KBG Syndrome

Mendelian MONDO:0007846 Pathograph 27 Show in embeddings browser autosomal dominant syndromic intellectual disability multiple congenital anomalies/dysmorphic syndrome-intellectual disability chromatinopathy

KBG syndrome (MONDO:0007846, OMIM #148050) is a rare autosomal dominant multisystem neurodevelopmental disorder caused by haploinsufficiency of ANKRD11, a chromatin-associated transcriptional regulator at 16q24.3. It is classically characterized by macrodontia of the upper central incisors, a distinctive facial gestalt (triangular face, thick/bushy eyebrows, prominent ears, long philtrum), postnatal short stature, skeletal (notably costovertebral and hand) anomalies, and developmental delay / intellectual disability with frequent behavioral comorbidity. Disease results from either heterozygous loss-of-function ANKRD11 sequence variants (most often frameshift or nonsense) or 16q24.3 copy-number deletions involving ANKRD11. The disorder is increasingly classified among the chromatinopathies and has a recognizable blood DNA methylation signature.

Ask OpenScientist

Ask a research question about KBG Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

4
Pathophys.
23
Phenotypes
27
Pathograph
1
Genes
5
Medical Actions
1
Trials
3
References
1
Deep Research
⚙

Pathophysiology

4
ANKRD11 Haploinsufficiency
KBG syndrome results predominantly from haploinsufficiency of ANKRD11 (ankyrin repeat domain-containing protein 11) at 16q24.3. Heterozygous loss-of-function sequence variants (most frequently frameshift and nonsense), as well as 16q24.3 microdeletions encompassing part or all of ANKRD11 (and even deletions limited to the non-coding exon 1 / upstream region), reduce functional ANKRD11 dosage. Precise levels of ANKRD11 transcript/protein are essential for normal human development, so reduced dosage is the unifying mechanism shared by sequence-variant and CNV cases.
neuron CL:0000540
regulation of transcription GO:0006355 ↓ DECREASED
Downstream
Disrupted Chromatin-Associated Transcriptional Regulation Reduced ANKRD11 dosage impairs its function as a nuclear chromatin-associated transcriptional regulator.
Impaired Growth Plate Chondrocyte Differentiation ANKRD11 deficiency disrupts the orderly differentiation of growth plate chondrocytes, contributing to postnatal short stature.
Show evidence (2 references)
PMID:29258554 SUPPORT Human Clinical
"The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity."
The foundational Orphanet review states that ANKRD11 loss-of-function variants and 16q24.3 deletions act through haploinsufficiency.
PMID:40004465 SUPPORT Human Clinical
"Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development."
Confirms that both CNV deletions and LoF mutations converge on ANKRD11 haploinsufficiency, and that ANKRD11 dosage is developmentally critical.
Disrupted Chromatin-Associated Transcriptional Regulation
ANKRD11 is a nuclear transcriptional regulator that controls expression of key developmental genes by recruiting chromatin remodelers and interacting with transcriptional repressors and activators, including HDAC-containing and p160 coactivator complexes. Reduced ANKRD11 function therefore impairs chromatin-linked transcriptional regulation, placing KBG syndrome among the "chromatinopathies." Functional studies of truncating variants show escape from nonsense-mediated decay, aberrant nuclear accumulation of truncated protein, and reduced transactivation of target promoters such as CDKN1A/P21, implicating impaired transcriptional regulatory function and, for some alleles, a possible dominant-negative effect.
neuron CL:0000540
chromatin remodeling GO:0006338 ⚠ ABNORMAL chromatin organization GO:0006325 ⚠ ABNORMAL protein deacetylation (HDAC recruitment) GO:0006476 ⚠ ABNORMAL
Downstream
Global Transcriptome Dysregulation Impaired chromatin-linked transcriptional regulation produces broad downstream transcriptional changes across developmental gene programs.
Show evidence (3 references)
PMID:39135054 SUPPORT Human Clinical
"Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators..."
Defines ANKRD11's molecular role as a nuclear transcriptional regulator acting through chromatin remodelers and transcriptional repressors/ activators.
PMID:36440975 SUPPORT Human Clinical
"The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development."
Supports ANKRD11's role as a transcriptional regulator expressed in brain and implicated in neural development, the basis of the neurodevelopmental phenotype.
PMID:38515699 SUPPORT In Vitro
"the truncated protein significantly reduced CDKN1A/P21-promoter luciferase activity in comparison to wild-type ANKRD11 protein, as well as a remarkably decrease in the endogenous CDKN1A/P21 mRNA level in HEK293 cells. These findings suggest a loss of transcriptional activation function and..."
