| Category | Key points | Quantitative data | Key sources (DOI/year) |
|---|---|---|---|
| Disease definition / identifiers | KBG syndrome is a rare autosomal dominant neurodevelopmental disorder caused by ANKRD11 disruption; OMIM identifier explicitly reported as **#148050** in cohort/review literature. Clinical diagnosis has historically relied on aggregated disease-level resources and cohort studies, with molecular confirmation by ANKRD11 sequencing/CNV analysis. (pqac-00000001, pqac-00000003) | OMIM **148050**; >100 patients reported by 2017 review; 49-patient European natural history cohort. (pqac-00000001, pqac-00000003) | 10.1093/hmg/ddac167 (2022); 10.1186/s13023-017-0736-8 (2017) |
| Causal gene and inheritance | **ANKRD11** is the causal gene; disease is typically **autosomal dominant**. Both heterozygous sequence variants and **16q24.3 CNVs/microdeletions** involving ANKRD11 cause KBG syndrome. About one-third of causal variants were reported as de novo in the 2017 review; in a newer cohort, most sequence variants were de novo. (pqac-00000003, pqac-00000030) | ~1/3 de novo in 2017 review; **86%** de novo in 2023 cohort subset. (pqac-00000003, pqac-00000030) | 10.1186/s13023-017-0736-8 (2017); 10.1136/jmg-2022-108632 (2023) |
| Molecular mechanism | Predominant mechanism is **ANKRD11 haploinsufficiency**; ANKRD11 is a chromatin-associated transcriptional regulator interacting with HDAC-containing complexes. Truncating variants are most common; some variants may escape NMD and produce dysfunctional truncated proteins with impaired transcriptional activity, and some data suggest dominant-negative effects for specific alleles. Regulatory-region deletions can also reduce transcript levels. (pqac-00000024, pqac-00000022, pqac-00000029, pqac-00000027) | In ClinVar/literature review, **583** pathogenic/likely pathogenic ANKRD11 variants cataloged; frameshift and nonsense were the most frequent classes. Case functional study showed mutant ANKRD11 truncated protein ~**85 kDa** vs WT ~**292 kDa**. (pqac-00000015, pqac-00000022) | 10.1186/s13023-024-03301-y (2024); 10.1016/j.heliyon.2024.e28082 (2024); 10.3390/ijms23115912 (2022) |
| Variant spectrum / CNVs | Pathogenic variant classes include **frameshift, nonsense, splice-site, missense**, intragenic deletions/duplications, promoter/non-coding deletions, and larger **16q24.3 microdeletions**. CNVs share core phenotype with sequence-variant KBG, though some genotype-phenotype differences exist. (pqac-00000004, pqac-00000029, pqac-00000026) | Molecular diagnosis in 22/33 (**67%**) clinically suspected cases using multi-test strategy in one study; 16q24.3 microdeletion review summarized **68** cases. (pqac-00000029, pqac-00000000) | 10.3390/ijms23115912 (2022); 10.3389/fped.2026.1742479 (2026) |
| Proposed diagnostic framework | Updated diagnostic approach from the large 2023 cohort: neurodevelopmental delay and/or ID/ADHD/ASD plus characteristic phenotypic features and/or major comorbidities. Earlier criteria emphasized macrodontia, characteristic face, short stature, hearing/otitis, family history, hand anomalies, seizures, cryptorchidism, feeding/palate problems, ASD, and wide fontanelle. (pqac-00000030, pqac-00000033) | Low et al. criteria reportedly met by **70%** of patients in the 2023 analysis. (pqac-00000030) | 10.1136/jmg-2022-108632 (2023); 10.1002/ajmg.a.37842 (2016) |
| Core phenotypic features | Most prevalent features are neurodevelopmental delay, macrodontia, triangular face, characteristic ears/nose/eyebrows, short stature, hand anomalies, and comorbid hearing/vision/feeding/cardiac/seizure issues. (pqac-00000035, pqac-00000032, pqac-00000036) | New 67-patient cohort: neurodevelopmental delay **95%**, macrodontia **80.9%**, triangular face **71.2%**, ears **76%**, nose **75.9%**, eyebrows **67.3%**. Combined cohort: macrodontia **79.6%** (211/265), bushy eyebrows **81.3%** (126/155), long philtrum **74.1%** (117/158), large/prominent ears **74.5%** (70/94), anteverted nares **72.4%** (76/105), brachydactyly/clinodactyly **69.5%** (189/272), triangular face **64.8%** (83/128). (pqac-00000035, pqac-00000032) | 10.1136/jmg-2022-108632 (2023); 10.1093/hmg/ddac167 (2022) |
| Neurodevelopmental/behavioral phenotype | Intellectual disability, language delay, ADHD and ASD are common; severity is variable. Epilepsy is associated with poorer developmental outcome in affected subsets. (pqac-00000030, pqac-00000031, pqac-00000041) | 2023 cohort: ID **82.1%**, language delay **72%**, ADHD **63.3%**, ASD **41.5%**. European cohort: ID **82%**. (pqac-00000034, pqac-00000036) | 10.1136/jmg-2022-108632 (2023); 10.1093/hmg/ddac167 (2022); 10.1016/j.ebr.2024.100647 (2024) |
| Major comorbidities | Hearing/otitis, visual problems, cryptorchidism, congenital heart defects, feeding difficulties, seizures, and brain anomalies are frequent and clinically actionable. (pqac-00000030, pqac-00000032, pqac-00000036) | 2023 combined/new cohort examples: hearing loss and/or otitis media **55.6%**; feeding difficulties **43.2%** (70/162); cryptorchidism **44.2%** (42/95); congenital heart defects **35.7%** (71/199); seizures **33.8%** (73/216). European cohort: cerebral anomalies **56%**; prenatal ultrasound anomalies **28.5%**. (pqac-00000030, pqac-00000032, pqac-00000036) | 10.1136/jmg-2022-108632 (2023); 10.1093/hmg/ddac167 (2022) |
