A Novel Variant in KCTD3 Gene in Patients with Global Developmental Delay, Seizures, and Cerebellar Hypoplasia

Pathogenic variants in KCTD3 are linked to severe neurodevelopmental disorders, but the clinical and genetic spectrum remains limited; reporting additional cases contributes to a better understanding of genotype–phenotype correlations. We report two affected siblings from a consanguineous Jordanian family. The first patient was a 7-year-old boy, one of a twin pair, who presented with global developmental delay, hypotonia, recurrent seizures, feeding difficulties, and inability to achieve independent sitting or standing. Abdominal ultrasound at 6 months of age revealed bilateral hydronephrosis. Brain magnetic resonance imaging (MRI) demonstrated ventriculomegaly, mild hydrocephalus, an insult in the right frontal periventricular white matter, and features consistent with a Dandy–Walker variant. His twin sibling was unaffected. The second patient was a 3-year-old girl who exhibited a similar clinical phenotype. Reanalysis of whole-exome sequencing identified a novel homozygous nonsense variant in KCTD3 (NM_016121.5: C.1042C>T; p. Arg348*), which segregated with disease in the family and was classified as likely pathogenic. Both patients received supportive care, including antiepileptic therapy, physiotherapy, and regular developmental and renal follow-up. Genetic counseling was provided to the parents for future reproductive planning. At the latest assessment, the children continued to show persistent motor and cognitive delays. This report expands the genotypic and phenotypic spectrum of KCTD3 -related neurodevelopmental disorders, highlights renal involvement as part of the phenotype, and underscores the importance of including KCTD3 in diagnostic gene panels and reanalyzing whole-exome sequencing data for accurate diagnosis, particularly in population with high rates of consanguinity.