Home / Deep Research / Koolen-de Vries syndrome

Koolen-de Vries syndrome

1. Disease Information

2026-05-09
Falcon MONDO:0012496 Model: Edison Scientific Literature 38 citations

1. Disease Information

1.1 Concise overview (current understanding)

Koolen–de Vries syndrome is a rare, multisystem neurodevelopmental disorder caused by either a recurrent 17q21.31 microdeletion that includes KANSL1 or by a heterozygous intragenic pathogenic variant in KANSL1. Core features across cohorts include developmental delay, hypotonia, intellectual disability (often moderate), speech/language disorder, and frequent multisystem comorbidities (cardiac, renal/urogenital, musculoskeletal, sensory, sleep, and behavioral features). (colin2023genidaaparticipatory pages 2-3, houser2025neuroimagingofkoolende pages 2-8)

1.2 Key identifiers

1.3 Synonyms and alternative names

Commonly used synonyms in the clinical literature include: - 17q21.31 microdeletion syndrome (farne2022koolen‐devriessyndrome pages 10-12) - KANSL1-related intellectual disability syndrome (farne2022koolen‐devriessyndrome pages 10-12)

1.4 Evidence source types

The report integrates: - Aggregated disease-level resources via cohorts/registries: e.g., GenIDA caregiver-reported cohort (n=237) (colin2023genidaaparticipatory pages 3-4) - Clinician-assessed cohort study: large speech/language and medical phenotype cohort (n=81) (john2023expandingthespeech pages 2-2) - Primary mechanistic studies: mouse model and human iPSC-derived neuronal models (li2022kansl1haploinsufficiencyimpairs pages 1-2, linda2022imbalancedautophagycauses pages 1-3)

2. Etiology

2.1 Disease causal factors

KdVS is a genetic disorder caused by KANSL1 haploinsufficiency, either from: - a 17q21.31 deletion including KANSL1, or - a heterozygous pathogenic variant in KANSL1 (houser2025neuroimagingofkoolende pages 2-8, colin2023genidaaparticipatory pages 2-3)

2.2 Risk factors

  • Primary genetic risk factor: de novo heterozygous 17q21.31 deletion or de novo heterozygous pathogenic KANSL1 variant (autosomal dominant) (houser2025neuroimagingofkoolende pages 2-8, saxena2021koolen‐devriessyndrome pages 2-4)
  • Environmental risk factors / protective factors / gene–environment interactions: No KdVS-specific evidence identified in the retrieved texts.

2.3 Inheritance

KdVS is described as autosomal dominant, typically arising de novo (houser2025neuroimagingofkoolende pages 2-8, saxena2021koolen‐devriessyndrome pages 2-4).

3. Phenotypes (with frequencies, onset, and suggested HPO terms)

3.1 Summary of highest-yield phenotypes (recent large cohorts)

Two major recent data sources provide quantitative phenotype frequencies: - GenIDA caregiver registry (n=237; mean age 14.0 years; 116 males/121 females) (colin2023genidaaparticipatory pages 3-4) - St John et al. 2023 clinical cohort (n=81; mean age 9y10mo; age range 1.5–40.2y) (john2023expandingthespeech pages 2-2)

Neurodevelopmental

Speech/language and communication

Epilepsy and seizures

Motor development / musculoskeletal

Congenital anomalies and organ involvement

Sleep, dental, sensory, behavior

3.2 Quality of life and adaptive function

The 2023 speech/language cohort reported relative strengths in social competence and behavioral/emotional control, but communication difficulties impacted daily living skills (john2023expandingthespeech pages 1-2).

4. Genetic/Molecular Information

4.1 Causal gene(s)

4.2 Variant spectrum (examples and classes)

4.3 Genotype–phenotype correlations

4.4 Epigenetic information (2024–key development)

A 2024 European Journal of Human Genetics study identified a blood DNA methylation episignature of 456 CpG sites for KdVS and used an SVM classifier to support diagnosis and classify KANSL1 VUS (awamleh2024anewblood pages 1-2, awamleh2024anewblood pages 2-3).

5. Environmental Information

No specific environmental contributors, protective factors, or infectious triggers were supported by the retrieved KdVS-focused evidence.

