Using comprehensive genomic and functional analyses for resolving genotype-phenotype mismatches in children with suspected CMMRD in Lebanon: an IRRDC study.

Autor: Hamideh D; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Das A; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Bianchi V; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Chung J; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Negm L; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Levine A; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Basbous M; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Sanchez-Ramirez S; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Mikael L; Department of Pediatric Hematology-Oncology, McGill University Heath Centre, Montreal, Canada., Jabado N; Department of Pediatric Hematology-Oncology, McGill University Heath Centre, Montreal, Canada., Atweh L; Department of Diagnostic Radiology, American University of Beirut Medical Center, Beirut, Lebanon.; Department of Diagnostic Radiology, Nationwide Children's Hospital, Columbus, OH, USA., Lteif M; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Mahfouz R; Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Tarek N; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Abboud M; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Muwakkit S; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon., Hawkins C; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada., Tabori U; The Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto, ON, M5G1X8, Canada. uri.tabori@sickkids.ca., Saab R; Children's Cancer Institute, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon. rsaab@stanford.edu.; Department of Pediatrics, Stanford University School of Medicine, Palo Alto, USA. rsaab@stanford.edu.
Jazyk: angličtina
Zdroj: Human genetics [Hum Genet] 2023 Apr; Vol. 142 (4), pp. 563-576. Date of Electronic Publication: 2023 Feb 15.
DOI: 10.1007/s00439-023-02530-8
Abstrakt: Constitutional mismatch repair deficiency (CMMRD) is an aggressive and highly penetrant cancer predisposition syndrome. Because of its variable clinical presentation and phenotypical overlap with neurofibromatosis, timely diagnosis remains challenging, especially in countries with limited resources. Since current tests are either difficult to implement or interpret or both we used a novel and relatively inexpensive functional genomic assay (LOGIC) which has been recently reported to have high sensitivity and specificity in diagnosing CMMRD. Here we report the clinical and molecular characteristics of nine patients diagnosed with cancer and suspected to have CMMRD and highlight the challenges with variant interpretation and immunohistochemical analysis that led to an uncertain interpretation of genetic findings in 6 of the 9 patients. Using LOGIC, we were able to confirm the diagnosis of CMMRD in 7 and likely exclude it in 2 patients, resolving ambiguous result interpretation. LOGIC also enabled predictive testing of asymptomatic siblings for early diagnosis and implementation of surveillance. This study highlights the varied manifestations and practical limitations of current diagnostic criteria for CMMRD, and the importance of international collaboration for implementing robust and low-cost functional assays for resolving diagnostic challenges.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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