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Bayat S, Gholami M, Khodadadi H, Ghazavi M, Nasiri J, Kheirollahi M. Expanding the Phenotype and Genotype Spectrum of a Novel Mutation in Hypomyelinating Leukodystrophy-5 With a Review of the Literature on 42 Cases. BCN 2025; 16 (2) :505-518
URL: http://bcn.iums.ac.ir/article-1-3026-en.html

Introduction: Hypomyelinating leukodystrophy-5 (HLD-5) is a rare multiple congenital anomaly with intellectual disability caused by an autosomal recessive mutation in the FAM126A gene. It is characterized by bilateral congenital cataracts, developmental delay, cerebellar ataxia, slowly progressive gait disturbance, and cognitive impairment. This study aims to contribute to a better understanding of HLD-5 by reviewing previous patients and introducing a novel variant in a new case. 
Methods: We subjected a case with an initial diagnosis of HLD-5 in an Iranian family. To identify the possible genetic cause(s), whole exome sequencing (WES) was conducted to detect exon mutations. Sanger sequencing was performed to verify the DNA sequence variants and co-segregation analysis. We predicted the potential deleterious effects of the novel mutation using in silico predictive tools. 
Results: WES identified a novel homozygous mutation (NM_032581: c.636_639del p.C213Dfs*7) in the FAM126A gene. The variant can cause premature termination of amino acid translation or affect mRNA expression.
Conclusion: This study explained the clinical manifestations and molecular findings of HLD-5. Additionally, we reported a novel variant and some rare clinical features, such as exophthalmos and strabismus, in our proband for the first time. Further research is needed to clarify the molecular mechanisms underlying HLD-5 pathogenesis.