6. Mechanism / Pathophysiology

6.1 Core mechanistic chain (evidence-backed)

KANSL1 haploinsufficiency → dysregulated chromatin/NSL complex function and H4K16 acetylation → transcriptional dysregulation of autophagy machinery and cellular homeostasis → oxidative stress, impaired lysosomal/autophagic clearance and synaptic dysfunction → neurodevelopmental phenotype; plus cardiac dysfunction in mouse models. (linda2022imbalancedautophagycauses pages 1-3, li2022kansl1haploinsufficiencyimpairs pages 1-2)

6.2 Autophagy/lysosome and oxidative stress (human neuronal models)

In KANSL1-deficient human iPSC-derived neurons, decreased SOD1 leads to increased oxidative stress and autophagosome accumulation; autophagosomes accumulate at excitatory synapses with reduced synaptic density and reduced AMPA receptor-mediated transmission, impairing network activity. Antioxidant/oxidative stress reduction rescued autophagosomes and neuronal function. (linda2022imbalancedautophagycauses pages 1-3)

Direct abstract quotes (primary literature): - “In KANSL1-deficient neurons, autophagosome accumulation at excitatory synapses resulted in reduced synaptic density, reduced GRIA/AMPA receptor-mediated transmission and impaired neuronal network activity.” (linda2022imbalancedautophagycauses pages 1-3) - “By pharmacologically reducing oxidative stress, we could rescue the aberrant autophagosome formation as well as synaptic and neuronal network activity in KANSL1-deficient neurons.” (linda2022imbalancedautophagycauses pages 1-3)

6.3 Autophagosome–lysosome fusion and mitophagy (mouse model)

A Nature Communications mouse study identified KANSL1 as essential for autophagy and showed KANSL1 modulates autophagosome–lysosome fusion via transcriptional regulation of STX17. Kansl1+/− mice show impaired clearance of damaged mitochondria, increased ROS, and neuronal/cardiac dysfunction; 13-cis retinoic acid reversed mitophagic defects and neurobehavioral abnormalities. (li2022kansl1haploinsufficiencyimpairs pages 1-2)

6.4 Suggested ontology terms

7. Anatomical Structures Affected

From cohort data, the primary impacted system is the nervous system, with frequent multisystem involvement: - CNS/neurodevelopment: developmental delay, ID, seizures; imaging anomalies in a subset (john2023expandingthespeech pages 2-2) - Cardiac: ASD/VSD and other defects in substantial fractions (colin2023genidaaparticipatory pages 3-4, john2023expandingthespeech pages 2-2) - Renal/urogenital: relatively common (colin2023genidaaparticipatory pages 3-4) - Musculoskeletal: hypermobility/scoliosis, etc. (colin2023genidaaparticipatory pages 7-9)

8. Temporal Development

9. Inheritance and Population

9.1 Epidemiology

9.2 Population demographics

10. Diagnostics

10.1 Genetic testing (current practice)

Diagnosis is molecular and includes: - Chromosomal microarray (CMA) to detect 17q21.31 deletions - Single-gene testing / multigene panels for KANSL1 variants - Broader genomic approaches when phenotype is atypical (houser2025neuroimagingofkoolende pages 2-8)

10.2 Omics-based diagnostics (major 2024 development)

A 2024 study developed a blood DNA methylation episignature (456 CpGs) and demonstrated diagnostic utility for classification of KANSL1 VUS and atypical cases, with validation case scores 75–92% vs controls 0–13%. (awamleh2024anewblood pages 2-3, awamleh2024anewblood pages 1-2)

Direct abstract quote (Awamleh 2024): “In this study, we identified a robust DNAm signature of 456 significant CpG sites…” (awamleh2024anewblood pages 1-2)

10.3 Differential diagnosis

Differential diagnoses are not systematically enumerated in the retrieved evidence; however, KdVS is placed among syndromic neurodevelopmental disorders with overlapping features, and facial/speech phenotyping tools are used in the broader field (e.g., NDD cohorts referenced indirectly). Evidence in this run is insufficient to list a complete differential.

11. Outcome/Prognosis

12. Treatment

12.1 Current standard management (real-world implementation)

There is no curative therapy described in clinical summaries; management is symptomatic and multidisciplinary, including physiotherapy for motor delays, speech/feeding therapy, and educational supports, with multispecialty monitoring (houser2025neuroimagingofkoolende pages 2-8).

