A Pair of Compound Heterozygous IARS2 Variants Manifesting West Syndrome and Electrolyte Disorders in a Chinese Patient

**Background** Aminoacyl-tRNA synthetases (ARSs) are evolutionarily conserved enzymes that ensure accurate translation by attaching amino acids to their cognate tRNAs. Isoleucyl-tRNA synthetase 2 (IARS2) is a mitochondrial ARS encoded by the IARS2 gene at 1q41. Pathogenic IARS2 variants cause mitochondrial disease with broad clinical phenotypes including West syndrome, Leigh syndrome, and CAGSSS (cataract, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, skeletal dysplasia). Only 29 cases have been reported worldwide. This report describes a Chinese patient with compound heterozygous IARS2 variants presenting West syndrome, electrolyte disorders, and recurrent infections, expanding the clinical spectrum.

**Methods** Whole-exome sequencing (WES) was performed on the proband, a 13-month-old girl with West syndrome. DNA was extracted from peripheral blood at Tianjin Children's Hospital in August 2022 and sequenced on an Illumina platform. Three-dimensional structure reconstruction and thermodynamic stability prediction were performed to analyze variant-phenotype relationships. Variants were classified per American College of Medical Genetics guidelines.

**Key Results** The proband, a 14-month-old Asian female (birth weight 3,190 g) born to non-consanguineous parents, presented with infantile spasms at 6 months. Laboratory studies showed elevated serum lactic acid (9.4 mmol/L; reference 0.5–2.2) and hypocalcemia (1.52 mmol/L; reference 2.10–2.80). Video EEG showed suspicious seizures with extensive medium-high amplitude slow waves. Head MRI revealed symmetric point-like lamellar high signal in the posterior limb of the internal capsule and corpus callosum bilaterally on T2WI and DWI, consistent with Leigh syndrome. Echocardiography showed left ventricular wall thickening and tricuspid regurgitation. At 13 months, growth parameters were weight 11.8 kg (+2SD), height 75 cm, head circumference 43 cm (−2SD). Persistent hypocalcemia (1.73 mmol/L), hyperlactatemia (3.82 mmol/L), and hypoparathyroidism (0.26 pmol/L; reference 1.6–6.9) were detected. The patient had intractable epilepsy, visual impairment, left ventricular hypertrophy, anemia, and multiple infections. WES identified compound heterozygous IARS2 variants: c.2450G>A (Arg817His) inherited from mother, and a novel copy number variation (CNV) [NC_000001.11: g.(220267549_220284289) del] (approximately 16.7-kb deletion involving exons 1–11) inherited from father. The c.2450G>A variant has been previously reported in CAGSSS, Leigh syndrome, and West syndrome. The CNV is novel and classified as uncertain significance. The deletion destroys the HIGH domain of IARS2, likely impairing protein function.

**Clinical Implications** This case expands the clinical spectrum of IARS2 pathogenic variants by documenting electrolyte disorders (hypocalcemia, hypoparathyroidism) and recurrent infections, which were not previously emphasized. Among 29 reported IARS2 cases, only 4 had West syndrome and 10 had Leigh syndrome; hypoparathyroidism was reported in 5 cases including this one. The patient's normal stature (height 75 cm at 13 months) highlights that short stature is not universal (only 13/29 cases). The recurrent infections suggest possible immune barrier disruption from IARS2 dysfunction. WES is crucial for diagnosing highly heterogeneous neurodevelopmental disorders; early genetic testing is recommended when IARS2 disease is suspected. This case underscores the need for clinical awareness of IARS2-associated disease to reduce misdiagnosis.