Clinical and functional characterization of COL2A1 p.Gly444Ser variant: From a fetal phenotype to a previously undisclosed postnatal phenotype
Enrica Marchionni,
Maria Rosaria D'Apice,
Viviana Lupo,
Giovanna Lattanzi,
Elisabetta Mattioli,
Gina Lisignoli,
Elena Gabusi,
Gerardo Pepe,
Manuela Helmer Citterich,
Elena Campione,
Anna Maria Nardone,
Paola Spitalieri,
Noemi Pucci,
Dario Cocciadiferro,
Eliseo Picchi,
Francesco Garaci,
Antonio Novelli,
Giuseppe Novelli
Affiliations
Enrica Marchionni
Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy; Corresponding author.
Maria Rosaria D'Apice
Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy
Viviana Lupo
Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Giovanna Lattanzi
CNR Institute of Molecular Genetics ''Luigi Luca Cavalli-Sforza'' Unit of Bologna, Bologna, Italy; Istituto Ortopedico Rizzoli, Bologna, Italy
Elisabetta Mattioli
CNR Institute of Molecular Genetics ''Luigi Luca Cavalli-Sforza'' Unit of Bologna, Bologna, Italy; Istituto Ortopedico Rizzoli, Bologna, Italy
Gina Lisignoli
IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale Bologna, Italy
Elena Gabusi
IRCCS Istituto Ortopedico Rizzoli, Laboratorio di Immunoreumatologia e Rigenerazione Tissutale Bologna, Italy
Gerardo Pepe
Department of Biology, University of Rome Tor Vergata, Rome, Italy
Manuela Helmer Citterich
Department of Biology, University of Rome Tor Vergata, Rome, Italy
Elena Campione
Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
Anna Maria Nardone
Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy
Paola Spitalieri
Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Noemi Pucci
Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Dario Cocciadiferro
Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Eliseo Picchi
Diagnostic Imaging Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Francesco Garaci
Neuroradiology Unit, Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
Antonio Novelli
Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Giuseppe Novelli
Medical Genetics Unit, Policlinico Tor Vergata, University of Rome Tor Vergata, Rome, Italy; Department of Biomedicine and Prevention, University of Rome Tor Vergata, Rome, Italy
COL2A1 gene encodes the alpha-1 chain of type-II procollagen. Heterozygous pathogenic variants are associated with the broad clinical spectrum of genetic diseases known as type-II collagenopathies. We aimed to characterize the NM_001844.5:c.1330G>A;p.Gly444Ser variant detected in the COL2A1 gene through trio-based prenatal exome sequencing in a fetus presenting a severe skeletal phenotype at 31 Gestational Weeks and in his previously undisclosed mild-affected father. Functional studies on father's cutaneous fibroblasts, along with in silico protein modeling and in vitro chondrocytes differentiation, showed intracellular accumulation of collagen-II, its localization in external Golgi vesicles and nuclear morphological alterations. Extracellular matrix showed a disorganized fibronectin network. These results showed that p.Gly444Ser variant alters procollagen molecules processing and the assembly of mature type-II collagen fibrils, according to COL2A1-chain disorganization, displayed by protein modeling. Clinical assessment at 38 y.o., through a reverse-phenotyping approach, revealed limp gait, short and stocky appearance. X-Ray and MRI showed pelvis asymmetry with severe morpho-structural alterations of the femoral heads bilaterally, consistent with a mild form of type-II collagenopathy. This study shows how the fusion of genomics and clinical expertise can drive a diagnosis supported by cellular and bioinformatics studies to effectively establish variants pathogenicity.
