De Novo, Post-Zygotic, Inter-Tissue Mosaicism of Cell Autonomous ADNP Mutations in Autistic Individuals: Restricted Environmental Contribution

Many neurodevelopmental disorders, including autism, are caused by de novo mutations, that might arise as early as in the parental germline, during embryonic, fetal development, or as late as post-natal aging. Intra-tissue mutation-load variations could impact clinical presentation. One of the most common causes of autism is de novo mutations in ADNP. We developed an ultra-sensitive, highly-quantitative droplet digital PCR assay to determine ADNP mutation levels in patient tissues, including blood, teeth, hair, and 24 different tissues from a post-mortem de novo ADNP-mutated child ([~]6-years old), including a transplanted liver from a non-mutant donor (retained for 22 months). Striking variations of ADNP mosaicism arose between tissues of the same individual. Mutation load differences were evident between post-mortem tissues, but not in the transplanted liver -- supporting a cell autonomous genetic vulnerability to de novo mutations, arguing against a transferable environmentally-sensitive DNA damage/mutation predisposition. Variations between tissues suggest a developmental timing of the mutations. Most individuals showed at least one tissue with less than heterozygous mutations, where the presence of the homozygous non-mutant cells indicates that de novo ADNP mutations arose post-zygotically. Highly variable ADNP mosaicism between tissues, that within an individual can be less than heterozygous or approach homozygosity, indicate rapid ongoing post-zygotic, and possibly post-natal, somatic mutations, contributing to clinical variability.