[Genetic analysis of a child with co-commitment progressive multifocal leukoencephalopathy and X-linked hyper IgM
1Department of Pediatrics, West China Second Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, Chengdu, Sichuan 610041, China. 18681373671@163.com.
Insights
A genetic variant in the CD40L gene and Jamestown Canyon virus (JCV) infection were detected in a boy with X-linked hyper IgM syndrome (XHIGM) and progressive multifocal leukoencephalopathy (PML). This diagnosis confirms co-commitment of these conditions.
Area of Science:
- Genetics
- Virology
- Immunology
Background:
- X-linked hyper IgM syndrome (XHIGM) is an immunodeficiency disorder.
- Progressive multifocal leukoencephalopathy (PML) is a serious opportunistic infection of the brain.
- Co-occurrence of XHIGM and PML is rare and presents diagnostic challenges.
Observation:
- A 7-year-old boy presented with symptoms suggestive of both XHIGM and PML.
- Genetic analysis revealed a novel hemizygous missense variant (c.506 A>C, p.Y169S) in the CD40L gene.
- Jamestown Canyon virus (JCV) infection was detected in the patient's blood.
Findings:
- The identified CD40L variant is predicted to be damaging, affecting protein structure and function.
- The patient's mother is a heterozygous carrier of the CD40L variant.
- Sequencing confirmed 99% identity of the amplified JCV gene with known sequences.
Implications:
- The study identifies a genetic basis for XHIGM in the patient, linked to a CD40L variant.
- The presence of JCV supports its role in the observed PML in this immunocompromised child.
- This case highlights the importance of genetic and infectious agent detection for diagnosing complex co-occurring conditions.
Objective:
To detect variant of the CD40L gene and infection of Jamestown Canyon virus (JCV) in a 7-year-and-9-month-old boy with co-commitment progressive multifocal leukoencephalopathy (PML) and X-linked hyper IgM syndrome (XHIGM).
Methods:
Peripheral blood samples of the child and his parents were collected for the extraction of genomic DNA. The 5 exons and exon/intronic boundaries of the CD40L gene were subjected to PCR amplification and sequencing. Suspected variants were analyzed by using bioinformatic software. The JCV gene was amplified from genomic DNA by nested PCR and sequenced.
Results:
The child was found to harbor a hemizygous c.506 A>C (p.Y169S) missense variant in exon 5 of the CD40L gene. The variant may affect the TNFH domain of the CD40L protein and result in structural instability and loss of hydrophobic interaction between CD40L and CD40. As predicted by PolyPhen2 and SIFT software, the variant was probably damaging (score = 1.00) and deleterious (score= -8.868). His mother was found to be a heterozygous carrier, while the same variant was not found in his father. Gel electrophoresis of the nested PCR product revealed presence of target JCV band, which was confirmed to be 99% identical with the JCV gene by sequencing.
Conclusion:
The patient was diagnosed with co-commitment XHIGM and PML based on the testing of the CD40L gene and JCV infection.
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