Analysis of complex structural variants in the DMD gene in one family.

Autor: Luce L; Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Genética, Laboratorio de Distrofinopatías, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina., Abelleyro MM; CONICET-Academia Nacional de Medicina, Instituto de Medicina Experimental (IMEX), Buenos Aires, Argentina., Carcione M; Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Genética, Laboratorio de Distrofinopatías, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina., Mazzanti C; Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Genética, Laboratorio de Distrofinopatías, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina., Rossetti L; CONICET-Academia Nacional de Medicina, Instituto de Medicina Experimental (IMEX), Buenos Aires, Argentina., Radic P; CONICET-Academia Nacional de Medicina, Instituto de Medicina Experimental (IMEX), Buenos Aires, Argentina., Szijan I; Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Genética, Laboratorio de Distrofinopatías, Universidad de Buenos Aires, Buenos Aires, Argentina., Menazzi S; Hospital de Clínicas 'José de San Martín', División de Genética, Universidad de Buenos Aires, Buenos Aires Argentina., Francipane L; Hospital de Clínicas 'José de San Martín', División de Genética, Universidad de Buenos Aires, Buenos Aires Argentina., Nevado J; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma, Madrid, Spain; Centro de Investigaciones Biomédicas en Red para Enfermedades Raras (CIBERER), Madrid, Spain; ITHACA-ERN (European Reference Network), La Paz University Hospital, Madrid, Spain., Lapunzina P; Instituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Universidad Autónoma, Madrid, Spain; Centro de Investigaciones Biomédicas en Red para Enfermedades Raras (CIBERER), Madrid, Spain; ITHACA-ERN (European Reference Network), La Paz University Hospital, Madrid, Spain., De Brasi C; CONICET-Academia Nacional de Medicina, Instituto de Medicina Experimental (IMEX), Buenos Aires, Argentina., Giliberto F; Facultad de Farmacia y Bioquímica, Departamento de Microbiología, Inmunología, Biotecnología y Genética, Cátedra de Genética, Laboratorio de Distrofinopatías, Universidad de Buenos Aires, Buenos Aires, Argentina; Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET-Universidad de Buenos Aires, Buenos Aires, Argentina. Electronic address: gilibertoflor@gmail.com.
Jazyk: angličtina
Zdroj: Neuromuscular disorders : NMD [Neuromuscul Disord] 2021 Mar; Vol. 31 (3), pp. 253-263. Date of Electronic Publication: 2020 Dec 06.
DOI: 10.1016/j.nmd.2020.11.015
Abstrakt: This work describes a family with Duchenne muscular dystrophy (DMD) with a rare case of a symptomatic pregnant woman. The main aim was to perform prenatal molecular diagnosis to provide genetic counseling. The secondary aim was to suggest the molecular mechanisms causing the complex structural variant (cxSV) identified. To accomplish this, we used a multi-technique algorithm including segregation analysis, Multiplex Ligation-dependent Probe Amplification, PCR, X-chromosome inactivation studies, microarrays, whole genome sequencing and bioinformatics. We identified a duplication of exons 38-43 in the DMD gene in all affected and obligate carrier members, proving that this was the DMD-causing mutation. We also observed a skewed X-chromosome inactivation in the symptomatic woman that explained her symptomatology. In addition, we identified a cxSV (duplication of exons 38-43 and deletion of exons 45-54) in the affected boy. The molecular characterization and bioinformatic analyses of the breakpoint junctions allowed us to identify Double Strand Breaks stimulator motifs and suggested the replication-dependent Fork Stalling and Template Switching as the most probable mechanisms leading to the duplication. In addition, the de novo deletion might have been the result of a germline inter-chromosome non-allelic recombination involving the Non-Homologous End Joining mechanism. In conclusion, the diagnostic strategy used allowed us to provide accurate molecular diagnosis and genetic counseling. In addition, the familial molecular diagnosis together with the in-depth characterization of the cxSV helped to determine the chronology of the molecular events, and propose and understand the molecular mechanisms involved in the generation of this complex rearrangement.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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