TY - JOUR
T1 - A comparative analysis of RAS variants in patients with disorders of somatic mosaicism
AU - Claire Hou, Ying Chen
AU - Evenson, Michael J.
AU - Corliss, Meagan M.
AU - Mahapatra, Lily
AU - Aldawood, Ali
AU - Carpentieri, David F.
AU - Chamlin, Sarah L.
AU - Kulungowski, Ann M.
AU - Madan-Khetarpal, Suneeta
AU - Sebastian, Jessica
AU - Pet, Mitchell A.
AU - Coughlin, Carrie C.
AU - Willing, Marcia C.
AU - Pearson, Gregory D.
AU - Setty, Bhuvana A.
AU - El-Haffaf, Zaki
AU - Cottrell, Catherine E.
AU - Parikh, Bijal A.
AU - Krysiak, Kilannin
AU - Schroeder, Molly C.
AU - Heusel, Jonathan W.
AU - Neidich, Julie A.
AU - Cao, Yang
N1 - Publisher Copyright:
© 2022 American College of Medical Genetics and Genomics
PY - 2023/3
Y1 - 2023/3
N2 - Purpose: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. Methods: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing−based testing. We investigated the mutational spectrum and genotype−phenotype associations of mosaic RAS variants. Results: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
AB - Purpose: RAS genes (HRAS, KRAS, and NRAS) are commonly found to be mutated in cancers, and activating RAS variants are also found in disorders of somatic mosaicism (DoSM). A survey of the mutational spectrum of RAS variants in DoSM has not been performed. Methods: A total of 938 individuals with suspected DoSM underwent high-sensitivity clinical next-generation sequencing−based testing. We investigated the mutational spectrum and genotype−phenotype associations of mosaic RAS variants. Results: In this article, we present a series of individuals with DoSM with RAS variants. Classic hotspots, including Gly12, Gly13, and Gln61 constituted the majority of RAS variants observed in DoSM. Furthermore, we present 12 individuals with HRAS and KRAS in-frame duplication/insertion (dup/ins) variants in the switch II domain. Among the 18.3% individuals with RAS in-frame dup/ins variants, clinical findings were mainly associated with vascular malformations. Hotspots were associated with a broad phenotypic spectrum, including vascular tumors, vascular malformations, nevoid proliferations, segmental overgrowth, digital anomalies, and combinations of these. The median age at testing was higher and the variant allelic fraction was lower in individuals with in-frame dup/ins variants than those in individuals with mosaic RAS hotspots. Conclusion: Our work provides insight into the allelic and clinical heterogeneity of mosaic RAS variants in nonmalignant conditions.
KW - Disorders of somatic mosaicism
KW - HRAS
KW - In-frame insertions
KW - KRAS
KW - RAS
UR - http://www.scopus.com/inward/record.url?scp=85146628147&partnerID=8YFLogxK
U2 - 10.1016/j.gim.2022.11.016
DO - 10.1016/j.gim.2022.11.016
M3 - Article
C2 - 36571464
AN - SCOPUS:85146628147
SN - 1098-3600
VL - 25
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 3
M1 - 100348
ER -