Speech/language recommendations (2023 cohort) emphasize early AAC and ongoing targeted therapy across development. (john2023expandingthespeech pages 1-2)

12.2 Epilepsy management (real-world observational data)

Caregiver-reported medication effectiveness in GenIDA suggested reported efficacy for valproate (83%) and levetiracetam (67% good efficacy among reporters), with additional reported effectiveness of valproate and oxcarbazepine at cohort level. (colin2023genidaaparticipatory pages 7-9, colin2023genidaaparticipatory pages 1-2)

12.3 Experimental / translational therapeutic leads

12.4 Trial readiness and research infrastructure (expert/authoritative perspective)

A 2024 review describing the KdVS Foundation’s strategy emphasizes models, registries, natural history, and translational funding, with a stated goal of a first clinical trial in late 2026. (pfalzer2024koolendevriessyndrome pages 2-3)

12.5 MAXO term suggestions (examples)

13. Prevention

Primary prevention is not applicable to the de novo genetic cause, but genetic counseling is relevant given the autosomal dominant, typically de novo etiology. (houser2025neuroimagingofkoolende pages 2-8, saxena2021koolen‐devriessyndrome pages 2-4)

14. Other Species / Natural Disease

No evidence of naturally occurring KdVS-equivalent disease in non-human species was retrieved. KANSL1 is conserved and studied in model organisms, but veterinary natural disease evidence is not available in the retrieved texts.

15. Model Organisms

Evidence Gaps (limitations of this run)

  • MONDO, Orphanet, MeSH, ICD-10/11 codes were not extractable from the retrieved full-text chunks and thus cannot be cited here.
  • Mortality/life expectancy statistics and formal clinical diagnostic criteria (beyond molecular testing) were not found in the retrieved evidence.
  • Comprehensive differential diagnosis lists and environmental modifiers were not supported by the current evidence set.

High-utility Summary Table

The following artifact condenses the key actionable facts (identifiers, genetics, prevalence, phenotype frequencies, and 2024 diagnostic episignature metrics) with URLs and publication dates.

