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A Deep Intronic Splice Variant in COL1A1 Causing Osteogenesis Imperfecta Type II
Mackenna E Schouw1,2, Claudia A L Ruivenkamp1, Tamara T Koopmann1
1Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
American Journal of Medical Genetics. Part A
|December 23, 2024
Summary
Recurrent lethal Osteogenesis Imperfecta (OI) in two fetuses was linked to parental mosaicism for a deep intronic COL1A1 variant. This genetic finding underscores the need for comprehensive analysis in suspected OI cases.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Osteogenesis Imperfecta (OI) is a rare genetic disorder characterized by bone fragility and fractures, often caused by mutations in collagen genes.
- Type II OI represents the most severe form, leading to perinatal lethality.
Observation:
- Two fetuses presented with recurrent perinatal lethal OI.
- Parental mosaicism for a deep intronic variant (c.2451+77C>T) in intron 35 of the COL1A1 gene was identified.
Findings:
- The deep intronic variant induced aberrant splicing, resulting in a 75-nucleotide in-frame addition to the mRNA.
- This molecular alteration disrupts type I collagen production, consistent with severe OI.
Implications:
- Deep intronic variants in collagen genes should be considered in the genetic diagnosis of OI, especially in severe or recurrent cases.
- Conventional genetic testing may miss these variants, necessitating advanced molecular analysis for accurate diagnosis and genetic counseling.
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