A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II

American Journal of Medical Genetics Part A, vol. 197, pp. e63972

Abstract

Osteogenesis imperfecta (OI) is a rare disease, hallmarked by bone fragility, multiple fractures, and deformities, and is commonly caused by pathogenic variants in the genes encoding type I collagen. Type II OI is the most severe form and is lethal in the perinatal period. Here, we report recurrence of perinatal lethal OI in two fetuses due to parental mosaicism for a deep intronic pathogenic variant at c.2451 + 77C > T in intron 35 of COL1A1, which resulted in aberrant splicing and the in-frame addition of 75 nucleotides into the mRNA. These patients highlight the importance of considering deep intronic variants in type 1 collagen genes in patients with high suspicion of OI, which may be missed with conventional genetic analysis.

Authors 6

1. Mackenna E. Schouw Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · University Medical Center Utrecht · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Internal Medicine Amsterdam University Medical Center Amsterdam The Netherlands

   Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

   Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands

2. Claudia A. L. Ruivenkamp Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

3. Tamara T. Koopmann Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

4. Gijs W.E. Santen Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands

5. Peter G. J. Nikkels

   University Medical Center Groningen · University Medical Center Utrecht

   Affiliation as printed

   Department of Pathology University Medical Center Utrecht Utrecht The Netherlands

   Department of Clinical Genetics, University Medical Center Groningen, Groningen, The Netherlands

6. Karin van der Tuin corresponding Aachen Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands Department of Clinical Genetics

   University Medical Center Groningen · Leiden University Medical Center · Amsterdam UMC Location University of Amsterdam · Amsterdam University Medical Centers

   Affiliation as printed

   Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

   Department of Clinical Genetics University Medical Center Groningen Groningen The Netherlands

   Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

   Department of Internal Medicine, Amsterdam University Medical Center, Amsterdam, The Netherlands