Table (click to expand)
Category Data point Value/description Source (author/year/journal) URL Pub date
Disease information Primary disease name Koolen-de Vries syndrome (KdVS); rare multisystem neurodevelopmental disorder caused by 17q21.31 deletion including KANSL1 or heterozygous intragenic KANSL1 pathogenic variant (colin2023genidaaparticipatory pages 2-3, houser2025neuroimagingofkoolende pages 2-8) Colin et al. 2023, Genetics in Medicine Open; Houser et al. 2025, Cureus https://doi.org/10.1016/j.gimo.2023.100817; https://doi.org/10.7759/cureus.79194 2023-01; 2025-02
Disease information Key identifier OMIM 610443 (reported in GenIDA KdVS cohort excerpt) (colin2023genidaaparticipatory pages 2-3) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Disease information Common synonyms 17q21.31 microdeletion syndrome; KANSL1-related intellectual disability syndrome (colin2023genidaaparticipatory pages 2-3, farne2022koolen‐devriessyndrome pages 10-12) Colin et al. 2023, Genetics in Medicine Open; Farnè et al. 2022, Am J Med Genet A https://doi.org/10.1016/j.gimo.2023.100817; https://doi.org/10.1002/ajmg.a.62536 2023-01; 2022-10
Genetic etiology Typical recurrent deletion Typical recurrent 17q21.31 deletion ~500–650 kb; cohort wording also notes recurrent deletion spanning ~43.7–44.25 Mb region (john2023expandingthespeech pages 3-4, houser2025neuroimagingofkoolende pages 2-8) St John et al. 2023, Eur J Hum Genet; Houser et al. 2025, Cureus https://doi.org/10.1038/s41431-022-01230-7; https://doi.org/10.7759/cureus.79194 2023-12; 2025-02
Genetic etiology Deletion vs sequence variant proportion About 60% due to heterozygous 17q21.31 deletion and 40% due to KANSL1 sequence variants in one review excerpt (houser2025neuroimagingofkoolende pages 2-8) Houser et al. 2025, Cureus https://doi.org/10.7759/cureus.79194 2025-02
Genetic etiology GenIDA genotype counts In GenIDA cohort, 157 individuals with 17q21.31 deletion and 40 with pathogenic KANSL1 variant; no major clinical differences detected between groups (colin2023genidaaparticipatory pages 2-3) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Genetic etiology 2023 speech cohort genotype counts In speech/language cohort (n=81), 56/81 (69.1%) had typical 17q21.31 deletion and 19/81 had KANSL1-only sequence variants; no group score differences reported between deletion and KANSL1-variant groups (john2023expandingthespeech pages 2-2, john2023expandingthespeech pages 3-4) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Genetic etiology Variant classes observed Predominantly loss-of-function intragenic variants: truncating, frameshift, splice-site, small intragenic exon deletion; 2024 episignature study also discusses missense/nonsense/frameshift/deletion-insertion/mosaic variants for classification (john2023expandingthespeech pages 3-4, awamleh2024anewblood pages 3-5) St John et al. 2023, Eur J Hum Genet; Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7; https://doi.org/10.1038/s41431-024-01538-6 2023-12; 2024-01
Inheritance/epidemiology Inheritance pattern Autosomal dominant; typically de novo disease mechanism highlighted in KdVS descriptions (houser2025neuroimagingofkoolende pages 2-8, prat2021ocularmanifestationsand pages 4-4, saxena2021koolen‐devriessyndrome pages 2-4) Houser et al. 2025, Cureus; Prat et al. 2021, Ophthalmic Genetics; Saxena et al. 2021, Am J Med Genet A https://doi.org/10.7759/cureus.79194; https://doi.org/10.1080/13816810.2020.1868012; https://doi.org/10.1002/ajmg.a.62008 2025-02; 2021-01; 2021-12
Inheritance/epidemiology Estimated prevalence Estimated prevalence for 17q21.31 deletion approximately 1:55,000 births (houser2025neuroimagingofkoolende pages 2-8, prat2021ocularmanifestationsand pages 4-4) Houser et al. 2025, Cureus; Prat et al. 2021, Ophthalmic Genetics https://doi.org/10.7759/cureus.79194; https://doi.org/10.1080/13816810.2020.1868012 2025-02; 2021-01
Epidemiology Sex distribution in GenIDA 116 males / 121 females; mean age 14.0 years in GenIDA cohort (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Epidemiology Sex/age in speech cohort 35 female / 46 male; age 1.5–40.2 years, mean 9 years 10 months (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (GenIDA 2023) Prenatal/perinatal problems 77.9% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Hypotonia 61.5% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Feeding difficulties 60.2% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Intellectual disability Formal ID diagnosis in 89.2%; severity: mild 16.9%, moderate 60.2%, severe 2.4%, profound 20.5% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Epilepsy 47.3% (97/204) with epilepsy/seizures (colin2023genidaaparticipatory pages 6-7, colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Seizure types among seizure cases Tonic-clonic 38.1%, absence 28.9%, complex partial 22.7%, nocturnal 21.6%, febrile convulsions 19.6%, infantile spasms 14.4%, atonic 9.3% (colin2023genidaaparticipatory pages 6-7) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Age at first seizure Average 3.4 years, median 2.0 years (colin2023genidaaparticipatory pages 7-9) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Speech/language delay 73.6% in children >2 years; first words average 2.2 years (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Motor milestone delay Median sit 