Identification of MCOLN۱ and C۱۹orf۱۲ gene variants in two Iranian families with brain iron accumulation

Introduction and objectives: Iron is an essential element necessary for energy production, DNA and neurotransmitter synthesis, myelination and phospholipid metabolism. It has been shown that aberrant brain iron deposition is associated with common and rare neurodegenerative disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), Neurodegeneration with Brain Iron Accumulation (NBIA) and mucolipidosis type ۴ (MLIV).Here, we present the results of genetic analysis of two patients who manifested iron accumulation in their own brain magnetic resonance imaging (MRI).Methods: DNAs were isolated from peripheral blood leukocytes of two unrelated Iranian families with brain iron accumulation in their brain MRI. Whole-exome sequencing (WES) was performed on DNAs of two probands. Preliminary filtering was done to identify all homozygous variants, based on the recessive pattern of inheritance. Then, variants that did not affect amino-acid chain or splicing site were filtered out. Thereafter, SNPs with a minimal allele frequency >۰.۰۱ in the public databases were removed. The remaining variants were evaluated based on the American College of Medical Genetics (ACMG) criteria. Candidate variants were amplified by PCR and Sanger sequenced in the probands, then screened in the family members to co-segregation analysis.Results: A novel homozygous variant, c.۳۶۲C>T:p.(Thr۱۲۱Met) in the MCOLN۱ gene was identified in the first proband that confirmed MLIV in this family. The proband was a ۴۲ years old woman who manifested intellectual disability, dysarthria, lower-limb spasticity, dystonia, motor deficits, and progressive visual disturbances. She demonstrated signal abnormalities in the white matter, thinning of the corpus callosum, as well as iron accumulation in the globus pallidus in her brain MRI. In the beginning, she was diagnosed as a case of atypical NBIA. The second proband revealed a homozygous missense mutation in the C۱۹orf۱۲ gene (c.C۳۲T:p.Thr۱۱Met). She was a ۳۸-year-old female with neuropsychiatric symptoms, dysarthria, imbalance and gait disturbance, tremor and spasticity of limbs and urinary and bowel incontinency. Brain MRI showed low signal intensity, brain iron accumulation, in the caudate, putamen, and substantial nigra bilaterally. So, Mitochondrial Membrane Protein Associated Neurodegeneration (MPAN) subtype of NBIA was confirmed in this family. Based on ACMG criteria, MCOLN۱ and C۱۹orf۱۲ variants were predicted as uncertain significance (VUS) and likely pathogenic, respectively.Conclusion: Correct diagnosis of rare diseases, particularly for cases with atypical presentations and overlapping phenotypes like the probands in this study who affected with NBIAs and MLIV can be challenging. Our study confirms the importance of high throughput genetic methods such as WES for diagnosis and identification of genetic cause of diseases with clinical heterogeneity.

کلیدواژه ها:

Neurodegeneration with brain iron accumulation ، NBIA ، Mucolipidosis type IV ، MLIV ، Whole exome sequencing ، WES