In vitro functional assay demonstrating that a truncating ANKRD11 variant impairs transcriptional activation of CDKN1A/P21, supporting loss of transcriptional regulatory function.
Global Transcriptome Dysregulation
Reduced ANKRD11 dosage produces broad downstream transcriptional changes. Patient-derived cells carrying ANKRD11-involving deletions (including microdeletions limited to the non-coding exon 1 and upstream region) show reduced ANKRD11 transcript levels together with global transcriptome alterations resembling those seen in classic KBG syndrome, linking the primary chromatin-regulatory defect to systems-level developmental dysregulation.
neuron CL:0000540
regulation of transcription GO:0006355 ⚠ ABNORMAL
Downstream
Macrodontia of upper central incisors
Triangular face
Thick eyebrows
Long philtrum
Intellectual disability
Global developmental delay
Delayed speech and language development
Attention deficit hyperactivity disorder
Autistic behavior
Seizures
Hearing impairment
Recurrent otitis media
Feeding difficulties
Cryptorchidism
Congenital heart defect
Strabismus and refractive errors
Palatal anomalies
Brain malformations
Show evidence (1 reference)
PMID:40004465 SUPPORT In Vitro
"Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients."
Shows that reduced ANKRD11 dosage from a non-coding deletion drives global transcriptome alterations resembling KBG syndrome.
Impaired Growth Plate Chondrocyte Differentiation
Postnatal short stature, a hallmark feature, is hypothesized to arise from ANKRD11 deficiency disrupting the orderly differentiation of growth plate chondrocytes and thereby impairing longitudinal endochondral bone growth. This connects the chromatin/transcriptional defect to the skeletal growth phenotype.
growth plate chondrocyte CL:0000138
chondrocyte differentiation GO:0002062 ⚠ ABNORMAL endochondral bone growth GO:0003416 ↓ DECREASED
Downstream
Short stature
Brachydactyly
Clinodactyly of the 5th finger
Scoliosis and costovertebral anomalies
Large anterior fontanelle with delayed closure
Show evidence (1 reference)
PMID:39135054 SUPPORT Human Clinical
"ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes."
Proposes the mechanistic link between ANKRD11 deficiency and short stature via disrupted growth plate chondrocyte differentiation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for KBG Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Cardiovascular 1
Congenital heart defect FREQUENT Abnormal heart morphology HP:0001627
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"congenital heart defects, strabismus / refractive errors, and"
GeneReviews documents congenital heart defects among the manifestations requiring treatment.
Digestive 1
Feeding difficulties FREQUENT Feeding difficulties HP:0011968
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"feeding difficulties (particularly in infancy)"
GeneReviews documents feeding difficulties, particularly in infancy.
Ear 2
Hearing impairment FREQUENT Hearing impairment HP:0000365
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"hearing loss (conductive, mixed, and sensorineural)"
GeneReviews documents conductive, mixed, and sensorineural hearing loss in KBG syndrome.
Recurrent otitis media FREQUENT Recurrent otitis media HP:0000403
Show evidence (1 reference)
PMID:29565525 PARTIAL Human Clinical
"for chronic otitis media"
GeneReviews documents chronic otitis media requiring management in KBG syndrome.
Eye 1
Strabismus and refractive errors FREQUENT Strabismus HP:0000486
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"strabismus / refractive errors"
GeneReviews lists strabismus / refractive errors among the manifestations requiring standard treatment and recommends routine vision monitoring.
Genitourinary 1
Cryptorchidism FREQUENT Cryptorchidism HP:0000028
Show evidence (1 reference)
PMID:29565525 PARTIAL Human Clinical
"standard treatment of seizure disorder, undescended testis in"
GeneReviews documents undescended testis (cryptorchidism) among the manifestations requiring standard treatment in affected males.
Head and Neck 3
Triangular face FREQUENT Triangular face HP:0000325
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip)"
GeneReviews documents triangular face as part of the characteristic KBG facial features.
Long philtrum FREQUENT Long philtrum HP:0000343
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"anteverted nares, long philtrum, and thin vermilion of the upper lip"
GeneReviews lists long philtrum among the characteristic facial features.
Large anterior fontanelle with delayed closure Large fontanelles HP:0000239
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis)"
GeneReviews documents large anterior fontanelle with delayed closure.
Limbs 1
