Novel findings and expansion of phenotype in a mosaic <scp>RASopathy</scp> caused by somatic <scp><i>KRAS</i></scp> variants

Chang, Caitlin; Perrier, Renee; Kurek, Kyle C.; Estrada-Veras, Juvianee; Lehman, Anna; Yip, Stephen; Hendson, Glenda; Diamond, Carol; Pinchot, Jason W.; Tran, Jennifer; Arkin, Lisa M.; Drolet, Beth A.; Napier, Melanie; O'Neill, Sarah A; Balci, Tugce B.; Keppler‐Noreuil, Kim M.

doi:10.1002/ajmg.a.62356

Cited by 29 publications

(31 citation statements)

References 44 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, mosaic KRAS variants have been identified in vascular malformations, most frequently within arteriovenous malformations of the brain and spinal cord with venous and lymphatic malformations less frequently reported ( Jiang et al 2017 ; Hong et al 2019 ; Priemer et al 2019 ; Ten Broek et al 2019 ). The phenotypic spectrum associated with mosaic KRAS variants extends further to individuals with keratinocytic epidermal nevus syndrome (KENS), somatic overgrowth, encephalocraniocutaneous lipomatosis, renovascular hypertension, Wilms’ tumors, and Gorham–Stout disease ( Farschtschi et al 2015 ; McDonell et al 2018 ; Nozawa et al 2020 ; Chang et al 2021 ). In contrast, activating germline KRAS variants are an infrequent cause of RASopathies, specifically cardio-facio-cutaneous syndrome and Noonan syndrome; however, these variants are located elsewhere in the gene, in positions not typically associated with cancer ( Schubbert et al 2006 , 2007 ; Søvik et al 2007 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome

Green

MacGregor

Carden

et al. 2021

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

Nevus sebaceous syndrome (NSS) is a rare multisystem neurocutaneous syndrome, characterised by a congenital nevus, and may include brain malformations such as hemimegalencephaly or focal cortical dysplasia, ocular and skeletal features. It has been associated with several eponyms including Schimmelpenning and Jadassohn. The isolated skin lesion, nevus sebaceous, is associated with post-zygotic variants in HRAS or KRAS in all patients studied. The RAS proteins encode a family of GTPases that form part of the RAS/MAPK signalling pathway, which is critical for cell cycle regulation and differentiation during development. We studied an individual with nevus sebaceous syndrome with an extensive nevus sebaceous, epilepsy, intellectual disability, and hippocampal sclerosis without pathological evidence of a brain malformation. We utilized high depth gene panel sequencing and sensitive droplet digital PCR to detect and quantify RAS/MAPK gene variants in nevus sebaceous and temporal lobe tissue collected during plastic and epilepsy surgery, respectively. A mosaic KRAS c.34G>T; p.(Gly12Cys) variant, also known as G12C, was detected in nevus sebaceous tissue at 25% variant allele fraction (VAF), at the residue most commonly substituted in KRAS. Targeted droplet digital PCR validated the variant and quantified the mosaicism in other tissues. The variant was detected at 33% in temporal lobe tissue, but was absent from blood and healthy skin. We provide molecular confirmation of the clinical diagnosis of NSS. Our data extends the histopathological spectrum of KRAS G12C mosaicism beyond nevus sebaceous to involve brain tissue and more specifically, hippocampal sclerosis.

show abstract

Section: Discussionmentioning

confidence: 99%

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome

Green

MacGregor

Carden

et al. 2021

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

show abstract

“…The spectrum of pathogenic variants in these genes in human cancer and in mosaic RASopathies differs from the mutation spectrum observed in germline RASopathies, suggesting their lethality in the germline form and explaining the markedly different phenotype of mosaic RASopathies when compared to the germline ones [81,85]. Downregulation of the RAS/MAPK over signaling with targeted medical therapies, such as MEK inhibitors, is a recently introduced promising therapeutic option for these patients [83,84].…”

