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Page 176 Bone et al. J Transl Genet Genom 2022;6:169-78 https://dx.doi.org/10.20517/jtgg.2021.56

epileptiform discharges, and one had focal slowing. This suggests that in the presence of epileptiform EEG
abnormalities, there is a high likelihood of seizures and epilepsy. In contrast, none of the individuals with
normal EEGs were diagnosed with clinical epilepsy. Larger studies are needed to confirm this observation,
which may guide the prognosis and diagnosis of epilepsy in PTHS. PTHS patients have three types of
paroxysmal events: epileptic seizures, abnormal breathing spells, and motor stereotypies. Because patients
can have any combination of these events, it can be challenging to clinically distinguish between spell types.
Consequently, abnormal breathing spells are frequently misdiagnosed as epileptic seizures. Further, patients
[4]
can have apnea or overbreathing just prior to onset of seizures which can add to the diagnostic challenge .
Breath-holding events were present in nearly half of our cohort, and these events, when captured on EEG,
were not epileptic. Epilepsy monitoring unit evaluation with video EEG recording can be helpful for the
characterization of spells and accurate diagnosis and management.

Previous studies report an increased frequency of epilepsy in patients with missense mutations; however,
[2]
there has not been a reliable or reproducible genotype-phenotype correlation in this disorder . We did not
identify any specific phenotypic differences (e.g., diagnosis of epilepsy, abnormal EEG, abnormal MRI,
delayed ambulation) among those with a missense variant compared to those with a non-missense variant.
The TCF4 gene encodes for transcription factor 4, which is a basic helix-loop-helix E protein responsible for
neuronal differentiation in early brain development. Haploinsufficiency of TCF4 has been associated with
significant dysregulation of pathways critical for brain development and function, including synaptic and
neuronal plasticity, calcium signaling, and neurotransmission through altered expression of
neuroreceptors . TCF4 may be transcribed into at least 18 different isoforms with varying N-termini,
[15]
which impact subcellular localization and function . Functional analyses and mapping of missense variants
[16]
reveal that different functional domains exist within the TCF4 gene and can alter transcriptional activation
of downstream genes, including NRXN1 and CNTNAP2, which cause Pitt-Hopkins-like syndromes 1 and 2,
[17]
respectively . The variable effects of pathogenic variants on TCF4 functioning likely contribute to
phenotypic variability . Larger studies of patients coupled with functional variant analyses are needed to
[18]
fully explore the genotype-phenotype relationship in PTHS.
Clinically, patients with PTHS resemble those with Angelman and Rett syndromes, with severe
developmental delays, limited to absent language abilities, motor incoordination, abnormal breathing spells,
and epilepsy. Patients with Rett and Angelman syndromes tend to have abnormal EEG with recognizable
patterns. In Rett syndrome, this is characterized by EEG that is initially normal, then abnormal with diffuse
slowing, rhythmic theta slowing in the centrotemporal region, and multifocal and generalized epileptiform
discharges . In Angelman syndrome, the most common pattern consists of high amplitude frontal delta
[19]
activity with superimposed epileptiform discharges . In contrast, as we demonstrate here, patients with
[14]
PTHS seem to lack a characteristic EEG signature and can have a normal EEG background for age. When
they do have abnormalities on EEG, they differ between patients and can include generalized slowing, focal
slowing, and focal epileptiform discharges. A normal or non-specific EEG with a clinical phenotype
suggestive of Angelman or Rett syndrome should raise the consideration for a diagnosis of Pitt Hopkins
syndrome.

There were three major limitations in this study: (1) small sample size; (2) EEG reports were generated by
multiple different institutions; and (3) EEGs were obtained with a clinical suspicion of seizures. Because
EEGs were completed at numerous institutions, reports did not contain a unified set of elements, and we
were only able to review tracings on the EEGs that were completed at our institution. Therefore,
abnormalities reported in the studies completed by other institutions could not be independently verified by
a single EEG reader. Further, studies were not uniform in their duration, and included both routine EEGs