Brachydactyly FREQUENT Brachydactyly HP:0001156
Show evidence (1 reference)
PMID:35861666 SUPPORT Human Clinical
"skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age"
The European cohort documents brachydactyly among the skeletal hand anomalies in KBG syndrome.
Musculoskeletal 1
Scoliosis and costovertebral anomalies OCCASIONAL Scoliosis HP:0002650
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis)"
GeneReviews lists scoliosis among the skeletal anomalies of KBG syndrome.
Nervous System 6
Intellectual disability VERY_FREQUENT Intellectual disability HP:0001249
Show evidence (1 reference)
PMID:35861666 SUPPORT Human Clinical
"Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients."
The European natural history cohort reports ID in 82% of patients, typically mild to moderate, supporting VERY_FREQUENT.
Global developmental delay VERY_FREQUENT Global developmental delay HP:0001263
Show evidence (1 reference)
PMID:36446582 SUPPORT Human Clinical
"Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures."
The 340-patient cohort identifies neurodevelopmental delay as among the most prevalent features.
Delayed speech and language development FREQUENT Delayed speech and language development HP:0000750
Show evidence (1 reference)
PMID:29565525 PARTIAL Human Clinical
"Surgical corrections and/or speech"
GeneReviews documents the need for speech therapy in KBG syndrome management, consistent with frequent speech/language involvement (reported ~72% in the 340-patient cohort).
Attention deficit hyperactivity disorder FREQUENT Attention deficit hyperactivity disorder HP:0007018
Show evidence (1 reference)
PMID:36446582 PARTIAL Human Clinical
"the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants)"
The 340-patient cohort reports ADHD as part of the neurodevelopmental comorbidity profile (cohort ADHD ~63%).
Autistic behavior FREQUENT Autistic behavior HP:0000729
Show evidence (1 reference)
PMID:36446582 PARTIAL Human Clinical
"the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants)"
The 340-patient cohort reports autism spectrum disorder as part of the neurodevelopmental comorbidity profile (cohort ASD ~41.5%).
Seizures OCCASIONAL Seizure HP:0001250
Show evidence (2 references)
PMID:35861666 SUPPORT Human Clinical
"Epilepsy was present in 26.5%."
The European cohort reports epilepsy in 26.5% of patients, consistent with OCCASIONAL.
PMID:38317675 SUPPORT Human Clinical
"This report expands the phenotype of ANKRD11-related KBG syndrome to include epileptic dyskinetic encephalopathy."
Documents the severe end of the KBG epilepsy spectrum (epileptic dyskinetic encephalopathy / Lennox-Gastaut syndrome).
Growth 1
Short stature FREQUENT Short stature HP:0004322
Show evidence (2 references)
PMID:39135054 SUPPORT Human Clinical
"Among the 245 KBGS patients with height data, approximately 50% displayed short stature."
Quantifies short stature in ~50% of KBGS patients with height data, consistent with FREQUENT.
PMID:35861666 SUPPORT Human Clinical
"Short stature was consistent over time"
The European natural history cohort reports short stature is consistent over time, supporting it as a persistent feature.
Other 5
Macrodontia of upper central incisors VERY_FREQUENT Macrodontia HP:0001572
Show evidence (2 references)
PMID:29565525 SUPPORT Human Clinical
"KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors)"
GeneReviews identifies macrodontia of the upper central incisors as a defining feature.
PMID:36446582 PARTIAL Human Clinical
"Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures."
The 340-patient cohort lists macrodontia among the most prevalent features (reported ~79.6% in the cohort), supporting VERY_FREQUENT.
Thick eyebrows VERY_FREQUENT Thick eyebrow HP:0000574
Show evidence (1 reference)
PMID:29258554 SUPPORT Human Clinical
"distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys"
The Orphanet review documents the characteristic craniofacial features including synophrys (fused/bushy eyebrows).
Clinodactyly of the 5th finger FREQUENT Clinodactyly of the 5th finger HP:0004209
Show evidence (1 reference)
PMID:35861666 SUPPORT Human Clinical
"skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age"
The European cohort documents fifth finger clinodactyly among the skeletal hand anomalies.
Palatal anomalies Abnormal palate morphology HP:0000174
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"therapy for palatal anomalies"
GeneReviews management documents surgical correction and/or speech therapy for palatal anomalies.
Brain malformations FREQUENT Abnormal brain morphology HP:0012443
Show evidence (1 reference)
PMID:35861666 SUPPORT Human Clinical
"Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature"
The European cohort reports cerebral anomalies in 56% of patients.
🧬

