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. 2022 Jan;43(1):74-84.
doi: 10.1002/humu.24294. Epub 2021 Nov 15.

Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience

Arkadiusz Piotrowski  1   2   3 , Magdalena Koczkowska  1   2   3 , Andrzej B Poplawski  1 , Rafał Bartoszewski  3 , Jarosław Króliczewski  3 , Alina Mieczkowska  3 , Alicia Gomes  1 , Michael R Crowley  4 , David K Crossman  4 , Yunjia Chen  1 , Ping Lao  1 , Eduard Serra  5 , Meritxell C Llach  5 , Elisabeth Castellanos  6   7 , Ludwine M Messiaen  1
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Targeted massively parallel sequencing of candidate regions on chromosome 22q predisposing to multiple schwannomas: An analysis of 51 individuals in a single-center experience

Arkadiusz Piotrowski et al. Hum Mutat. 2022 Jan.

Abstract

Constitutional LZTR1 or SMARCB1 pathogenic variants (PVs) have been found in ∼86% of familial and ∼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.

Keywords: LZTR1; MYO18B; NEFH; NF2; SBF1; SGSM1; SGSM3; SMARCB1; deep intronic variant; low level mosaicism; massively parallel sequencing; schwannomatosis.

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