Autism Spectrum Disorder in a Boy with Clinically Diagnosed Kabuki Syndrome and a YWHAG Variant of Uncertain Significance: A Case Report

Abstract

Background: Kabuki syndrome is a rare multisystem neurodevelopmental disorder usually caused by pathogenic KMT2D or KDM6A variants, although a substantial minority of clinically typical patients remain molecularly unresolved. Autism spectrum disorder (ASD) has been reported in this population, but its prevalence and relationship to genotype remain poorly characterized. Case Presentation: We report a 12-year-old Moroccan boy, born to consanguineous parents, referred for severe behavioral disturbances including psychomotor hyperactivity, self-injurious behavior, and marked language delay. Physical examination showed characteristic craniofacial dysmorphism, long palpebral fissures with eversion of the lateral lower eyelids, blue sclerae, broad arched eyebrows, a depressed nasal tip, and a high-arched palate, together with microcephaly, postnatal growth restriction, infantile hypotonia, a waddling gait, and possible scoliosis, fulfilling international consensus criteria on dysmorphology, growth restriction, hypotonia, and musculoskeletal abnormalities for a clinical diagnosis of Kabuki syndrome. He also presented with severe ASD, attention-deficit/hyperactivity disorder, intellectual developmental disorder, and generalized epilepsy, established according to DSM5 criteria. Whole-exome sequencing identified no pathogenic variant in KMT2D or KDM6A, but revealed a heterozygous variant of uncertain significance in YWHAG (NM_012479.3:c.340G>A; p.Glu114Lys), a gene associated with developmental and epileptic encephalopathy. Pharmacological management included extended-release methylphenidate, which was discontinued because of paradoxical worsening of hyperactivity, followed by low-dose aripiprazole, which improved self-injurious behavior and agitation but caused a persistent tremor. Conclusions: This case shows that a well-characterized clinical gestalt remains sufficient to diagnose Kabuki syndrome despite negative first-line genetic testing, and that residual possibilities