| Finding | Key details | Best recent source (year, DOI/URL) | Evidence type |
|---|---|---|---|
| Identifiers and synonyms | Preferred names: **ADNP-related syndrome**, **ADNP syndrome**, **Helsmoortel–Van der Aa syndrome (HVDAS)**; MONDO: **ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder** (**MONDO:0014379**); OMIM: **615873**; disorder is a rare monogenic neurodevelopmental syndrome caused by pathogenic **ADNP** variants at **20q13.13** (pqac-00000000, pqac-00000002, pqac-00000006) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Ge et al., 2024, https://doi.org/10.1186/s13229-024-00584-7 | Disease review + cohort + curated disease-target association |
| Core phenotype frequencies | D’Incal 2023 Table 1 summarizes high-frequency features: **intellectual disability 100%**, **speech delay 99%**, **motor delay 96%**, **autism/autistic features 93%**, **feeding/GI problems 83%**, **behavioral problems 78%**, **visual problems 74%**, **sleep problems 65%**, **hand/foot abnormalities 62%**, **brain abnormalities/seizures 62%**, **musculoskeletal issues 55%**, **frequent infections 51%**; image-confirmed from Table 1 (pqac-00000011, pqac-00000047) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8 | Review synthesizing human cohorts; table/image evidence |
| Additional cohort frequencies (Van Dijck 2019) | In a **78-person** cohort: **GI/feeding problems 83%**, **visual problems 73.6%** (including **strabismus 49.2%**, **hypermetropia 40.3%**, **cortical visual impairment 41%**), **oral movement problems 45.6%**, **recurrent infections 51%**, **male cryptorchidism 34%**, **overweight 20.9%**, **obesity 7.5%**, **mild childhood hearing loss 11.7%**; brain malformations and several comorbidities were also common (pqac-00000013, pqac-00000007) | Van Dijck et al., 2019, https://doi.org/10.1016/j.biopsych.2018.02.1173 | Large human clinical cohort |
| Genetics and variant spectrum | Pathogenic variants are predominantly **heterozygous de novo loss-of-function** changes, especially **nonsense** and **frameshift** variants; most cluster in **exon 5 / last exon**, often predicted to **escape nonsense-mediated decay (NMD)**, supporting expression of truncated protein rather than simple haploinsufficiency alone; recurrent hotspots include **p.Tyr719\***, **p.Arg730\***, and **p.Asn832Lysfs\*81 / p.Leu831Ilefs\*82**; a single whole-gene deletion has been reported (pqac-00000003, pqac-00000005, pqac-00000009, pqac-00000011, pqac-00000013) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Helsmoortel et al., 2014, https://doi.org/10.1038/ng.2899 | Human genetics studies + review |
| Epidemiology / contribution to ASD | Original discovery screened **5,776** patients and identified **10 ADNP mutations**; authors estimated **ADNP is mutated in at least 0.17% of ASD cases**, making it one of the more frequent single-gene ASD causes; truncating de novo variants were significantly enriched in cases (**Fisher p=0.001852; OR 13.24668**) (pqac-00000009, pqac-00000012) | Helsmoortel et al., 2014, https://doi.org/10.1038/ng.2899 | Human sequencing discovery cohort |
| Epigenetic / episignature diagnostics | Blood DNA methylation studies identified **two mutation-location-dependent episignatures**: class I (outside ~c.2000–2340) and class II (within that region, including **p.Tyr719\***). In independent replication, **24 affected individuals** split evenly by class; class I showed **6,448** differentially methylated autosomal CpGs and class II **2,582**. Utility appears strongest for **variant interpretation/diagnosis**, while phenotype correlation is **modest** and should not be overinterpreted clinically (pqac-00000021, pqac-00000023, pqac-00000024, pqac-00000025) | Breen et al., 2020, https://doi.org/10.1016/j.ajhg.2020.07.003 | Human methylation biomarker study |
| Ketamine clinical development (2022 trial) | Open-label, single-dose **IV ketamine 0.5 mg/kg over 40 min** in **10 children** with molecularly confirmed ADNP syndrome; generally well tolerated with **no serious adverse events**. Common AEs included **elation/silliness 50%**, **fatigue 40%**, **increased aggression 40%**; caregiver/clinician measures showed nominal short-term improvements in irritability, social withdrawal, stereotypies, sensory symptoms, and attention-related measures; trial registered as **NCT04388774**, completed, results posted 2023-07-07 (pqac-00000029, pqac-00000033, pqac-00000034, pqac-00000046) | Kolevzon et al., 2022, https://doi.org/10.1016/j.xhgg.2022.100138; ClinicalTrials.gov NCT04388774 | Human open-label interventional trial |
| Ketamine molecular follow-up (2024) | Transcriptomic follow-up after the same **single 0.5 mg/kg ketamine infusion** in **10 individuals** found **immediate and profound** but **transient** blood RNA changes, enriched for **monocyte-related** signals, with **upregulation of immune/inflammatory processes** and **downregulation of RNA processing/metabolism**; changes returned toward baseline by **24 h to 1 week** (pqac-00000001, pqac-00000027, pqac-00000031) | Grice et al., 2024, https://doi.org/10.1038/s41398-024-03005-8 | Human longitudinal transcriptomics |
| NAP / davunetide / CP201 | **NAP (NAPVSIPQ; davunetide; CP201)** is an ADNP-derived peptide that binds **EB1/EB3** via an **SxIP/SIP** motif and supports microtubule- and tau-related functions. In **Adnp+/−** and mutant models it partially rescued dendritic spine deficits, developmental delay, vocalization, gait/motor phenotypes, social/object memory, autophagy-related abnormalities, and some microbiome changes; delivery reported as **systemic/nasal** in mice, including **intranasal** use in some studies. Clinical status remains **preclinical/early translational for ADNP syndrome**; review and case literature note prior non-ADNP human exposure with favorable safety, and one report notes **FDA orphan drug designation** for ADNP syndrome (pqac-00000035, pqac-00000036, pqac-00000037, pqac-00000038, pqac-00000039, pqac-00000041) | D’Incal et al., 2023, https://doi.org/10.1186/s13148-023-01450-8; Hacohen-Kleiman et al., 2018, https://doi.org/10.1172/jci98199 | Preclinical mouse/cellular studies + translational review |
| Ongoing natural history / characterization study | Observational study **NCT03718936** (Mount Sinai Seaver Autism Center) is **recruiting** and aims to characterize ADNP-related neurodevelopmental disorders using standardized autism, developmental, neurological, EEG, eyetracking, and biospecimen measures; planned enrollment **30**; useful as current real-world natural history infrastructure (pqac-00000044, pqac-00000045) | ClinicalTrials.gov NCT03718936, https://clinicaltrials.gov/study/NCT03718936 | Observational natural history study |


*Table: This table compacts the most actionable disease-characteristics evidence for ADNP-related syndrome, including identifiers, phenotype frequencies, variant architecture, and the current therapeutic landscape. It is designed to support rapid knowledge-base population with recent, source-linked findings.*