A child with autism spectrum disorder and Alagille Syndrome: dual molecular diagnosis with de novo FOXP1 and NOTCH2 variants

Introduction: Alagille syndrome is a multisystemic disorder most commonly associated with pathogenic variants in JAG1 and less frequently in NOTCH2. Pathogenic variants in FOXP1 cause a neurodevelopmental syndrome characterized by global developmental delay, severe language impairment, intellectual disability and impairments in communication, accompanied by restricted and repetitive patterns of interest. The FOXP1 protein plays a key role in neuronal differentiation and in the formation of neural circuits underlying language and social cognition. NOTCH2, a component of the Notch signaling pathway, plays a critical role in embryonic development, cell differentiation and neural maturation. The neurodevelopmental manifestations associated with NOTCH2 variants have not yet been fully characterized. Here, we present a child diagnosed with autism spectrum disorder(ASD) who was found to have a de novo pathogenic FOXP1 variant and a de novo likely pathogenic NOTCH2 variant consistent with Alagille syndrome.

Case: A 3-year girl was referred to child and adolescent psychiatry due to absence of meaningful speech. She was born at 38+6 weeks via cesarean section following an unremarkable pregnancy. The neonatal course was complicated by jaundice beginning on postnatal day 2, requiring phototherapy and hospitalization in the neonatal intensive care unit for 12 days. During follow-up, she was found to have persistent cholestasis and acholic stools. Laboratory findings showed hyperlipidemia and elevated liver enzymes consistent with cholestasis. Biliary atresia was suspected but ruled out intraoperatively. Physical examination revealed scratch marks, broad forehead, deep-set eyes, palmar erythema, digital clubbing and hepatosplenomegaly. Echocardiography demonstrated patent ductus arteriosus, secundum atrial septal defect and mild pulmonary stenosis. Developmental milestones were delayed; independent walking and beginning to produce single words were achieved at 20 months of age. At psychiatric evaluation, she had no phrase speech, and had an expressive vocabulary of fewer than 10 words. Her speech was limited and not yet meaningful, fluent, or clearly intelligible. She showed limited social reciprocity, reduced joint attention, poor eye contact, hypersensitivity to loud sounds and minimal interest in peer interaction. On otolaryngologic examination, no hearing loss was identified. Her repetitive behaviors included spinning, particularly when excited. A child psychiatrist diagnosed the child with ASD according to DSM-5-TR criteria. The Childhood Autism Rating Scale (CARS) score was 39. Whole-exome sequencing identified a de novo pathogenic FOXP1 variant (NM_001349338:c.1550T>G) and a de novo likely pathogenic NOTCH2 variant (NM_024408.4:c.1646A>G), classified according to ACMG criteria. Clinical findings were consistent with NOTCH2-related Alagille syndrome.

Conclusion: The pathogenic FOXP1 variant appears to explain the core features of severe language impairment, developmental delay and autism spectrum disorder, while the coexisting likely pathogenic NOTCH2 variant associated with Alagille syndrome may have further modified the neurodevelopmental trajectory. These observations suggest that the dual molecular diagnosis may underlie the complexity of both the neurodevelopmental and systemic features observed in this patient. Recognition of dual genetic diagnoses may help explain the clinical variability observed in syndromic neurodevelopmental disorders and support a more comprehensive, individualized approach to evaluation and management.

References

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