysis of GTP. Recently, intragenic duplications of RAS have been identified in patients with CS or cancers (Gremer et al, 2010; Gripp et al, 2020; Lorenz et al, 2013; Xu et al, 2015). The reported intragenic duplications are located in the switch I region (p.(Glu37dup)) and the switch II region (p.(Glu63_Asp69dup) or p.(Glu62_Arg68dup)).…”

Section: Introductionmentioning

confidence: 99%

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

et al. 2021

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Costello syndrome (CS) is an autosomal-dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers. Germline variants in HRAS have been identified in patients with CS. Intragenic HRAS duplications have been reported in three patients with a milder phenotype of CS. In this study, we identified two known HRAS variants, p.(Glu63_Asp69dup), p.(Glu62_Arg68dup), and one novel HRAS variant, p.(Ile55_Asp57dup), in patients with CS, including a patient with craniosynostosis. These intragenic duplications are located in the G3 domain and the switch II region. Cells expressing cDNA with these three intragenic duplications showed an increase in ELK-1 transactivation. Injection of wild-type or mutant HRAS mRNAs with intragenic duplications in zebrafish embryos showed significant elongation of the yolk at 11 h postfertilization, which was improved by MEK inhibitor treatment, and a variety of developmental abnormalities at 3 days post fertilization was observed. These results indicate that small in-frame duplications affecting the G3 domain and switch II region of HRAS increase the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish or patients with CS.

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Recurrent duplication mutation inHRAScausing mild Costello syndrome in a Chinese patient

Cited by 10 publications

References 10 publications

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Costello syndrome: Clinical phenotype, genotype, and management guidelines

Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS

Duplications in the G3 domain or switch II region in HRAS identified in patients with Costello syndrome

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