KARS1-Related Infantile-Onset Progressive Leukoencephalopathy With or Without Deafness: A Novel Variant and Phenotypic Expansion

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Abstract
Biallelic variants in the KARS1 gene, encoding lysyl-tRNA synthetase, are responsible for autosomal recessive disorders such as infantile-onset progressive leukoencephalopathy with or without deafness (LEPID; OMIM #619147) and nonsyndromic hearing loss (DFNB89). Common features of LEPID include sensorineural hearing loss, developmental delay, and leukoencephalopathy, but dysmorphic facial features and cardiac anomalies are not commonly reported. This study presents the first documented LEPID case in Iran, expanding the phenotypic and genetic spectrum of KARS1-related disorders. Whole exome sequencing (WES) was performed on a two-year-old Iranian boy from non-consanguineous parents, without a positive history of any neurologic conditions. Identified variants were validated by Sanger sequencing, with familial segregation analysis. Moreover, a literature review of 41 KARS1-related cases was conducted to compare clinical and genetic findings. WES identified two compound heterozygous KARS1 variants (NM_005548.3): c.959G > A (p.Arg320His) and c.2T > C (p.Met1Thr), previously reported and novel, respectively, both of which were classified as likely pathogenic according to the American College of Medical Genetics and Genomics criteria. The patient exhibited typical LEPID features (sensorineural hearing loss, developmental delay, seizures, leukoencephalopathy) alongside unprecedented dysmorphic facial features (e.g., synophrys, pointed triangular chin) and cardiac anomalies (pulmonary stenosis, atrial septal defect). Literature review confirmed these dysmorphic features as novel, absent in prior cases, with cardiac involvement in a limited number of patients. This study highlights a novel KARS1 variant and an expanded phenotypic spectrum of LEPID, emphasizing the role of WES in diagnosing rare disorders even in non-consanguineous marriages. These findings advocate for broader phenotypic recognition and functional studies to elucidate KARS1’s role in neurodevelopmental, craniofacial, and cardiac abnormalities.

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