Duplications in the G3 domain or switch II region in
            <i>HRAS</i>
            identified in patients with Costello syndrome

Nagai, Koki; Niihori, Tetsuya; Okamoto, Nobuhiko; Kondo, Akane; Suga, Kenichi; Ohhira, Tomoko; Hayabuchi, Yasunobu; Homma, Yukako; Nakagawa, Ryuji; Ifuku, Toshinobu; Abe, Taiki; Mizuguchi, Takeshi; Matsumoto, Naomichi; Aoki, Yoko

doi:10.1002/humu.24287

Cited by 9 publications

(5 citation statements)

References 42 publications

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“…Craniosynostosis has been described in individuals with pathogenic variants in other genes of the RAS/MAPK pathway including BRAF (Davis et al, 2019; Ueda et al, 2017), KRAS (Addissie et al, 2015; Brasil et al, 2012; Kratz et al, 2009; Lo et al, 2009; Schubbert et al, 2006; Ueda et al, 2017), PPP1CB (Bertola et al, 2017), SHOC2 (Takenouchi et al, 2014), PTPN11 (Davis et al, 2019; McDonald et al, 2018; Ueda et al, 2017), RAF1 (Rodriguez et al, 2019), and HRAS (Nagai et al, 2021; Weaver et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

“…Although craniosynostosis is an unusual finding among individuals with RASopathies, more cases are being reported (Addissie et al, 2015; Brasil et al, 2012; Davis et al, 2019; Kratz et al, 2009; Lo et al, 2009; Nagai et al, 2021; Rodriguez et al, 2019; Takenouchi et al, 2014; Weaver et al, 2022; Zenker, 2022). The relationship between craniosynostosis and the underlying diagnosis needs to be further characterized to improve early recognition, diagnosis, and intervention.…”

Section: Introductionmentioning

confidence: 99%

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Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies

Serbinski,

Vanderwal,

Chadwell

et al. 2023

American J of Med Genetics Pt A

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Fetuses with RASopathies can have a wide variety of anomalies including increased nuchal translucency, hydrops fetalis, and structural anomalies (typically cardiac and renal). There are few reports that describe prenatal‐onset craniosynostosis in association with a RASopathy diagnosis. We present clinical and molecular characteristics of five individuals with RASopathy and craniosynostosis. Two were diagnosed with craniosynostosis prenatally, 1 was diagnosed as a neonate, and 2 had evidence of craniosynostosis noted as neonates without formal diagnosis until later. Two of these individuals have Noonan syndrome (PTPN11 and KRAS variants) and three individuals have Cardiofaciocutaneous syndrome (KRAS variants). Three individuals had single suture synostosis and two had multiple suture involvement. The most common sutures involved were sagittal (n = 3), followed by coronal (n = 3), and lambdoid (n = 2) sutures. This case series confirms craniosynostosis as one of the prenatal findings in individuals with RASopathies and emphasizes the importance of considering a RASopathy diagnosis in fetuses with multiple anomalies in combination with craniosynostosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies

Serbinski,

Vanderwal,

Chadwell

et al. 2023

American J of Med Genetics Pt A

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“…In accordance with this model, histological sections through the testis of ageing males have revealed the predicted clusters of the mutated germ cells, each one of which is capable of differentiating into a spermatozoon that will result in the emergence of genetic disease in the progeny ( Goriely et al , 2003 ; Maher et al , 2018 ). This hypothesis may also be applicable to other dominant genetic diseases caused by paternal age, including multiple endocrine neoplasia type 2b, where the causative mutation can be found in the RET (rearranged during transfection) proto-oncogene ( Choi et al , 2012 ), Noonan syndrome, which is driven by a mutation in the PTPN11 gene (encoding protein tyrosine phosphatase non-receptor type 11) ( Liao and Mehta, 2019 ), and Costello syndrome, which involves a mutation in the HRAS proto-oncogene(Harvey rat sarcoma viral oncogene homolog, GTPase) ( Nagai et al , 2022 ). Other rare conditions, such as the so-called RASopathies, are also associated with mutations in genes encoding components of the RAS (reticular activating system)/rapidly accelerated fibrosarcoma/mitogen-activated protein kinases signal transduction pathway, including LEOPARD syndrome and hereditary gingival fibromatosis ( Tidyman and Rauen, 2009 ; Maher et al , 2018 ).…”

