Clinical trio genome sequencing facilitates the interpretation of variants in cancer predisposition genes in paediatric tumour patients
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Published:2023-07-28
Issue:10
Volume:31
Page:1139-1146
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ISSN:1018-4813
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Container-title:European Journal of Human Genetics
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language:en
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Short-container-title:Eur J Hum Genet
Author:
Schroeder ChristopherORCID, Faust Ulrike, Krauße LuisaORCID, Liebmann Alexandra, Abele MichaelORCID, Demidov GermanORCID, Schütz Leon, Kelemen Olga, Pohle Alexandra, Gauß Silja, Sturm MarcORCID, Roggia Cristiana, Streiter Monika, Buchert RebeccaORCID, Armenau-Ebinger Sorin, Nann Dominik, Beschorner RudiORCID, Handgretinger Rupert, Ebinger Martin, Lang Peter, Holzer Ursula, Skokowa JuliaORCID, Ossowski Stephan, Haack Tobias B., Mau-Holzmann Ulrike A., Dufke Andreas, Riess Olaf, Brecht Ines B.ORCID
Abstract
AbstractThe prevalence of pathogenic and likely pathogenic (P/LP) variants in genes associated with cancer predisposition syndromes (CPS) is estimated to be 8-18% for paediatric cancer patients. In more than half of the carriers, the family history is unsuspicious for CPS. Therefore, broad genetic testing could identify germline predisposition in additional children with cancer resulting in important implications for themselves and their families. We thus evaluated clinical trio genome sequencing (TGS) in a cohort of 72 paediatric patients with solid cancers other than retinoblastoma or CNS-tumours. The most prevalent cancer types were sarcoma (n = 26), neuroblastoma (n = 15), and nephroblastoma (n = 10). Overall, P/LP variants in CPS genes were identified in 18.1% of patients (13/72) and P/LP variants in autosomal-dominant CPS genes in 9.7% (7/72). Genetic evaluation would have been recommended for the majority of patients with P/LP variants according to the Jongmans criteria. Four patients (5.6%, 4/72) carried P/LP variants in autosomal-dominant genes known to be associated with their tumour type. With the immediate information on variant inheritance, TGS facilitated the identification of a de novo P/LP in NF1, a gonadosomatic mosaic in WT1 and two pathogenic variants in one patient (DICER1 and PALB2). TGS allows a more detailed characterization of structural variants with base-pair resolution of breakpoints which can be relevant for the interpretation of copy number variants. Altogether, TGS allows comprehensive identification of children with a CPS and supports the individualised clinical management of index patients and high-risk relatives.
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
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