Genetic Associations

1
ANKRD11 (Causative)
Gene: ANKRD11 hgnc:21316
Autosomal dominant
Show evidence (2 references)
PMID:39135054 SUPPORT Human Clinical
"Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene."
Quantifies the ANKRD11 variant spectrum, showing frameshift and nonsense (truncating) variants predominate.
PMID:36446582 SUPPORT Human Clinical
"Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome"
Confirms that both sequence variants and 16q24.3 CNVs involving ANKRD11 cause KBG syndrome.
💊

Medical Actions

5
Multidisciplinary Supportive Care
Action: supportive care MAXO:0000950
Management is multidisciplinary and symptomatic, addressing developmental/behavioral needs, feeding/nutrition, ENT/hearing, ophthalmology, cardiology, and urology. GeneReviews recommends routine surveillance of hearing, vision, growth, pubertal status, and cognitive development.
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"Routine monitoring of hearing, vision,"
GeneReviews specifies routine multidisciplinary surveillance as the standard of care.
Growth Hormone Therapy
Action: growth hormone therapy Ontology label: hormone modifying therapy MAXO:0000283
Recombinant human growth hormone (rhGH) is considered for short stature. Evidence is limited and non-randomized, but most reported treated children improved height SDS. GeneReviews lists consideration of growth hormone therapy for short stature.
Show evidence (2 references)
PMID:29565525 SUPPORT Human Clinical
"consideration of growth hormone therapy for short stature"
GeneReviews lists growth hormone therapy as a treatment consideration for short stature.
PMID:39135054 SUPPORT Human Clinical
"Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited."
The short-stature review reports a positive rhGH response in most treated patients while noting limited evidence.
Antiseizure Medication
Action: antiseizure pharmacotherapy Ontology label: Pharmacotherapy NCIT:C15986
Agent: anticonvulsant agent NCIT:C264 lacosamide CHEBI:135939
Seizures are managed with individualized antiseizure medication. Responses vary; refractory epilepsy occurs in a subset. Lacosamide has shown benefit for focal seizures in some patients, and vagus nerve stimulation has helped selected severe refractory cases.
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"standard treatment of seizure disorder"
GeneReviews recommends standard treatment of the seizure disorder in KBG syndrome.
Avoid Ototoxic Drugs
Action: supportive care MAXO:0000950
Ototoxic drugs should be avoided in KBG syndrome because of the risk for hearing loss (GeneReviews "Agents/Circumstances to Avoid").
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"Ototoxic drugs should be avoided because of the risk for hearing loss."
GeneReviews drug-safety warning: ototoxic drugs should be avoided given the risk for hearing loss.
ENT Surgical Management for Chronic Otitis Media
Action: surgical procedure MAXO:0000004
Pressure-equalizing tubes and/or tonsillectomy/adenoidectomy are used for chronic otitis media.
Show evidence (1 reference)
PMID:29565525 SUPPORT Human Clinical
"tubes and/or tonsillectomy/adenoidectomy for chronic otitis media"
GeneReviews documents ENT surgical interventions for chronic otitis media.
🔬

Clinical Trials

1
NCT06465641 NOT_APPLICABLE RECRUITING
Methylphenidate in KBG Syndrome: N-of-1 Series (Radboud University Medical Center). A randomized, quadruple-masked crossover N-of-1 series evaluating methylphenidate for ADHD-like symptoms in molecularly confirmed KBG syndrome, with the SDQ ADHD subscale as the primary endpoint.
Target Phenotypes: Attention deficit hyperactivity disorder HP:0007018
Show evidence (1 reference)
clinicaltrials:NCT06465641 SUPPORT Human Clinical
"What is the effectiveness of methylphenidate on attention deficit and ADHD-related symptoms in children and adolescents with KBG syndrome?"
ClinicalTrials.gov registration confirms an interventional N-of-1 series evaluating methylphenidate for ADHD-related symptoms in KBG syndrome.
{ }

