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Exome Sequence Analysis to Characterize Undiagnosed Family Segregating Motor Impairment and Dystonia
Ahmad M Almatrafi1,2, Abdulfatah M Alayoubi3, Majed Alluqmani4
1Department of Biology, College of Science, Taibah University, Medina 42353, Saudi Arabia.
Abstract:
Background: Hypermanganesemia with dystonia 1 (HMNDYT1) is a rare genetic disorder characterized by elevated blood manganese levels. This condition is associated with polycythemia, motor neurodegeneration with extrapyramidal features, and hepatic dysfunction, which can progress to cirrhosis in some patients. Materials and Methods: In this study, a consanguineous Saudi family with two affected individuals exhibiting symptoms of severe motor impairment, spastic paraparesis, postural instability, and dystonia was studied. Clinical and radiographic evaluations were conducted on the affected individuals. Whole exome sequencing (WES) was performed to diagnose the disease and to determine the causative variant underlying the phenotype. Moreover, Sanger sequencing was used for validation and segregation analysis of the identified variant. Bioinformatics tools were utilized to predict the pathogenicity of candidate variants based on ACMG criteria. Results: Exome sequencing detected a recurrent homozygous missense variant (c.266T>C; p.L89P) in exon 1 of the SLC30A10 gene. Sanger sequencing was employed to validate the segregation of the discovered variant in all available family members. Bioinformatics tools predicted that the variant is potentially pathogenic. Moreover, conservation analysis showed that the variant is highly conserved in vertebrates. Conclusions: This study shows that exome sequencing is instrumental in diagnosing undiagnosed neurodevelopmental disorders. Moreover, this study expands the mutation spectrum of SLC30A10 in distinct populations.
Insights
Hypermanganesemia with dystonia 1 (HMNDYT1), a rare genetic disorder, was diagnosed in a Saudi family using whole exome sequencing. A novel SLC30A10 gene variant was identified, expanding the known mutation spectrum.
Area of Science:
- Genetics
- Neuroscience
- Biochemistry
Background:
- Hypermanganesemia with dystonia 1 (HMNDYT1) is a rare genetic disorder.
- Characterized by elevated blood manganese, polycythemia, motor neurodegeneration, and hepatic dysfunction.
- Can progress to cirrhosis.
Purpose of the Study:
- Diagnose a rare genetic disorder in a consanguineous Saudi family.
- Identify the causative genetic variant.
- Expand the mutation spectrum of the SLC30A10 gene.
Main Methods:
- Clinical and radiographic evaluations.
- Whole exome sequencing (WES) for diagnosis.
- Sanger sequencing for validation and segregation analysis.
- Bioinformatics tools for variant pathogenicity prediction.
Main Results:
- A recurrent homozygous missense variant (c.266T>C; p.L89P) in the SLC30A10 gene was identified.
- Sanger sequencing confirmed variant segregation within the family.
- Bioinformatics predicted the variant as potentially pathogenic and highly conserved.
Conclusions:
- Whole exome sequencing is crucial for diagnosing undiagnosed neurodevelopmental disorders.
- This study expands the mutation spectrum of SLC30A10 in diverse populations.
- Identified a novel variant contributing to HMNDYT1 phenotype.
