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Published on: August 8, 2022
[Genetic analysis of a child with Primary hypertrophic osteoarthropathy]
Chen Wang1, Xueping Qiu, Yating Cheng
1Center for Gene Diagnosis/Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, Hubei 430071, China. zhengfang@whu.edu.cn.
Insights
Genetic testing identified compound heterozygous variants in the HPGD gene, including a deletion and a splicing variant, causing Primary hypertrophic osteoarthropathy in a child.
Area of Science:
- Genetics
- Molecular Biology
- Pediatrics
Background:
- Primary hypertrophic osteoarthropathy (PHO) is a rare genetic disorder.
- Genetic mutations, particularly in the HPGD gene, are implicated in PHO pathogenesis.
- Understanding the genetic basis is crucial for diagnosis and management.
Purpose of the Study:
- To investigate the genetic cause of PHO in a pediatric patient.
- To identify specific variants in the HPGD gene responsible for the condition.
Main Methods:
- Whole exome sequencing (WES) was performed on the patient and parents.
- Sanger sequencing, long-fragment PCR, and minigene assays were used for variant validation.
- Functional studies were conducted to confirm the impact of the splicing variant.
Main Results:
- The child presented with compound heterozygous variants in the HPGD gene: a deletion (exon 3 del) from the father and a splicing variant (c.421+1G>T) from the mother.
- Long-fragment PCR confirmed a 7565 bp heterozygous deletion (c.218-1304_324+6156del) in the child and father.
- Minigene assay demonstrated that the splicing variant leads to exon 4 skipping.
Conclusions:
- Compound heterozygous variants in the HPGD gene, specifically the c.218-1304_324+6156del deletion and c.421+1G>T splicing variant, are likely responsible for the patient's PHO.
- This study expands the known mutation spectrum of the HPGD gene.
- Findings provide a foundation for genetic counseling and prenatal diagnosis for affected families.
Objective:
To explore the genetic etiology of a child with Primary hypertrophic osteoarthropathy.
Methods:
A child who was admitted to Zhongnan Hospital of Wuhan University on July 27, 2021 was selected as the study subject. Genomic DNA was extracted from peripheral blood samples of the child and his parents and subjected to whole exome sequencing. Suspected splicing variant was verified by Sanger sequencing of family members. In vitro function was validated through a minigene assay, whilst the suspected exonic deletion was validated by long-fragment PCR.
Results:
Whole exome sequencing revealed that the child has harbored compound heterozygous variants of HPGD gene, including a heterozygous deletion (exon 3 del) derived from his father and a splicing variant (c.421+1G>T) derived from his mother. Long-fragment PCR verified that the child and his father had both harbored a 7 565 bp heterozygous deletion (c.218-1304_324+6156del), whilst the minigene assay proved that the splicing variant has resulted in skipping of exon 4.
Conclusion:
The heterozygous c.218-1304_324+6156del deletion and the c.421+1G>T splicing variant of the HPGD gene probably underlay the pathogenesis in this child. Above finding has enriched the mutational spectrum of the HPGD gene and provided a basis for genetic counseling and prenatal diagnosis for this family.
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