Source YAML

click to show 
name: KBG Syndrome
creation_date: "2026-06-04T12:00:00Z"
category: Mendelian
description: >-
  KBG syndrome (MONDO:0007846, OMIM #148050) is a rare autosomal dominant
  multisystem neurodevelopmental disorder caused by haploinsufficiency of
  ANKRD11, a chromatin-associated transcriptional regulator at 16q24.3. It is
  classically characterized by macrodontia of the upper central incisors, a
  distinctive facial gestalt (triangular face, thick/bushy eyebrows, prominent
  ears, long philtrum), postnatal short stature, skeletal (notably
  costovertebral and hand) anomalies, and developmental delay / intellectual
  disability with frequent behavioral comorbidity. Disease results from either
  heterozygous loss-of-function ANKRD11 sequence variants (most often frameshift
  or nonsense) or 16q24.3 copy-number deletions involving ANKRD11. The disorder
  is increasingly classified among the chromatinopathies and has a recognizable
  blood DNA methylation signature.
disease_term:
  preferred_term: KBG Syndrome
  term:
    id: MONDO:0007846
    label: KBG syndrome

parents:
  - autosomal dominant syndromic intellectual disability
  - multiple congenital anomalies/dysmorphic syndrome-intellectual disability
  - chromatinopathy

references:
  - reference: PMID:29565525
    title: "KBG Syndrome."
    tags:
      - GeneReviews
  - reference: PMID:29258554
    title: "KBG syndrome."
  - reference: PMID:36446582
    title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."

pathophysiology:
  - name: ANKRD11 Haploinsufficiency
    description: >
      KBG syndrome results predominantly from haploinsufficiency of ANKRD11
      (ankyrin repeat domain-containing protein 11) at 16q24.3. Heterozygous
      loss-of-function sequence variants (most frequently frameshift and
      nonsense), as well as 16q24.3 microdeletions encompassing part or all of
      ANKRD11 (and even deletions limited to the non-coding exon 1 / upstream
      region), reduce functional ANKRD11 dosage. Precise levels of ANKRD11
      transcript/protein are essential for normal human development, so reduced
      dosage is the unifying mechanism shared by sequence-variant and CNV cases.
    downstream:
      - target: Disrupted Chromatin-Associated Transcriptional Regulation
        description: >
          Reduced ANKRD11 dosage impairs its function as a nuclear
          chromatin-associated transcriptional regulator.
      - target: Impaired Growth Plate Chondrocyte Differentiation
        description: >
          ANKRD11 deficiency disrupts the orderly differentiation of growth
          plate chondrocytes, contributing to postnatal short stature.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: regulation of transcription
        term:
          id: GO:0006355
          label: regulation of DNA-templated transcription
        modifier: DECREASED
    evidence:
      - reference: PMID:29258554
        reference_title: "KBG syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The vast majority of identified variants are loss of function, which include nonsense and frameshift variants and larger deletions at 16q24.3. Haploinsufficiency appears to be the mechanism of pathogenicity."
        explanation: >
          The foundational Orphanet review states that ANKRD11 loss-of-function
          variants and 16q24.3 deletions act through haploinsufficiency.
      - reference: PMID:40004465
        reference_title: "16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development."
        explanation: >
          Confirms that both CNV deletions and LoF mutations converge on ANKRD11
          haploinsufficiency, and that ANKRD11 dosage is developmentally critical.

  - name: Disrupted Chromatin-Associated Transcriptional Regulation
    description: >
      ANKRD11 is a nuclear transcriptional regulator that controls expression of
      key developmental genes by recruiting chromatin remodelers and interacting
      with transcriptional repressors and activators, including HDAC-containing
      and p160 coactivator complexes. Reduced ANKRD11 function therefore impairs
      chromatin-linked transcriptional regulation, placing KBG syndrome among the
      "chromatinopathies." Functional studies of truncating variants show escape
      from nonsense-mediated decay, aberrant nuclear accumulation of truncated
      protein, and reduced transactivation of target promoters such as
      CDKN1A/P21, implicating impaired transcriptional regulatory function and,
      for some alleles, a possible dominant-negative effect.
    downstream:
      - target: Global Transcriptome Dysregulation
        description: >
          Impaired chromatin-linked transcriptional regulation produces broad
          downstream transcriptional changes across developmental gene programs.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: chromatin remodeling
        term:
          id: GO:0006338
          label: chromatin remodeling
        modifier: ABNORMAL
      - preferred_term: chromatin organization
        term:
          id: GO:0006325
          label: chromatin organization
        modifier: ABNORMAL
      - preferred_term: protein deacetylation (HDAC recruitment)
        term:
          id: GO:0006476
          label: protein deacetylation
        modifier: ABNORMAL
    evidence:
      - reference: PMID:39135054
        reference_title: "Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ankyrin repeat domain containing-protein 11 (ANKRD11), a transcriptional factor predominantly localized in the cell nucleus, plays a crucial role in the expression regulation of key genes by recruiting chromatin remodelers and interacting with specific transcriptional repressors or activators during numerous biological processes."
        explanation: >
          Defines ANKRD11's molecular role as a nuclear transcriptional regulator
          acting through chromatin remodelers and transcriptional repressors/
          activators.
      - reference: PMID:36440975
        reference_title: "ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "The ANKRD11 gene encodes the ankyrin repeat-containing protein 11A transcriptional regulator, which is expressed in the brain and implicated in neural development."
        explanation: >
          Supports ANKRD11's role as a transcriptional regulator expressed in
          brain and implicated in neural development, the basis of the
          neurodevelopmental phenotype.
      - reference: PMID:38515699
        reference_title: "Functional investigation of a novel ANKRD11 frameshift variant identified in a Chinese family with KBG syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "the truncated protein significantly reduced CDKN1A/P21-promoter luciferase activity in comparison to wild-type ANKRD11 protein, as well as a remarkably decrease in the endogenous CDKN1A/P21 mRNA level in HEK293 cells. These findings suggest a loss of transcriptional activation function and potentially a dominant-negative mechanism."
        explanation: >
          In vitro functional assay demonstrating that a truncating ANKRD11
          variant impairs transcriptional activation of CDKN1A/P21, supporting
          loss of transcriptional regulatory function.