10.7 mo, stand 17.5 mo, walk 23.4 mo (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Musculoskeletal findings Joint laxity 50.0%, scoliosis 25.5%, hip dislocation/dysplasia 18.0%, pes planus 22.0%; musculoskeletal anomalies overall 75.5% in later excerpt (colin2023genidaaparticipatory pages 3-4, colin2023genidaaparticipatory pages 7-9) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Sleep disorders 42.6% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Dental problems 65.1% (colin2023genidaaparticipatory pages 3-4) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Cardiac anomalies Atrial septal defect 18.9%; ventricular septal defect 10.9% (colin2023genidaaparticipatory pages 3-4, colin2023genidaaparticipatory pages 6-7) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Renal/urogenital issues Approximately 38.3%; male cryptorchidism 22.6% (colin2023genidaaparticipatory pages 3-4, colin2023genidaaparticipatory pages 7-9) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Vision/hearing Hypermetropia 38.8%, strabismus 34.7%; hearing problems 40.8%, deafness 12.2% (colin2023genidaaparticipatory pages 6-7) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Respiratory issues Respiratory issues 39.8%; laryngomalacia 15.4%; tracheomalacia 8.5%; asthma 16.4%; recurrent pneumonia noted in 13 persons (colin2023genidaaparticipatory pages 6-7, colin2023genidaaparticipatory pages 7-9, colin2023genidaaparticipatory pages 1-2) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (GenIDA 2023) Behavioral profile Behavioral problems 54.8%; repetitive behaviors 35.2%, attention deficit 32.7%, anxiety 31.2%, obsessive behavior 29.6%, hyperactivity 27.6%; sociable with familiar adults 98.1% and children 88.6% (colin2023genidaaparticipatory pages 6-7, colin2023genidaaparticipatory pages 7-9) Colin et al. 2023, Genetics in Medicine Open https://doi.org/10.1016/j.gimo.2023.100817 2023-01
Phenotypes (EJHG speech cohort 2023) Developmental delay 78/81 (96.3%) (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Dysmorphic features 73/81 (90.1%); pear-shaped bulbous nose 48/81 (59.3%) (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Intellectual disability Among assessed individuals (n=56), 49/56 (87.5%) had ID; 51.8% moderate, 19.6% severe (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Structural brain anomalies 33/62 (53.2%) with imaging had structural brain anomalies (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Epilepsy/seizures 29/81 (35.8%) (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Hearing loss 24/81 (29.6%), often moderate and conductive (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Cardiac/musculoskeletal/sleep Cardiac defects 32/81 (39.5%); musculoskeletal problems 32/81 (39.5%); sleep disturbances 33/81 (40.7%) (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Other systemic features Dental problems 36/72 (50.0%); renal/urogenital complications 25/81 (30.9%); GI concerns 24/81 (29.6%); mental health problems 23/81 (28.4%); cryptorchidism 21/46 (45.7%) of males (john2023expandingthespeech pages 2-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Verbal status 62/81 (76.5%) verbal; minimally verbal participants used AAC successfully (john2023expandingthespeech pages 1-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Motor speech disorders Apraxia in 39/61 (63.9%) verbal participants; dysarthria in 28/61 (45.9%) (john2023expandingthespeech pages 1-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Phenotypes (EJHG speech cohort 2023) Stuttering 36/47 (76.6%) of verbal participants; described as late-onset and fluctuating (john2023expandingthespeech pages 1-2) St John et al. 2023, Eur J Hum Genet https://doi.org/10.1038/s41431-022-01230-7 2023-12
Diagnostics / omics 2024 blood DNAm episignature cohort Whole-blood DNAm profiled in 13 individuals with KANSL1 variants, 4 with 17q21.31 microdeletions, and 21 controls using Illumina EPIC array (awamleh2024anewblood pages 1-2) Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-024-01538-6 2024-01
Diagnostics / omics 2024 episignature size Robust blood DNA methylation signature of 456 significant CpG sites (awamleh2024anewblood pages 1-2, awamleh2024anewblood pages 2-3) Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-024-01538-6 2024-01
Diagnostics / omics Discovery and validation Discovery cohort n=8 KdVS cases; independent validation cohort n=8; validation SVM scores for KdVS cases 75–92% vs controls 0–13% (awamleh2024anewblood pages 5-7, awamleh2024anewblood pages 2-3, awamleh2024anewblood pages 7-8) Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-024-01538-6 2024-01
Diagnostics / omics Variant classification utility Used to classify 2 KANSL1 VUS and 4 atypical-presentation variants; one missense p.Thr887Met scored KdVS-like (~72%), while p.Gly900Glu scored control-like (~4.7%) (awamleh2024anewblood pages 3-5, awamleh2024anewblood pages 1-2, awamleh2024anewblood pages 7-8) Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-024-01538-6 2024-01
Diagnostics / omics Microdeletion vs sequence variant DNAm difference No significant DNAm difference between 17q21.31 microdeletion carriers and KANSL1 sequence-variant carriers (adjusted p = 0.34) (awamleh2024anewblood pages 2-3) Awamleh et al. 2024, Eur J Hum Genet https://doi.org/10.1038/s41431-024-01538-6 2024-01

