Abstract
Deleterious variants in collagen genes are the most common cause of hereditary connective tissue disorders (HCTD). Adaptations of the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria are still lacking. A multidisciplinary team was set up for developing specifications of the ACMG/AMP criteria for COL1A1, COL1A2, COL2A1, COL3A1, COL5A1, COL5A2, COL11A1, COL11A2 and COL12A1, associated with various forms of HCTD featuring joint hypermobility, which is becoming one of the most common reasons of referral for molecular testing in this field. Such specifications were validated against 209 variants, and resulted effective for classifying as pathogenic and likely pathogenic null alleles without downgrading of the PVS1 level of strength and recurrent Glycine substitutions. Adaptations of selected criteria reduced uncertainties on private Glycine substitutions, intronic variants predicted to affect the splicing, and null alleles with a downgraded PVS1 level of strength. Segregation and multigene panel sequencing data mitigated uncertainties on non-Glycine substitutions by the attribution of one or more benignity criteria. These specifications may improve the clinical utility of molecular testing in HCTD by reducing the number of variants with neutral/conflicting interpretations. Close interactions between laboratory and clinicians are crucial to estimate the a priori utility of molecular test and to improve medical reports.
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Data availability
The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors thank the family for their kind availability in sharing the findings within the scientific community. M.C. is a member of the European Reference Network for rare and complex diseases ReCONNET and ERN-Skin. A.F. is a member of the European Reference Network for rare and complex diseases ReCONNET.
Funding
This work was supported by the Italian Ministry of Health ‘Ricerca Corrente 2022–2024. M.C. has received research support from the Patients’ Association ‘Con Giacomo contro vascular Ehlers–Danlos syndrome’. This study was supported by "Ministero della Salute"
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MC, MPL, LM and SM contributed to the study conception and design. Material preparation, data collection and interpretation were performed by MC, CF, VG, MPL, LM, GN, and RP. The first draft of the manuscript was written by MC, MPL, and LM and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Leone, M.P., Morlino, S., Nardella, G. et al. Specifications and validation of the ACMG/AMP criteria for clinical interpretation of sequence variants in collagen genes associated with joint hypermobility. Hum Genet 142, 785–808 (2023). https://doi.org/10.1007/s00439-023-02547-z
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DOI: https://doi.org/10.1007/s00439-023-02547-z