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Prenatal Cases Reflect the Complexity of the COL1A1/2 Associated Osteogenesis Imperfecta
1Prenatal Diagnosis Center, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing 100026, China.
Insights
Genetic testing using whole-exome sequencing identified Osteogenesis Imperfecta (OI) variants in COL1A1/2 genes in all ten fetal cases. This study highlights the complexity of prenatal OI and its genetic causes.
Area of Science:
- Genetics
- Skeletal Dysplasias
- Prenatal Diagnosis
Background:
- Osteogenesis Imperfecta (OI) is a rare, inherited skeletal disorder.
- Prenatal diagnosis of OI presents challenges due to diverse clinical and genetic factors.
Purpose of the Study:
- To investigate the genetic basis of suspected fetal OI.
- To identify diagnostic variants and understand the complexity of prenatal OI.
Main Methods:
- Ten suspected fetal OI cases underwent genetic testing.
- Methods included karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES).
- Sanger sequencing and in silico analysis validated variants.
Main Results:
- Karyotyping and CMA yielded normal results for all cases.
- WES detected OI-associated variants in COL1A1/2 genes in all ten cases.
- Six novel variants were identified, and four cases showed unique characteristics like mosaicism and dual nosogenesis.
Conclusions:
- Whole-exome sequencing is crucial for diagnosing prenatal OI.
- Expands the known spectrum of COL1A1/2 related OI.
- Emphasizes the need to clarify pathogenic mechanisms in complex prenatal OI cases.
Introduction:
Osteogenesis imperfecta (OI) is a rare mendelian skeletal dysplasia with autosomal dominant or recessive inheritance pattern, and almost the most common primary osteoporosis in prenatal settings. The diversity of clinical presentation and genetic etiology in prenatal OI cases presents a challenge to counseling yet has seldom been discussed in previous studies.
Methods:
Ten cases with suspected fetal OI were enrolled and submitted to a genetic detection using conventional karyotyping, chromosomal microarray analysis (CMA), and whole-exome sequencing (WES). Sanger sequencing was used as the validation method for potential diagnostic variants. In silico analysis of specific missense variants was also performed.
Results:
The karyotyping and CMA results of these cases were normal, while WES identified OI-associated variants in the COL1A1/2 genes in all ten cases. Six of these variants were novel. Additionally, four cases here exhibited distinctive clinical and/or genetic characteristics, including the situations of intrafamilial phenotypic variability, parental mosaicism, and "dual nosogenesis" (mutations in collagen I and another gene).
Conclusion:
Our study not only expands the spectrum of COL1A1/2-related OI, but also highlights the complexity that occurs in prenatal OI and the importance of clarifying its pathogenic mechanisms.
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