Table: This table condenses the most actionable disease-level facts for Koolen-de Vries syndrome, including identifiers, causal genetics, prevalence, major 2023 cohort phenotype frequencies, and the 2024 DNA methylation episignature findings. It is useful as a quick-reference artifact for knowledge-base population and evidence-backed summarization.

References

  1. (colin2023genidaaparticipatory pages 2-3): Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel. Genida, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with koolen-de vries syndrome. Genetics in Medicine Open, 1:100817, Jan 2023. URL: https://doi.org/10.1016/j.gimo.2023.100817, doi:10.1016/j.gimo.2023.100817. This article has 9 citations and is from a peer-reviewed journal.

  2. (houser2025neuroimagingofkoolende pages 2-8): Karis Houser, Sara C Esteves, and Michael S. Kuwabara. Neuroimaging of koolen-de vries syndrome: a rare genetic disorder. Cureus, Feb 2025. URL: https://doi.org/10.7759/cureus.79194, doi:10.7759/cureus.79194. This article has 1 citations.

  3. (farne2022koolen‐devriessyndrome pages 10-12): Marianna Farnè, Laura Bernardini, Anna Capalbo, Giusy Cavarretta, Barbara Torres, Mariabeatrice Sanchini, Sergio Fini, Alessandra Ferlini, and Stefania Bigoni. Koolen‐de vries syndrome in a 63‐year‐old woman: report of the oldest patient and a review of the adult phenotype. American Journal of Medical Genetics. Part a, 188:692-707, Oct 2022. URL: https://doi.org/10.1002/ajmg.a.62536, doi:10.1002/ajmg.a.62536. This article has 10 citations and is from a peer-reviewed journal.

  4. (colin2023genidaaparticipatory pages 3-4): Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel. Genida, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with koolen-de vries syndrome. Genetics in Medicine Open, 1:100817, Jan 2023. URL: https://doi.org/10.1016/j.gimo.2023.100817, doi:10.1016/j.gimo.2023.100817. This article has 9 citations and is from a peer-reviewed journal.

  5. (john2023expandingthespeech pages 2-2): Miya St John, Olivia van Reyk, David Koolen, Bert de Vries, David Amor, and Angela Morgan. Expanding the speech and language phenotype in koolen-de vries syndrome: late onset and periodic stuttering a novel feature. European Journal of Human Genetics, 31:531-540, Dec 2023. URL: https://doi.org/10.1038/s41431-022-01230-7, doi:10.1038/s41431-022-01230-7. This article has 18 citations and is from a domain leading peer-reviewed journal.

  6. (li2022kansl1haploinsufficiencyimpairs pages 1-2): Tingting Li, Dingyi Lu, C. Yao, Tingting Li, Hua Dong, Zhanqi Li, Guang Xu, Jiayi Chen, Hao Zhang, Xiaoyu Yi, Haizhen Zhu, Guangqin Liu, Kaiqing Wen, Haixin Zhao, Jun Gao, Yakun Zhang, Qiu-Ying Han, Teng Li, Weina Zhang, Jie Zhao, Tao Li, Zhaofang Bai, Moshi Song, Xin Hua He, Tao Zhou, Qing Xia, Ai-ling Li, and Xin Pan. Kansl1 haploinsufficiency impairs autophagosome-lysosome fusion and links autophagic dysfunction with koolen-de vries syndrome in mice. Nature Communications, Feb 2022. URL: https://doi.org/10.1038/s41467-022-28613-0, doi:10.1038/s41467-022-28613-0. This article has 52 citations and is from a highest quality peer-reviewed journal.

  7. (linda2022imbalancedautophagycauses pages 1-3): Katrin Linda, Elly I. Lewerissa, Anouk H. A. Verboven, Michele Gabriele, Monica Frega, Teun M. Klein Gunnewiek, Lynn Devilee, Edda Ulferts, Marina Hommersom, Astrid Oudakker, Chantal Schoenmaker, Hans van Bokhoven, Dirk Schubert, Giuseppe Testa, David A. Koolen, Bert B.A. de Vries, and Nael Nadif Kasri. Imbalanced autophagy causes synaptic deficits in a human model for neurodevelopmental disorders. Autophagy, 18:423-442, Jul 2022. URL: https://doi.org/10.1080/15548627.2021.1936777, doi:10.1080/15548627.2021.1936777. This article has 88 citations and is from a domain leading peer-reviewed journal.

