[Genetic analysis of a child with Malan syndrome]
Baosong Wang1, Xuexi Zhang, Yunjia Li
1Department of Reproductive Medicine, Linyi People's Hospital, Linyi, Shandong 276003, China. mq002@163.com.
Insights
A genetic study identified a new NFIX gene variant (c.697+1G>A) in a child with developmental delay and intellectual disability. This pathogenic variant likely causes abnormal gene splicing, leading to the observed neurodevelopmental disorder.
Area of Science:
- Genetics
- Neurodevelopmental Disorders
- Molecular Biology
Background:
- Developmental delay and intellectual disability are complex neurodevelopmental disorders with diverse genetic etiologies.
- Identifying the specific genetic basis is crucial for accurate diagnosis and potential therapeutic strategies.
Purpose of the Study:
- To investigate the genetic underpinnings of a child presenting with mental retardation and developmental delay.
- To identify novel genetic variants associated with neurodevelopmental phenotypes.
Main Methods:
- Utilized trio-whole genome sequencing (trio-WGS) on a child and her parents.
- Performed Sanger sequencing and RNAseq to validate candidate variants and assess their impact on gene splicing.
- Conducted clinical assessments including the simplified Peabody scale, electroencephalogram, and brain MRI.
Main Results:
- Trio-WGS identified a novel pathogenic variant (c.697+1G>A) in the NFIX gene.
- This variant is predicted to cause abnormal NFIX gene splicing, a likely mechanism for the child's condition.
- Standard genetic and imaging tests, including chromosomal karyotyping and metabolic screening, revealed no significant abnormalities.
Conclusions:
- The de novo c.697+1G>A variant in the NFIX gene is strongly implicated as the cause of the child's developmental delay and intellectual disability.
- Abnormal splicing resulting from this variant is the probable pathogenic mechanism.
- This finding highlights the role of NFIX gene variants in neurodevelopmental disorders.
Objective:
To explore the genetic basis of a child with mental retardation and developmental delay.
Methods:
A child who had attended the genetic clinic of Linyi People's Hospital from October 2023 to April 2024 was selected as the study subject. Intelligence and development were assessed with simplified Peabody scale. Electroencephalogram and imaging data were collected. Peripheral blood samples of the child and her parents were collected for the screening of genetic metabolic diseases, chromosomal karyotyping, and trio-whole genome sequencing (trio-WGS) analysis. Candidate variant was verified by Sanger sequencing, and RNAseq was carried out to verify the alternative splicing due to the candidate variant. This study has been approved by the Medical Ethics Committee of Linyi People's Hospital (No. YX200083).
Results:
The patient was an 8-year-and-11-month-old girl. Both of her parents had normal phenotypes. The child was assessed by the simplified Peabody scale as having intellectual disability and developmental delay. MRI showed no definite abnormal signals within the brain parenchyma, and electroencephalogram was normal. Screening of genetic metabolic diseases showed no obvious abnormality. Chromosomal karyotype was normal. Trio-WGS has detected a c.697+1G>A variant in the intron 4 of the NFIX gene, along with 9 other variants within eight genes. The c.697+1G>A variant may cause abnormal splicing of the NFIX gene transcript. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.697+1G>A variant was predicted to be pathogenic (PVS1+PS2+PM2_Supporting), while the evidence for pathogenicity of the other 9 variants was insufficient.
Conclusion:
The novel de novo c.697+1G>A variant of the NFIX gene probably underlay the pathogenesis of the child, which may have caused the disease by leading to abnormal splicing.
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