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Novel deep intronic and frameshift mutations causing a TRIP11-related disorder
Yeqing Qian1,2, Gang Hu1,2, Min Chen1,2
1Women's Hospital, School of Medicine, Zhejiang University, Zhejiang, China.
American Journal of Medical Genetics. Part A
|May 20, 2021
Summary
Genetic mutations in the TRIP11 gene cause severe fetal limb shortening. A novel deep intronic mutation was identified using high-precision sequencing, offering new diagnostic approaches for recurrent pregnancy loss.
Area of Science:
- Genetics
- Developmental Biology
- Molecular Medicine
Background:
- Mutations in the thyroid hormone receptor interactor 11 (TRIP11) gene are linked to achondrogenesis type IA and osteochondrodysplasia.
- Severe fetal limb shortening presents a significant diagnostic challenge in prenatal cases.
Observation:
- A Chinese family presented with two consecutive pregnancies affected by severe fetal limb shortening.
- Whole exome sequencing (WES) identified a frameshift mutation in TRIP11, but suggested an additional unidentified mutation.
Findings:
- High-precision clinical exome sequencing (HPCES) revealed a deep intronic mutation (c.5457+77T>G) in TRIP11, missed by WES due to low sequencing depth.
- RT-PCR confirmed the intronic mutation leads to aberrant transcripts incorporating a 77-bp intronic sequence, likely causing premature protein termination.
Implications:
- This study highlights the importance of deep intronic regions in genetic disorders and the limitations of standard WES for detecting such variants.
- The findings introduce a novel diagnostic strategy for deep intragenic mutations in families with recurrent aberrant fetal phenotypes, improving genetic counseling and reproductive planning.
Keywords:
Achondrogenesis type IATRIP11deep intronic mutationhigh-precision clinical exome sequencingosteochondrodysplasiawhole exome sequencingMore Related Videos
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