| Epilepsy prevalence and spectrum | Epilepsy is a clinically important but heterogeneous feature, ranging from focal and generalized seizures to DEE/Lennox-Gastaut syndrome, EMAS, febrile seizures, and newer phenotype expansions. Presence of epilepsy is linked to worse developmental outcomes. (pqac-00000041, pqac-00000038, pqac-00000042) | European cohort: epilepsy **26.5%**. Combined 2023 cohort: seizures **33.8%** (73/216). Buijsse data cited in 2024 report: epilepsy **26/75**; seizure types generalized **15/38 (39%)**, focal **12/38 (31.6%)**, combined **11/38 (31.6%)**; median onset ~**3–4 years**. Literature review: refractory epilepsy about **27.8%**; multiple seizure types **36.3%**. (pqac-00000036, pqac-00000032, pqac-00000041, pqac-00000042, pqac-00000045) | 10.1093/hmg/ddac167 (2022); 10.1136/jmg-2022-108632 (2023); 10.1016/j.ebr.2024.100647 (2024); 10.21203/rs.3.rs-8780749/v1 (2026) |
| Epilepsy treatment signals | No disease-specific antiseizure standard exists; responses vary widely. Severe cases may be drug-resistant, but some focal seizures appear responsive to **lacosamide**; VNS and adjunctive therapies have also shown benefit in selected refractory cases. (pqac-00000038, pqac-00000040, pqac-00000045) | In one 4-case series, **2** focal-epilepsy patients achieved seizure control with lacosamide; doses reported ~**6.25–7.14 mg/kg/day** in one extract. Literature review estimated monotherapy effective in **37.5%** and valproate monotherapy response ~**32.3%**; refractory epilepsy ~**27.8%**. (pqac-00000040, pqac-00000045) | 10.1016/j.ebr.2024.100647 (2024); 10.21203/rs.3.rs-8780749/v1 (2026) |
| Short stature burden | Short stature is a hallmark but variably expressed feature; likely relates to impaired growth-plate chondrocyte differentiation and bone elongation due to ANKRD11 dysfunction. (pqac-00000015, pqac-00000017, pqac-00000018) | Short stature in **47.35%** (116/245) or **48.76%** (59/121) depending on analytic subset; combined 2023 cohort short stature **57.9%** (150/259). European cohort notes persistence over time. (pqac-00000018, pqac-00000032, pqac-00000036) | 10.1186/s13023-024-03301-y (2024); 10.1136/jmg-2022-108632 (2023); 10.1093/hmg/ddac167 (2022) |
| rhGH treatment summary | **Recombinant human growth hormone (rhGH)** has emerging supportive evidence for short stature in KBG syndrome, but data remain limited and non-randomized. Most reported treated children improved height SDS; endocrine evaluation often includes bone age, GH stimulation, and IGF-1 testing. (pqac-00000014, pqac-00000016, pqac-00000020) | Review summarized **9** treated patients; treatment duration ~**0.58–3 years**; height SDS gains about **+0.14 to +1.87**. In microdeletion-type KBG, 2 children had catch-up growth of **+1.66 SD** and **+0.68 SD**; another series reported improvement in **2/4** patients. (pqac-00000014, pqac-00000016, pqac-00000019, pqac-00000020) | 10.1186/s13023-024-03301-y (2024); 10.3389/fped.2026.1742479 (2026) |
| Epigenetic / DNAm signature | A blood-based **DNA methylation signature** has been described for KBG syndrome caused by pathogenic ANKRD11 variants and 16q24.3 microdeletions, supporting its status as an epigenetic/chromatinopathy-related disorder and offering diagnostic help for VUS interpretation. (pqac-00000010, pqac-00000012, pqac-00000009) | Discovery cohort: **14** KBG cases vs **28** controls; broader profiling included **21** ANKRD11-variant cases, **2** microdeletion cases, and **28** controls. Signature comprised **95 CpG** sites. Validation: **7** KBG cases classified with **100% sensitivity** and **150** controls with **100% specificity**. Four VUS were tested; two were control-like, and a parent-child duo had intermediate/KBG-like probabilities. (pqac-00000010, pqac-00000012, pqac-00000009, pqac-00000046) | 10.1093/hmg/ddac289 (2023) |
| Natural history / progression | KBG syndrome is lifelong, with evolving recognizability across age. Short stature tends to persist, while head circumference may normalize. Some seizures remit after adolescence, but a subset develop severe refractory epilepsy. Adult functional outcomes are variable, with some individuals achieving partial or full independence. (pqac-00000001, pqac-00000002, pqac-00000041) | OFC median at birth **−0.88 SD** and tends to normalize over time; epilepsy present in **26.5%** in European cohort; cognitive impairment usually mild–moderate in most reported patients. (pqac-00000001, pqac-00000002) | 10.1093/hmg/ddac167 (2022); 10.1186/s13023-017-0736-8 (2017); 10.1016/j.ebr.2024.100647 (2024) |


*Table: This table summarizes high-yield knowledge base fields for KBG syndrome using only the extracted evidence, including genetics, phenotype frequencies, epilepsy, growth, and epigenetic diagnostics. It is designed as a compact evidence-backed reference for disease curation.*