Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience
Por:
Piotrowski, A, Koczkowska, M, Poplawski, AB, Bartoszewski, R, Kroliczewski, J, Mieczkowska, A, Gomes, A, Crowley, MR, Crossman, DK, Chen, YJ, Lao, P, Serra, E, Llach, MC, Castellanos, E and Messiaen, LM
Publicada:
1 ene 2022
Ahead of Print:
1 nov 2021
Resumen:
Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in similar to 86% of familial and similar to 40% of sporadic schwannomatosis cases. Hence, we performed massively parallel sequencing of the entire LZTR1, SMARCB1, and NF2 genomic loci in 35 individuals with schwannomas negative for constitutional first-hit PVs in the LZTR1/SMARCB1/NF2 coding sequences; however, with 22q deletion and/or a different NF2 PV in each tumor, including six cases with only one tumor available. Furthermore, we verified whether any other LZTR1/SMARCB1/NF2 (likely) PVs could be found in 16 cases carrying a SMARCB1 constitutional variant in the 3 '-untranslated region (3 '-UTR) c.*17C>T, c.*70C>T, or c.*82C>T. As no additional variants were found, functional studies were performed to clarify the effect of these 3 '-UTR variants on the transcript. The 3 '-UTR variants c.*17C>T and c.*82C>T showed pathogenicity by negatively affecting the SMARCB1 transcript level. Two novel deep intronic SMARCB1 variants, c.500+883T>G and c.500+887G>A, resulting in out-of-frame missplicing of intron 4, were identified in two unrelated individuals. Further resequencing of the entire repeat-masked genomics sequences of chromosome 22q in individuals negative for PVs in the SMARCB1/LZTR1/NF2 coding- and noncoding regions revealed five potential schwannomatosis-predisposing candidate genes, that is, MYO18B, NEFH, SGSM1, SGSM3, and SBF1, pending further verification.
Filiaciones:
Piotrowski, A:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
Med Univ Gdansk, 3P Med Lab, Gdansk, Poland
Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80210 Gdansk, Poland
Koczkowska, M:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
Med Univ Gdansk, 3P Med Lab, Gdansk, Poland
Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80210 Gdansk, Poland
Poplawski, AB:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
Bartoszewski, R:
Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80210 Gdansk, Poland
Kroliczewski, J:
Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80210 Gdansk, Poland
Mieczkowska, A:
Med Univ Gdansk, Dept Biol & Pharmaceut Bot, PL-80210 Gdansk, Poland
Gomes, A:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
Crowley, MR:
Univ Alabama Birmingham, Genom Core Facil, Birmingham, AL 35294 USA
Crossman, DK:
Univ Alabama Birmingham, Genom Core Facil, Birmingham, AL 35294 USA
Chen, YJ:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
Lao, P:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
:
Germans Trias & Pujol Res Inst IGTP, Program Predict & Personalized Med Canc PMPPC, Hereditary Canc Grp, Barcelona, Spain
:
Germans Trias & Pujol Res Inst IGTP, Program Predict & Personalized Med Canc PMPPC, Hereditary Canc Grp, Barcelona, Spain
:
Germans Trias & Pujol Res Inst IGTP, Program Predict & Personalized Med Canc PMPPC, Clin Genom Res Grp, Barcelona, Spain
Germans Trias & Pujol Univ Hosp HUGTiP, Clin Genet Serv, Clin Genom Unit, Northern Metropolitan Clin Lab, Barcelona, Spain
Messiaen, LM:
Univ Alabama Birmingham, Dept Genet, Birmingham, AL 35294 USA
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