The case centers on an Iranian girl referred to the Genetic Research Center in Meybod, Yazd, with a constellation of symptoms that had resisted every conventional diagnostic approach. She presented with developmental delay, low muscle tone, and refractory epilepsy — seizures that persisted despite multiple anticonvulsant medications. For her family, the diagnostic odyssey had been long and exhausting, a familiar story for parents of children with rare genetic conditions who often spend years undergoing test after test without ever receiving a definitive answer.

To crack the case, the team led by Noorodin Karami of Shahid Sadoughi University of Medical Sciences turned to whole exome sequencing, a technique that reads the roughly one to two percent of the genome containing the instructions for building proteins. This targeted approach captures the most likely disease-causing variants while keeping the enormous data volume of whole genome sequencing manageable. The sequencing revealed something remarkable: a novel frameshift variant in the CDKL5 gene, never before documented in any patient anywhere in the world.

The variant, designated c.1037_1038delTCinsCAGATCTAA, p.Ile346Thrfs*14, is what geneticists call a frameshift mutation. Rather than simply swapping one DNA letter for another, it disrupts the reading frame of the gene — the triplet code that determines how the cellular machinery translates DNA into protein. Think of it as deleting a word in the middle of a sentence and inserting nine letters in its place: everything downstream becomes gibberish. In this case, the mutation introduces a premature stop codon just 14 amino acids after the disruption point, truncating the CDKL5 protein far shorter than its normal length and stripping away essential functional domains it needs to do its job in the brain.

CDKL5 stands for Cyclin-Dependent Kinase-Like 5, a serine-threonine kinase located on the X chromosome. The protein it encodes acts as a molecular switch, adding phosphate groups to other proteins to regulate their activity. Among its known targets is Cav2.3, a voltage-gated calcium channel that plays a crucial role in controlling neuronal excitability. When CDKL5 phosphorylates Cav2.3, it alters the channel’s inactivation kinetics — essentially changing how quickly the channel closes and resets. Disruption of this process can shift the delicate balance of electrical signaling in the brain, potentially lowering the threshold for seizures. The protein also contains nuclear localization signals and a nuclear exit signal, indicating it shuttles between the nucleus and cytoplasm, where it influences gene expression and other cellular processes critical for healthy brain development.

Because the girl is an only child with no family history of similar illness, the researchers performed Sanger sequencing — a gold-standard validation technique — on her parents to determine whether the variant was inherited or had arisen spontaneously. The results confirmed the mutation was de novo, meaning it appeared for the first time in the child and was absent from both parents. This pattern is common in CDKL5 deficiency disorder, where most affected individuals carry mutations that no one else in the family has. The finding also carries important implications for genetic counseling: since neither parent carries the variant, the recurrence risk for future pregnancies in this family is extremely low, though not zero due to the theoretical possibility of germline mosaicism.

The team classified the variant as pathogenic according to the American College of Medical Genetics and Genomics criteria, the international standard for evaluating disease-causing potential. Bioinformatic analyses further supported this classification, predicting that the truncation would trigger nonsense-mediated mRNA decay — a cellular quality control mechanism that destroys mRNA transcripts containing premature stop codons before they can be translated into protein. The consequence is a double hit: the truncated protein that is produced lacks essential domains, and much of the mRNA never even survives long enough to be translated. The net result is a profound loss of CDKL5 function in the developing brain.

On the treatment front, the case yielded a clinically significant observation. After trying various medication combinations, the team found that valproate combined with lamotrigine produced a considerable reduction in the number of seizures. Valproate is a broad-spectrum anticonvulsant that works through multiple mechanisms, including enhancing GABA signaling — the brain’s primary inhibitory neurotransmitter system — and blocking voltage-gated sodium channels. Lamotrigine, meanwhile, primarily blocks sodium channels and reduces glutamate release, the brain’s main excitatory neurotransmitter. The combination targets both sides of the excitation-inhibition balance that goes awry in epilepsy. While CDKL5 deficiency disorder has no cure and the seizures rarely disappear entirely, meaningful seizure reduction can dramatically improve quality of life for affected children and their families.

CDKL5 deficiency disorder, sometimes described as a cousin of Rett syndrome, affects an estimated one in 40,000 to 60,000 live births worldwide, though the true prevalence may be higher due to underdiagnosis. The condition typically manifests with early-onset epileptic seizures within the first months of life, followed by severe developmental delay, hypotonia, and a range of other neurological problems. Because the gene sits on the X chromosome, females are more commonly affected, though males with CDKL5 mutations can also develop the disorder. The clinical spectrum is broad, and genotype-phenotype studies have begun to map how specific mutation locations correlate with disease severity — information that helps clinicians anticipate complications and tailor management strategies.

The Iranian case expands the mutational spectrum of CDKL5 and reinforces a message that geneticists have been championing for years: sequencing-based genetic testing should be considered early in the diagnostic workup of children with refractory epilepsy and developmental delay. Early molecular diagnosis not only ends the diagnostic odyssey but also enables personalized therapeutic management, informed genetic counseling, and access to emerging targeted therapies now in development for CDKL5 deficiency disorder. As research into this condition accelerates globally — from zebrafish models revealing dysregulated gene expression to international consensus recommendations for clinical management — each newly identified variant adds another piece to the puzzle, bringing the field closer to understanding this rare and relentless disease.

Subject of Research: Identification and characterization of a novel de novo CDKL5 frameshift variant causing infantile-onset refractory epilepsy and developmental delay in an Iranian child

Article Title: A novel de novo variant of CDKL5 in an Iranian child with infantile-onset refractory epilepsy

Article References: Karami, N., Dehghani, M., Asadollahi, S., Ghasemi, N., Movahedinia, M., & Kalantar, S. M. (2026). A novel de novo variant of CDKL5 in an Iranian child with infantile-onset refractory epilepsy. Molecular Biology Reports, 53(1), Article 1729. https://doi.org/10.1007/s11033-026-12884-7

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12884-7

Keywords: CDKL5, epilepsy, novel variant, whole exome sequencing, developmental delay, pediatric neurology, genetics, refractory seizures, novel, novo, variant, Iranian