Novel TLR7 hemizygous variant in post-COVID-19 neurological deterioration: a case report with literature review

**Background:** The COVID-19 pandemic has affected over 600 million people worldwide. While most cases are mild, some patients develop severe pneumonia or acute respiratory distress syndrome. Genetic factors, particularly variants in the X-linked Toll-like receptor 7 (TLR7) gene, may influence COVID-19 severity and long-term complications. TLR7 recognizes single-stranded RNA viruses like SARS-CoV-2 and activates innate immune responses, including type I and II interferon production. This case report presents a novel TLR7 variant in a pediatric patient with severe neurological deterioration following COVID-19.

**Methods:** The patient was a previously healthy 10-year-old boy born to consanguineous parents. He presented with ataxia, left arm dystonia, and episodic neck flexion two weeks after a moderate COVID-19 infection. Symptoms progressed to dysarthria, dysphagia, and hyperreflexia. Extensive workup included brain and spinal cord MRI, EEG, CSF analysis, autoimmune serology, and genetic testing via whole exome sequencing (WES) and whole genome sequencing (WGS). The patient received sodium valproate, IVIG, rituximab, steroid pulse therapy, and multiple anti-epileptic drugs. A literature review of TLR7 variants in COVID-19 patients was also conducted.

**Key Results:** WGS identified a hemizygous, likely pathogenic frameshift variant in TLR7 (chrX:12886892, NM_016562.4: c.1386_1389dup; p.His464Ilefs*7), consistent with X-linked recessive COVID-19-related immunodeficiency type 74. Additional variants of uncertain significance were found in MEFV, SCN5A, and STAT3 genes. Brain MRI showed progressive multifocal leukoencephalopathy with brainstem and spinal cord involvement, and MR spectroscopy suggested an inflammatory or demyelinating process. CSF analysis revealed high total protein (0.37 mmol/L), elevated IgG/albumin ratio (2.67), and oligoclonal bands. Despite immunotherapy, the patient's neurological status deteriorated, with GCS dropping to 3/15, fixed dilated pupils, and loss of reflexes. He eventually suffered a cardiac arrest and remained ventilator-dependent. The literature review identified 13 studies reporting TLR7 variants in COVID-19 patients, with one similar pediatric case (a 7-year-old boy with a hypomorphic TLR7 variant and ataxia-telangiectasia).

**Clinical Implications:** This case suggests that TLR7 loss-of-function variants may contribute to severe neurological complications after COVID-19, even in young patients with mild initial infections. The novel frameshift variant (c.1386_1389dup) results in a truncated protein and complete loss of function, potentially explaining the severity of the presentation. Screening for TLR7 variants in young males with unexplained post-COVID-19 neurological deterioration may be warranted. However, no specific treatment for TLR7 deficiency currently exists, and prognosis remains poor. Further research is needed to validate these findings and explore potential therapeutic targets.