  8. (saxena2021koolen‐devriessyndrome pages 2-4): Deepti Saxena, Amita Moirangthem, Arya Shambhavi, and Shubha R. Phadke. Koolen‐de vries syndrome: first report of two unrelated indian patients. American Journal of Medical Genetics Part A, 185:982-985, Dec 2021. URL: https://doi.org/10.1002/ajmg.a.62008, doi:10.1002/ajmg.a.62008. This article has 0 citations.

  9. (john2023expandingthespeech pages 1-2): Miya St John, Olivia van Reyk, David Koolen, Bert de Vries, David Amor, and Angela Morgan. Expanding the speech and language phenotype in koolen-de vries syndrome: late onset and periodic stuttering a novel feature. European Journal of Human Genetics, 31:531-540, Dec 2023. URL: https://doi.org/10.1038/s41431-022-01230-7, doi:10.1038/s41431-022-01230-7. This article has 18 citations and is from a domain leading peer-reviewed journal.

  10. (colin2023genidaaparticipatory pages 6-7): Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel. Genida, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with koolen-de vries syndrome. Genetics in Medicine Open, 1:100817, Jan 2023. URL: https://doi.org/10.1016/j.gimo.2023.100817, doi:10.1016/j.gimo.2023.100817. This article has 9 citations and is from a peer-reviewed journal.

  11. (colin2023genidaaparticipatory pages 7-9): Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel. Genida, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with koolen-de vries syndrome. Genetics in Medicine Open, 1:100817, Jan 2023. URL: https://doi.org/10.1016/j.gimo.2023.100817, doi:10.1016/j.gimo.2023.100817. This article has 9 citations and is from a peer-reviewed journal.

  12. (john2023expandingthespeech pages 3-4): Miya St John, Olivia van Reyk, David Koolen, Bert de Vries, David Amor, and Angela Morgan. Expanding the speech and language phenotype in koolen-de vries syndrome: late onset and periodic stuttering a novel feature. European Journal of Human Genetics, 31:531-540, Dec 2023. URL: https://doi.org/10.1038/s41431-022-01230-7, doi:10.1038/s41431-022-01230-7. This article has 18 citations and is from a domain leading peer-reviewed journal.

  13. (awamleh2024anewblood pages 3-5): Zain Awamleh, Sanaa Choufani, Wendy Wu, Dmitrijs Rots, Alexander J. M. Dingemans, Nael Nadif Kasri, Susana Boronat, Salvador Ibañez-Mico, Laura Cuesta Herraiz, Irene Ferrer, Antonio Martínez Carrascal, Luis A. Pérez-Jurado, Gemma Aznar Lain, Juan Dario Ortigoza-Escobar, Bert B. A. de Vries, David A. Koolen, and Rosanna Weksberg. A new blood dna methylation signature for koolen-de vries syndrome: classification of missense kansl1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32:324-332, Jan 2024. URL: https://doi.org/10.1038/s41431-024-01538-6, doi:10.1038/s41431-024-01538-6. This article has 13 citations and is from a domain leading peer-reviewed journal.

  14. (awamleh2024anewblood pages 1-2): Zain Awamleh, Sanaa Choufani, Wendy Wu, Dmitrijs Rots, Alexander J. M. Dingemans, Nael Nadif Kasri, Susana Boronat, Salvador Ibañez-Mico, Laura Cuesta Herraiz, Irene Ferrer, Antonio Martínez Carrascal, Luis A. Pérez-Jurado, Gemma Aznar Lain, Juan Dario Ortigoza-Escobar, Bert B. A. de Vries, David A. Koolen, and Rosanna Weksberg. A new blood dna methylation signature for koolen-de vries syndrome: classification of missense kansl1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32:324-332, Jan 2024. URL: https://doi.org/10.1038/s41431-024-01538-6, doi:10.1038/s41431-024-01538-6. This article has 13 citations and is from a domain leading peer-reviewed journal.

