ADNP – ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder

ADNP (activity-dependent neuroprotective protein) is a homeobox-containing transcription factor essential for neurodevelopment. Heterozygous mutations in ADNP cause Helsmoortel-Van der Aa syndrome, also termed ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, characterized by global developmental delay, intellectual disability, and frequent autism spectrum disorder features. Functional domains include a bipartite nuclear localization signal (NLS) and an 8-amino-acid neuroprotective peptide (NAPVSIPQ) that interacts with microtubule end-binding proteins to regulate cytoskeletal dynamics.

Inheritance is autosomal dominant, with de novo truncating and nonsense variants as the predominant mutational mechanism. To date, 43 unrelated probands have been reported harboring de novo ADNP truncating mutations (PMID:31029150; PMID:38254177; PMID:29780943).

The variant spectrum is dominated by frameshift and stop-gain mutations clustering in the NLS region of exon 5, with recurrent alleles such as c.2496_2499del (p.Asn832fs)(PMID:32275126). Missense variants are rare, accounting for <10% of cases.

Mechanistically, most pathogenic alleles cause loss of nuclear localization and increased proteasomal degradation of ADNP protein in HEK293T cells (PMID:29911927). Adnp+/- mouse models recapitulate dendritic spine deficits, motor dysfunction, and cognitive impairments, all of which are partially rescued by the NAP peptide (PMID:30106381). These concordant cellular and animal studies support haploinsufficiency as the disease mechanism.

No studies to date have provided evidence disputing the ADNP–Helsmoortel-Van der Aa syndrome association.

Collectively, the robust array of de novo truncating variants across >40 unrelated individuals, coupled with cellular mislocalization assays and in vivo rescue by NAP, fulfills criteria for a Definitive gene–disease relationship. Early genetic diagnosis informs referral for developmental interventions and emerging NAP-based therapies, underscoring significant clinical utility.

References

• Clinical Epigenetics • 2019 • Gene domain-specific DNA methylation episignatures highlight distinct molecular entities of ADNP syndrome. PMID:31029150
• Molecular Autism • 2024 • Clinical impact and in vitro characterization of ADNP variants in pediatric patients. PMID:38254177
• American Journal of Ophthalmology Case Reports • 2018 • Longitudinal ophthalmic findings in a child with Helsmoortel-Van der Aa Syndrome. PMID:29780943
• Molecular Genetics & Genomic Medicine • 2020 • Early behavioral and developmental interventions in ADNP-syndrome: A case report of SWI/SNF-related neurodevelopmental syndrome. PMID:32275126
• Cell Cycle • 2018 • Mutations in ADNP affect expression and subcellular localization of the protein. PMID:29911927
• The Journal of Clinical Investigation • 2018 • Activity-dependent neuroprotective protein deficiency models synaptic and developmental phenotypes of autism-like syndrome. PMID:30106381

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