Expanding the neurobehavioral phenotype of HERC2-related disorder in the Amish

Abstract Purpose HERC2-related disorder (Autosomal recessive intellectual developmental disorder-38 (MRT38); Online Mendelian Inheritance in Man #615516) is an autosomal recessive neurodevelopmental condition characterized by global developmental delay, hypotonia, autistic behaviors, mild dysmorphic features, and an increased risk of seizures. This study aimed to further characterize the clinical phenotype of Amish individuals with HERC2-related disorder caused by the founder variant HERC2 c.1781 C > T (NM_004667.5), delineate the neurobehavioral phenotype through psychometric testing, and explore parental experiences related to diagnosis and care. Methods Sixteen Amish individuals with HERC2-related disorder were enrolled. Clinical data were collected through review of medical records and parent questionnaires. Neurodevelopmental and behavioral phenotypes were assessed using standardized psychometric tools, including the Bayley Scales of Infant and Toddler Development, Fourth Edition (Bayley-4) and the Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Because participants were older than the Bayley-4 normative age range but had severe developmental delays, Bayley-4 results were used descriptively as developmental age-equivalent scores rather than age-normed standard scores. Results Global developmental delay was universal in the cohort. ASD classification by ADOS-2 was identified in 8/13 individuals (61.5%). The cohort also demonstrated significant medical comorbidities, including epilepsy (6/16), developmental regression (5/16), and hearing impairment (6/16), thereby expanding the currently recognized phenotype of HERC2-related disorder in the Amish population. Parental feedback emphasized the importance of early diagnosis, anticipatory guidance, and access to early intervention services. Conclusions This study expands the known clinical and neurobehavioral phenotype of HERC2-related disorder within the Amish community. The findings highlight frequent ASD-related features and additional medical comorbidities, including epilepsy, hearing impairment, and developmental regression. These results support the development of expert-informed clinical guidance and future studies of earlier molecular diagnosis, culturally appropriate behavioral supports, and systematic neurologic and audiologic surveillance.