  15. (awamleh2024anewblood pages 2-3): Zain Awamleh, Sanaa Choufani, Wendy Wu, Dmitrijs Rots, Alexander J. M. Dingemans, Nael Nadif Kasri, Susana Boronat, Salvador Ibañez-Mico, Laura Cuesta Herraiz, Irene Ferrer, Antonio Martínez Carrascal, Luis A. Pérez-Jurado, Gemma Aznar Lain, Juan Dario Ortigoza-Escobar, Bert B. A. de Vries, David A. Koolen, and Rosanna Weksberg. A new blood dna methylation signature for koolen-de vries syndrome: classification of missense kansl1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32:324-332, Jan 2024. URL: https://doi.org/10.1038/s41431-024-01538-6, doi:10.1038/s41431-024-01538-6. This article has 13 citations and is from a domain leading peer-reviewed journal.

  16. (colin2023genidaaparticipatory pages 1-2): Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel. Genida, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver-reported information on 237 individuals with koolen-de vries syndrome. Genetics in Medicine Open, 1:100817, Jan 2023. URL: https://doi.org/10.1016/j.gimo.2023.100817, doi:10.1016/j.gimo.2023.100817. This article has 9 citations and is from a peer-reviewed journal.

  17. (prat2021ocularmanifestationsand pages 4-4): Daphna Prat, William R. Katowitz, Alanna Strong, and James A. Katowitz. Ocular manifestations and surgical interventions in pediatric patients with koolen-de-vries syndrome. Ophthalmic Genetics, 42:186-188, Jan 2021. URL: https://doi.org/10.1080/13816810.2020.1868012, doi:10.1080/13816810.2020.1868012. This article has 7 citations and is from a peer-reviewed journal.

  18. (pfalzer2024koolendevriessyndrome pages 2-3): Anna C. Pfalzer, Blake Ivers, Alayna Haynam, Barbara Drake, David A. Koolen, Nael Nadif Kasri, Bert B. A. de Vries, Heather C. Mefford, Angela Morgan, Terry Jo Bichell, Elijah Simon, Ananya Terala, Kenneth A. Myers, and Ashley Point. Koolen-de vries syndrome: a journey from diagnosis to treatments. Therapeutic Advances in Rare Disease, Jan 2024. URL: https://doi.org/10.1177/26330040241265414, doi:10.1177/26330040241265414. This article has 1 citations.

  19. (awamleh2024anewblood pages 5-7): Zain Awamleh, Sanaa Choufani, Wendy Wu, Dmitrijs Rots, Alexander J. M. Dingemans, Nael Nadif Kasri, Susana Boronat, Salvador Ibañez-Mico, Laura Cuesta Herraiz, Irene Ferrer, Antonio Martínez Carrascal, Luis A. Pérez-Jurado, Gemma Aznar Lain, Juan Dario Ortigoza-Escobar, Bert B. A. de Vries, David A. Koolen, and Rosanna Weksberg. A new blood dna methylation signature for koolen-de vries syndrome: classification of missense kansl1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32:324-332, Jan 2024. URL: https://doi.org/10.1038/s41431-024-01538-6, doi:10.1038/s41431-024-01538-6. This article has 13 citations and is from a domain leading peer-reviewed journal.

  20. (awamleh2024anewblood pages 7-8): Zain Awamleh, Sanaa Choufani, Wendy Wu, Dmitrijs Rots, Alexander J. M. Dingemans, Nael Nadif Kasri, Susana Boronat, Salvador Ibañez-Mico, Laura Cuesta Herraiz, Irene Ferrer, Antonio Martínez Carrascal, Luis A. Pérez-Jurado, Gemma Aznar Lain, Juan Dario Ortigoza-Escobar, Bert B. A. de Vries, David A. Koolen, and Rosanna Weksberg. A new blood dna methylation signature for koolen-de vries syndrome: classification of missense kansl1 variants and comparison to fibroblast cells. European Journal of Human Genetics, 32:324-332, Jan 2024. URL: https://doi.org/10.1038/s41431-024-01538-6, doi:10.1038/s41431-024-01538-6. This article has 13 citations and is from a domain leading peer-reviewed journal.