Section: Ageing and Offspring Healthmentioning

confidence: 99%

Male reproductive ageing: a radical road to ruin

Aitken

2023

Human Reproduction

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In modern post-transition societies, we are reproducing later and living longer. While the impact of age on female reproductive function has been well studied, much less is known about the intersection of age and male reproduction. Our current understanding is that advancing age brings forth a progressive decline in male fertility accompanied by a reduction in circulating testosterone levels and the appearance of age-dependent reproductive pathologies including benign prostatic hypertrophy and erectile dysfunction. Paternal ageing is also associated with a profound increase in sperm DNA damage, the appearance of multiple epigenetic changes in the germ line and an elevated mutational load in the offspring. The net result of such changes is an increase in the disease burden carried by the progeny of ageing males, including dominant genetic diseases such as Apert syndrome and achondroplasia, as well as neuropsychiatric conditions including autism and spontaneous schizophrenia. The genetic basis of these age-related effects appears to involve two fundamental mechanisms. The first is a positive selection mechanism whereby stem cells containing mutations in a mitogen-activated protein kinase pathway gain a selective advantage over their non-mutant counterparts and exhibit significant clonal expansion with the passage of time. The second is dependent on an age-dependent increase in oxidative stress which impairs the steroidogenic capacity of the Leydig cells, disrupts the ability of Sertoli cells to support the normal differentiation of germ cells, and disrupts the functional and genetic integrity of spermatozoa. Given the central importance of oxidative stress in defining the impact of chronological age on male reproduction, there may be a role for antioxidants in the clinical management of this process. While animal studies are supportive of this strategy, carefully designed clinical trials are now needed if we are to realize the therapeutic potential of this approach in a clinical context.

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“…The patients reported owed mutations in BRAF, SHOC2, PTPN11 and KRAS genes, with the latter proposed to be correlated to more severe craniosynostosis ( 90 – 94 ). Craniosynostosis has been also described in a CS patient harboring a duplication in HRAS gene ( 95 ). It is worth to mention that in a recent retrospective study late onset synostosis was prominent ( 92 ), underscoring both the need for long-term monitoring and the record of this clinical sign.…”

Section: Musculoskeletal Features and Biochemical Bone Profilementioning

confidence: 99%

Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes

Papadopoulou,

Bountouvi

2023

Front. Endocrinol.

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Noonan, Costello and Cardio-facio-cutaneous syndromes belong to a group of disorders named RASopathies due to their common pathogenetic origin that lies on the Ras/MAPK signaling pathway. Genetics has eased, at least in part, the distinction of these entities as they are presented with overlapping clinical features which, sometimes, become more pronounced with age. Distinctive face, cardiac and skeletal defects are among the primary abnormalities seen in these patients. Skeletal dysmorphisms range from mild to severe and may include anterior chest wall anomalies, scoliosis, kyphosis, short stature, hand anomalies, muscle weakness, osteopenia or/and osteoporosis. Patients usually have increased serum concentrations of bone resorption markers, while markers of bone formation are within normal range. The causative molecular defects encompass the members of the Ras/MAPK/ERK pathway and the adjacent cascades, important for the maintenance of normal bone homeostasis. It has been suggested that modulation of the expression of specific molecules involved in the processes of bone remodeling may affect the osteogenic fate decision, potentially, bringing out new pharmaceutical targets. Currently, the laboratory imprint of bone metabolism on the clinical picture of the affected individuals is not clear, maybe due to the rarity of these syndromes, the small number of the recruited patients and the methods used for the description of their clinical and biochemical profiles.

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

Cited by 9 publications

References 42 publications

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies

Prenatal and infantile diagnosis of craniosynostosis in individuals with RASopathies

Male reproductive ageing: a radical road to ruin

Skeletal defects and bone metabolism in Noonan, Costello and cardio-facio-cutaneous syndromes

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