Section: Mosaic Rasopathiesmentioning

confidence: 99%

“…The main clinical features include vascular malformations, congenital nevi, eye, and brain anomalies. Segmental overgrowth is common as well as embryonal tumors have been described in the mosaic RASopathies [ 81 , 84 ], thus enclosing the mosaic RASopathies in the differential diagnosis of LO [ 83 , 84 , 85 ]. The phenotype is variable due to the timing of the mutational event during embryonal life, level of RAS/MAPK pathway over signaling, and body tissue distribution of the pathogenic variant [ 81 ].…”

Section: Mosaic Rasopathiesmentioning

confidence: 99%

See 1 more Smart Citation

Lateralized and Segmental Overgrowth in Children

Mussa¹,

Carli

Cardaropoli³

et al. 2021

Cancers

View full text Add to dashboard Cite

Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

show abstract

“…5,21,22 There is also emerging evidence for somatic variants in the RAS-RAF-MAPK pathway underlying MCD, with recent case studies reporting variants in KRAS associated with epilepsy-associated tumors and malformations. 23–25…”

Section: Introductionmentioning

confidence: 99%

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

López-Rivera

Leu

Macnee

et al. 2022

Preprint

View full text Add to dashboard Cite

Understanding the exact molecular mechanisms involved in the etiology of epileptogenic pathologies with or without tumor activity is essential for improving treatment of drug-resistant focal epilepsy. Here, we characterize the landscape of somatic genetic variants in resected brain specimens from 474 individuals with drug-resistant focal epilepsy using deep whole-exome sequencing (>350 ×) and whole-genome genotyping. Across the exome, we observe a greater number of somatic single-nucleotide variants (SNV) in low-grade epilepsy-associated tumors (LEAT; 7.92±5.65 SNV) than in brain tissue from malformations of cortical development (MCD; 6.11±4 SNV) or hippocampal sclerosis (HS; 5.1±3.04 SNV). Tumor tissues also had the largest number of likely pathogenic variant carrying cells. LEAT had the highest proportion of samples with one or more somatic copy number variants (CNV; 24.7%), followed by MCD (5.4%) and HS (4.1%). Recurring somatic whole chromosome duplications affecting Chromosome 7 (16.8%), chromosome 5 (10.9%), and chromosome 20 (9.9%) were observed among LEAT. For germline variant-associated MCD genes such as TSC2, DEPDC5, and PTEN, germline SNV were frequently identified within large loss of heterozygosity regions, supporting the recently proposed second hit disease mechanism in these genes. We detect somatic variants in twelve established lesional epilepsy genes and demonstrate exome-wide statistical support for three of these in the etiology of LEAT (e.g., BRAF) and MCD (e.g., SLC35A2 and MTOR). We also identify novel significant associations for PTPN11 with LEAT and NRAS Q61 mutated protein with a complex MCD characterized by polymicrogyria and nodular heterotopia. The variants identified in NRAS are known from cancer studies to lead to hyperactivation of NRAS, which can be targeted pharmacologically. We identify large recurrent 1q21-q44 duplication including AKT3 in association with focal cortical dysplasia type 2a with hyaline astrocytic inclusions, another rare and possibly under-recognized brain lesion. The clinical genetic analyses showed that the numbers of somatic SNV across the exome and the fraction of affected cells were positively correlated with the age at seizure onset and surgery in individuals with LEAT. Finally, we report that identifying a likely pathogenic variant enabled us to refine or reclassify previous histopathological classifications post hoc in 20.5% of diagnoses. In summary, our comprehensive genetic screen sheds light on the genome-scale landscape of genetic variants in epileptic brain lesions, informs the design of gene panels for clinical diagnostic screening, and guides future directions for clinical implementation of epilepsy surgery genetics.

show abstract

Novel findings and expansion of phenotype in a mosaic RASopathy caused by somatic KRAS variants

Cited by 29 publications

References 44 publications

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome

Identification of a recurrent mosaic KRAS variant in brain tissue from an individual with nevus sebaceous syndrome

Lateralized and Segmental Overgrowth in Children

The genomic landscape across 474 surgically accessible epileptogenic human brain lesions

Contact Info

Product

Resources

About