Improving Diagnostic Precision: Phenotype-Driven Analysis Uncovers a Maternal Mosaicism in an Individual with RYR1-Congenital Myopathy
Por:
Estévez-Arias B, Matalonga L, Martorell-Sampol L, Codina-Bergadà A, Ortez-Gonzalez CI, Carrera-García L, Exposito-Escudero JM, Yubero-Siles D, Hoenicka J, Jou-Munoz C, Palau F, Beltran S, Lochmüller H, Töpf A, Nascimento-Osorio A and Natera-de Benito D
Publicada:
1 ene 2024
Ahead of Print:
10 mar 2024
Resumen:
Congenital myopathies (CMs) are rare genetic disorders for which the diagnostic yield does not typically exceed 60%. We performed deep phenotyping, histopathological studies, clinical exome and trio genome sequencing and a phenotypedriven analysis of the genomic data, that led to the molecular diagnosis in a child with CM. We identified a heterozygous variant in RYR1 in the affected child, inherited from her asymptomatic mother. Given the alignment of the clinical and histopathological phenotype with RYR1-CM, we considered the potential existence of a missing second variant in trans in the proband, but also hypothesized that the variant might be mosaic in the mother, as subsequently demonstrated. Our study is an example of how heterozygous variants inherited from asymptomatic parents are frequently dismissed. When the genotype-phenotype correlation is strong, it is recommended to consider a parental mosaicism.
Filiaciones:
Estévez-Arias B:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Matalonga L:
Centro Nacional Análisis Genómico (CNAG), Barcelona, Spain
Martorell-Sampol L:
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Codina-Bergadà A:
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Ortez-Gonzalez CI:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Carrera-García L:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Exposito-Escudero JM:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Yubero-Siles D:
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Hoenicka J:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Jou-Munoz C:
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Department of Pathology, Hospital Sant Joan de Déu, Barcelona, Spain
Palau F:
Laboratory of Neurogenetics and Molecular Medicine - IPER, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Department of Genetic and Molecular Medicine - IPER, Hospital Sant Joan de Déu and Institut de Recerca Sant Joan de Déu, Barcelona, Spain
ERN ITHACA, Barcelona, Spain
Division of Pediatrics, Faculty of Medicine and Health Sciences, Universitat de Barcelona (UB), Barcelona, Spain
Beltran S:
Centro Nacional Análisis Genómico (CNAG), Barcelona, Spain
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
Lochmüller H:
Centro Nacional Análisis Genómico (CNAG), Barcelona, Spain
Childrens Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa, Canada
Töpf A:
The John Walton Muscular Dystrophy Research Centre, Translational and Clinical Research Institute, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK
Nascimento-Osorio A:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Center for Biomedical Research Network on Rare Diseases (CIBERER), ISCIII, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Natera-de Benito D:
Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu, Barcelona, Spain
Applied Research in Neuromuscular Diseases, Institut de Recerca Sant Joan de Déu, Barcelona, Spain
Green Submitted, Bronze
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