TCP1-Related Neurodevelopmental Disorder Expands Beyond Polymicrogyria in a New Pediatric Case
A 4-year-old girl with TCP1-related neurodevelopmental disorder presented with a phenotype that pushes the known clinical range in a new direction. Global developmental delay, speech and motor delay, behavioral dysregulation, microcephaly, hypotonia with core weakness, and an unreported heterozygous TCP1 frameshift variant formed the core picture, but the brain MRI introduced an unusual finding: absent septum pellucidum without polymicrogyria or seizures.
The variant, c.1392delT (p.A465Qfs*3), affects exon 11 and truncates the final 16.5% of the protein. In silico interpretation predicted nonsense-mediated decay, and the variant was absent from gnomAD, supporting a likely pathogenic interpretation. Biological parental testing was unavailable, so inheritance could not be established. Even without segregation data, the case adds a rare genotype-phenotype datapoint to a disorder already known for marked neurologic variability.
A Brain MRI Finding Outside the Usual TCP1 Pattern
Heterozygous TCP1 variants have been associated with an autosomal dominant neurodevelopmental disorder characterized by developmental delay or intellectual disability, seizures, pyramidal or cerebellar signs, and brain malformations, especially polymicrogyria. The imaging in this child did not follow that familiar template. Instead of cortical malformation with polymicrogyria, MRI showed an absent septum pellucidum and mild bilateral frontal sulcation and gyration asymmetry.
A single sentence in a neuroradiology report can change the clinical frame. Here, the absence of polymicrogyria matters because it separates this child from the best-described imaging signature of TCP1 disease and raises the possibility that the disorder affects midline brain development more broadly than previously appreciated. The optic nerves and pituitary were normal, which helps narrow the congenital midline differential and reduces immediate concern for the classic optic nerve-pituitary abnormalities often sought when septal structures are missing.
Absent septum pellucidum is not a diagnosis by itself; it is a marker that can travel with a wide range of developmental brain conditions. In this case, its presence alongside a TCP1 frameshift variant is hypothesis-generating rather than definitive. The case cannot prove causation, yet it does widen the field of suspicion for clinicians reviewing MRI findings in children with unexplained developmental delay and subtle dysmorphology.
Developmental Delay Without Seizures Through Age 4
The neurologic course is equally important. No seizures were documented through age 4 years, despite the fact that seizures have been part of the recognized TCP1 phenotype. The absence of epilepsy does not argue against the diagnosis; rather, it reinforces the degree of clinical heterogeneity already hinted at in prior descriptions. A disorder once framed around seizures and cortical malformation can present without either, at least in early childhood.
Microcephaly, hypotonia, and core weakness point toward a broader neurodevelopmental syndrome with both central and motor-system involvement. Speech and motor delay suggest that the phenotype is not confined to one developmental domain. Behavioral dysregulation adds another dimension, one that often complicates day-to-day care more than any single neurologic examination finding. In a toddler or preschooler, those combined features can drive much of the family burden long before a molecular diagnosis is secured.
A Frameshift Variant at the Tail End of TCP1
TCP1 encodes the TCP1α subunit of the chaperonin containing TCP1 ring complex, or TRiC. This complex is central to protein folding, so disruption can have broad downstream effects on neurodevelopment. A frameshift near the end of the protein, as seen here, does not spare the molecule from consequence. Truncation of the final 16.5% and predicted nonsense-mediated decay suggest loss of function rather than a subtle missense effect.
The position of the variant is clinically relevant because it offers a plausible mechanism for reduced protein dosage. In a chaperone system, impaired folding capacity can disrupt neuronal development, migration, and circuit formation in ways that may not be uniform across patients or brain regions. That biological flexibility may help explain why one child develops polymicrogyria, another shows a different cortical pattern, and this patient instead demonstrates midline nonseparation of the septum pellucidum without overt cortical overmigration.
This is exactly where rare-disease genetics becomes difficult. One gene can produce multiple neuroimaging signatures, and one imaging signature can arise from multiple genes. The only way to sort that out is through additional cases, segregation when possible, and functional work that tests how specific TCP1 variants alter protein behavior and neuronal development.
Cardiac and Atopic Findings Remain Unassigned
The child also had a bicuspid aortic valve with mild aortic insufficiency, asthma, severe eczema with atopy, and multiple food allergies. Those findings broaden the clinical picture, but they do not currently establish a syndromic link. The cardiac and allergic features may be coincidental, part of a wider constitutional susceptibility, or related in some indirect way to the underlying genetic change. No direct connection can be claimed from a single patient.
Still, these findings deserve attention in practice. A bicuspid aortic valve changes pediatric surveillance independent of the neurodevelopmental diagnosis, and the atopic burden has immediate implications for airway and skin management. Families often experience the child’s illness as one integrated problem even when the mechanistic links are not yet clear, and clinicians have to treat the observable problems on their own terms while the genetics are being sorted out.
Why This Case Changes the Clinical Question
The main value of this report is not certainty. It is expansion.
The case suggests that TCP1-related neurodevelopmental disorder may include brain malformations outside the previously emphasized pattern of polymicrogyria, and it shows that seizures are not obligatory in early childhood. It also draws attention to an absent septum pellucidum in the setting of a pathogenic-looking TCP1 frameshift variant, while stopping short of claiming a causal relationship.
For clinicians, the practical implication is narrower: when a child has developmental delay, microcephaly, hypotonia, and an unusual MRI with absent septum pellucidum but no polymicrogyria, TCP1 belongs on the differential if genomic testing identifies a qualifying variant. For geneticists and neurologists, the next step is larger case aggregation with careful imaging review and functional validation. Without that, the association between TCP1 and midline brain malformation remains an intriguing lead rather than an established part of the disorder.