Early-onset psychosis in a child with an intragenic ANKRD17 duplication: A case report

ANKRD17 encodes an ankyrin repeat–containing protein involved in cell cycle regulation, neurodevelopment, and immune responses [1]. Pathogenic variants, particularly heterozygous loss-of-function variants, are associated with a neurodevelopmental disorder characterized by intellectual disability, prominent speech delay, and dysmorphic features [1]. The clinical spectrum may also include autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), epilepsy, growth abnormalities, and other neurological findings. Craniofacial anomalies such as cleft palate have been reported as less common but distinctive features [1]. However, the psychiatric phenotype remains poorly defined, and psychotic symptoms have not been described as a core feature.

We report a 12-year-old boy with an intragenic ANKRD17 duplication presenting with early-onset psychosis. He had a 5-month history of visual hallucinations, accompanied by auditory and olfactory hallucinations. Over the preceding 2 months, paranoid ideation, marked anxiety, social withdrawal, and sleep disturbances developed. Retrospective history revealed a prodromal period of approximately one year, characterized by academic decline, reduced motivation, and impaired self-care. A diagnosis of early-onset psychosis was established.

Developmental history included speech delay, ADHD, and specific learning disorder, along with mild autistic traits such as limited peer interaction and restricted interests. Gross motor development was normal, while fine motor difficulties were noted. The patient had been exposed to peer bullying. Physical examination revealed operated cleft lip and palate and facial dysmorphic features. Chromosomal microarray analysis identified a heterozygous intragenic duplication involving exons 3–34 of ANKRD17. The variant was maternally inherited; the mother had no neurodevelopmental disorder but had isolated cleft lip. No additional pathogenic or likely pathogenic variants that could explain the neurodevelopmental phenotype were identified on whole exome sequencing. Cognitive assessment showed overall intelligence within the normal range. Family history included ASD in a cousin.

The patient’s developmental profile is consistent with the reported ANKRD17-related phenotype, and the presence of cleft palate supports this association [1]. However, early-onset psychosis is not a typical feature. This observation may indicate that the neuropsychiatric spectrum associated with ANKRD17 is broader than previously recognized.

The emergence of psychosis is likely multifactorial. Copy number variations (CNVs) have been shown to be associated with ASD, intellectual disability, and psychotic disorders, reflecting pleiotropic effects [2]. In this context, the ANKRD17 duplication may be considered not as a direct causal factor but as a contributor to neurodevelopmental vulnerability predisposing to psychosis. Psychosocial stressors such as peer bullying may also have contributed [3], although their relative impact cannot be determined.

Most pathogenic ANKRD17 variants are loss-of-function, and haploinsufficiency is considered the main mechanism [1]. The clinical significance of intragenic duplications remains unclear. Such variants may influence phenotype through gene dosage effects or altered gene regulation [4]. The maternal inheritance and milder phenotype in the mother may suggest incomplete penetrance or variable expressivity, although this remains uncertain. According to ACMG/ClinGen CNV guidelines, the variant was classified as a variant of uncertain significance (VUS) [5].

In conclusion, this case suggests that ANKRD17-related phenotypes may include early-onset psychosis and highlights the importance of genetic evaluation in neurodevelopmental presentations with atypical psychiatric features.

References

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