Background: Developmental and Epileptic Encephalopathy (DEE) is a severe and heterogeneous neurological disorder in infancy/early childhood. DEE’s genetic and phenotypic variability complicates diagnosis and treatment. This retrospective study aimed to identify genetic variants and explore genotype–phenotype correlations in children with DEE using a targeted epilepsy gene panel (TGP) and Whole Exome Sequencing (WES). Patients and Methods: Medical records of children who underwent custom-designed 55-gene TGP and WES were reviewed. The diagnostic yield of each method was determined based on the detection of pathogenic (P) and likely pathogenic (LP) variants. Results: A total of 129 patients (66 males, 63 females) underwent TGP, which identified P/LP variants in 29 cases (22.48%). Variants were detected in SCN1A, KCNQ2, STXBP1, CDKL5, PCDH19, PLCB1, WWOX, SCN2A, FGF12, HCN1, SCN8A, and SLC35A2. WES further identified several variants in children with West syndrome. A TSC1 variant was detected in a patient without cutaneous stigmata of tuberous sclerosis complex. The NALCN variant in a patient was linked to Infantile Hypotonia with Psychomotor Retardation and Characteristic Facies 1. A CTBP1 variant associated with extremely rare Hypotonia, Ataxia, Developmental Delay, and Tooth Enamel Defect Syndrome was detected in another patient. A PIEZO2 variant—associated with Marden–Walker syndrome—was found in a child with Early Infantile Developmental and Epileptic Encephalopathy. Conclusions: These findings highlight the extensive genetic heterogeneity and phenotypic variability of DEE. WES demonstrates substantial value in identifying novel gene-disease associations and may be considered as a first-tier diagnostic tool in epilepsy and DEE.

Acute ophthalmoparesis without ataxia (AO) is an atypical form of Miller- Fisher syndrome (MFS) and is rare in children. Anti-GQ1b antibodies can be detected in patients with AO, as in MFS. A 5.5-year-old girl had total ophthalmoparesis, blurred vision, ptosis, diplopia and mydriasis non-reactive to light or near stimuli with preserved consciousness and deep tendon reflexes. She had no ataxia. Cerebrospinal fluid (CSF) examination and cranial MRI were normal. Serum antiGQ1b antibodies were positive. She was diagnosed with AO and intravenous Immunoglobulin (IVIG) was ordered, 400 mg/ kg/day, for 5 days. Ophthalmoparesis and blurred vision improved in a few weeks. At the end of the first year, mydriasis still persisted, but improved and became responsive to near stimuli. Pupillary involvement may be seen in approximately 50% of MFS patients, and improvement in a few weeks or months has been reported in adults. Our case shows the expanding clinical spectrum of anti-GQ1b positive cranial neuropathy as early-onset AO and prolonged mydriasis more than one year.