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

Abstract

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.

The Pharmacorank Search Tool for the Retrieval of Prioritized Protein Drug Targets and Drug Repositioning Candidates According to Selected Diseases

“…The mutant GTPase KRas of the disease state has a higher proportion of HRAS-GTP activity than that found in wild-type cells [ 36 ]. The inhibitor sotorasib may therefore offer a treatment to reduce the relatively high activity seen of GTPase KRas in the disease state [ 37 ].…”

Pseudodidymosis aplasticosebacea: Binary phenomenon of congenital aplasia cutis congenita and nevus sebaceus

“… 5 The sebaceous component in our patient is most likely identical to that in the sebaceous nevus syndrome, which includes sebaceous nevus and cerebral, ocular, or skeletal abnormalities. 12 …”

Australian healthcare professionals' perspectives on genetic counseling and genetic diagnosis in vascular anomalies

“…Therefore, molecular testing of VAs is more complex than in many other areas of genetic healthcare. To combat this barrier, we and others across the world have demonstrated highly sensitive molecular strategies, such as droplet digital PCR (ddPCR), as useful approaches to detect recurrent variants at low VAFs in tissue samples, and therefore diagnose VAs (Green et al, 2021; Hildebrand et al, 2018; Limaye et al, 2009; Siegel et al, 2018).…”