Although this patient had both motor and vocal tics for more than one year with childhood onset, primary TS was not considered. She did not exhibit a waxing-waning course and had a general medical condition as KS1. KS1 is genetically and phenotypically heterogeneous with multisystem dysfunction [
3]. KS1 is characterized by a variable genotype-phenotype correlation, mainly owing to its heterogeneous genetic background. Both deletions and intragenic variants of the
EHMT1 gene can result in the KS1. The manifestations of KS1 are primarily attributed to the loss of function of the
EHMT1 gene. Individuals harboring intragenic pathogenic variants of the
EHMT1 gene (e.g., missense or frameshift mutations) or those with smaller deletions (less than 1 Mb) in the 9q34.3 region typically exhibit comparable phenotypic characteristics. However, those with larger deletions (≥ 1 Mb) tend to present more severe intellectual disability and additional medical complications, such as congenital anomalies and feeding issues [
3]. Upon literature review, approximately 120 cases with various
EHMT1 gene mutations have been reported to date [
4]. The distinctive facial features of KS1 are characterized by brachy(-micro)cephaly, broad forehead, unusual shape of eyebrows (arched or straight with synophrys), mildly upslanted palpebral fissures, midface retrusion, thickened ear helices, short nose with anteverted nares, fleshy everted vermilion of the lower lip and exaggerated cupid’s bow or “tented” appearance of the vermilion of the upper lip, and protruding tongue and relative prognathism [
3]. The craniofacial characteristics of this patient are closely aligned with the facial presentation typically associated with KS1. Other suggestive clinical findings include intellectual disability, childhood hypotonia, motor delay, hearing loss, and ASD. Apart from
EHMT1, the de novo 320-kb deletion in the 9q34.3 region also affects the
CACNA1B gene, which is associated with Dystonia 23 (DYT23). DYT23 is characterized by adult-onset, non-progressive, focal cervical dystonia, none of which were observed in our patient. Therefore, despite the deletion’s impact on the
CACNA1B gene, the lack of corresponding phenotypic evidence leads us to focus our interpretation on the effect of the
EHMT1 gene deletion in this case.
Tic disorders were rarely reported in KS1. Only one case has described a 24-year-old KS1 patient with childhood hypotonia, developmental delay, adolescent onset vocal tics (coprolalia), OCD, and ASD. The authors demonstrated that the strategic positioning of deep brain stimulation (DBS) leads within the bilateral ventral capsule/ventral striatum region led to a gradual and sustained amelioration of the patient’s compulsive behaviors, coprolalia, and social interaction [
5]. DBS has shown promise as a neurosurgical treatment for selected individuals with severe, treatment-refractory Tourette syndrome, and its safety profile is generally favorable when executed by an experienced multidisciplinary team. Numerous open-label and retrospective studies, along with multicenter retrospective studies and meta-analyses, have reported significant improvements in tics and neuropsychiatric symptoms following DBS [
2]. These suggest that targeted DBS holds promise as a viable therapeutic option for KS1 patients with intractable tics and other neuropsychiatric disorders. Further research and case studies are needed to provide more support for this treatment approach in the KS1 population.
Research over the past few decades has consistently shown that genetics plays a significant role in developing TS [
2]. The exact genetic mechanism underlying TS has yet to be fully understood. Still, it involves multiple genes that regulate neurotransmitters and synaptic plasticity [
6,
7]. Intriguingly, common TS comorbidities, including OCD, ADHD, and ASD, have been reported in KS1 patients, suggesting a shared genetic and neurobiological basis [
8‐
10]. The
EHMT1 gene encodes for Euchromatic Histone Methyltransferase-1, which, in conjunction with
EHMT2, is responsible for the dimethylation of ‘Lys-9’ (H3K9me2) on histone H3—a process vital to chromatin organization and gene expression. Research has shown that
EHMT1 plays an essential role in homeostatic synaptic scaling up [
11]. Synaptic scaling is a well-characterized form of homeostatic synaptic plasticity that maintains the stability of neuronal network activity by striking a balance between excitation and inhibition. Notably, aberrations in synaptic plasticity are observed in TS [
12]. Therefore, it is plausible to suggest that
EHMT1 haploinsufficiency could interfere with normal synaptic scaling up, thereby potentially contributing to the pathogenesis of TS. However, the exact mechanisms by which EHMT1 mutations may lead to TS remain to be elucidated. Further research is needed to fully comprehend the complexities of these interactions. In conclusion, our case suggests TS with ID and facial anomalies indicate a genetic cause and expands the phenotypic and genotypic spectrum of both TS and KS1.