A novel homozygous variant in an Iranian pedigree with cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4

Autor: Pegah Ghandil, Malihe Mohamadian, Afsane Bahrami, Mohsen Naseri, Ali Akbar Momen
Rok vydání: 2020
Předmět:
Male
0301 basic medicine
Microbiology (medical)
Proband
Adolescent
Cerebellar Ataxia
Genetic counseling
Clinical Biochemistry
rare disease
Iran
Biology
mental retardation
whole exome sequencing
Consanguinity
03 medical and health sciences
symbols.namesake
Rare Diseases
0302 clinical medicine
Neurodevelopmental disorder
Intellectual Disability
Exome Sequencing
medicine
Humans
Immunology and Allergy
Missense mutation
Phospholipid Transfer Proteins
Child
dysequilibrium syndrome 4
Research Articles
Exome sequencing
Adenosine Triphosphatases
Genetics
Sanger sequencing
Cerebellar ataxia
Biochemistry (medical)
Public Health
Environmental and Occupational Health
Hematology
medicine.disease
Hypotonia
Pedigree
Medical Laboratory Technology
ATP8A2
030104 developmental biology
030220 oncology & carcinogenesis
symbols
Female
medicine.symptom
Research Article
Zdroj: Journal of Clinical Laboratory Analysis
ISSN: 1098-2825
0887-8013
DOI: 10.1002/jcla.23484
Popis: Background Cerebellar ataxia, mental retardation, and dysequilibrium (CAMRQ) syndrome is a rare and early‐onset neurodevelopmental disorder. Four subtypes of this syndrome have been identified, which are clinically and genetically different. To date, altogether 32 patients have been described with ATP8A2 mutations and phenotypic features assigned to CAMRQ type 4. Herein, three additional patients in an Iranian consanguineous family with non‐progressive cerebellar ataxia, severe hypotonia, intellectual disability, dysarthria, and cerebellar atrophy have been identified. Methods Following the thorough clinical examination, consecutive detections including chromosome karyotyping, chromosomal microarray analysis, and whole exome sequencing (WES) were performed on the proband. The sequence variants derived from WES interpreted by a standard bioinformatics pipeline. Pathogenicity assessment of candidate variant was done by in silico analysis. The familial cosegregation of the WES finding was carried out by PCR‐based Sanger sequencing. Results A novel homozygous missense variant (c.1339G > A, p.Gly447Arg) in the ATP8A2 gene was identified and completely segregated with the phenotype in the family. In silico analysis and structural modeling revealed that the p.G477R substitution is deleterious and induced undesired effects on the protein stability and residue distribution in the ligand‐binding pocket. The novel sequence variant occurred within an extremely conserved subregion of the ATP‐binding domain. Conclusion Our findings expand the spectrum of ATP8A2 mutations and confirm the reported genotype‐phenotype correlation. These results could improve genetic counseling and prenatal diagnosis in families with clinical presentations related to CAMRQ4 syndrome.
A novel mutation (c.1339G>A; p.G447R) in ATP8A2 gene is responsible for cerebellar ataxia, mental retardation, and dysequilibrium syndrome type 4 (CAMRQ4) syndrome. WES could be a diagnostic approach in rare diseases with heterogeneous clinical presentations like CAMRQ4.
Databáze: OpenAIRE
Externí odkaz: