Keipert syndrome beyond classical features: novel GPC4 variant associated with epilepsy but preserved cognition

Abstract

Keipert syndrome (OMIM #301026) is a rare X-linked recessive disorder characterized by craniofacial and digital anomalies, variably expressed intellectual disability, and sensorineural hearing loss. Rare variants in the GPC4 gene have been reported in a limited number of cases. Here, we describe an 11-year-old male presenting with epilepsy and distinctive facial dysmorphism, in whom whole-exome sequencing identified a novel hemizygous missense variant in GPC4 (NM_001448.3:c.655 C> T; p.Arg219Cys). It was maternally inherited, absent in population databases, and located in a highly conserved region (phyloP100way: 7.716; PhastCons100way: 1.0). Clinically, the patient exhibited a long face, broad forehead, anteverted nares, and broad halluces, without brachydactyly, hearing loss, or cognitive impairment. Neuropsychiatric evaluation confirmed normal intellectual and adaptive functioning. EEG revealed left frontocentrotemporal epileptiform discharges, and brain MRI showed nonspecific subcortical white matter hyperintensities; seizures were controlled following anti seizure medication adjustment. This case expands the phenotypic spectrum of GPC4-related Keipert syndrome by demonstrating that epilepsy, EEG abnormalities, and subtle neuroimaging findings may accompany the classical craniofacial phenotype. Importantly, the absence of intellectual disability and hearing loss underscores the variable expressivity of GPC4 variants and has implications for genetic counseling.