  - name: Global Transcriptome Dysregulation
    description: >
      Reduced ANKRD11 dosage produces broad downstream transcriptional changes.
      Patient-derived cells carrying ANKRD11-involving deletions (including
      microdeletions limited to the non-coding exon 1 and upstream region) show
      reduced ANKRD11 transcript levels together with global transcriptome
      alterations resembling those seen in classic KBG syndrome, linking the
      primary chromatin-regulatory defect to systems-level developmental
      dysregulation.
    cell_types:
      - preferred_term: neuron
        term:
          id: CL:0000540
          label: neuron
    biological_processes:
      - preferred_term: regulation of transcription
        term:
          id: GO:0006355
          label: regulation of DNA-templated transcription
        modifier: ABNORMAL
    evidence:
      - reference: PMID:40004465
        reference_title: "16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients."
        explanation: >
          Shows that reduced ANKRD11 dosage from a non-coding deletion drives
          global transcriptome alterations resembling KBG syndrome.
    downstream:
      - target: Macrodontia of upper central incisors
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Triangular face
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Thick eyebrows
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Long philtrum
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Intellectual disability
        causal_link_type: DIRECT
      - target: Global developmental delay
        causal_link_type: DIRECT
      - target: Delayed speech and language development
        causal_link_type: DIRECT
      - target: Attention deficit hyperactivity disorder
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Autistic behavior
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Seizures
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Hearing impairment
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Recurrent otitis media
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Feeding difficulties
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Cryptorchidism
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Congenital heart defect
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Strabismus and refractive errors
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Palatal anomalies
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Brain malformations
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

  - name: Impaired Growth Plate Chondrocyte Differentiation
    description: >
      Postnatal short stature, a hallmark feature, is hypothesized to arise from
      ANKRD11 deficiency disrupting the orderly differentiation of growth plate
      chondrocytes and thereby impairing longitudinal endochondral bone growth.
      This connects the chromatin/transcriptional defect to the skeletal growth
      phenotype.
    cell_types:
      - preferred_term: growth plate chondrocyte
        term:
          id: CL:0000138
          label: chondrocyte
    biological_processes:
      - preferred_term: chondrocyte differentiation
        term:
          id: GO:0002062
          label: chondrocyte differentiation
        modifier: ABNORMAL
      - preferred_term: endochondral bone growth
        term:
          id: GO:0003416
          label: endochondral bone growth
        modifier: DECREASED
    evidence:
      - reference: PMID:39135054
        reference_title: "Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "ANKRD11 deficiency potentially disrupts longitudinal bone growth by affecting the orderly differentiation of growth plate chondrocytes."
        explanation: >
          Proposes the mechanistic link between ANKRD11 deficiency and short
          stature via disrupted growth plate chondrocyte differentiation.
    downstream:
      - target: Short stature
        causal_link_type: DIRECT
      - target: Brachydactyly
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Clinodactyly of the 5th finger
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Scoliosis and costovertebral anomalies
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
      - target: Large anterior fontanelle with delayed closure
        causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES

genetic:
  - name: ANKRD11
    gene_term:
      preferred_term: ANKRD11
      term:
        id: hgnc:21316
        label: ANKRD11
    association: Causative
    presence: Positive
    notes: >
      ANKRD11 (16q24.3) is the single causal gene for KBG syndrome. Disease is
      caused by heterozygous loss-of-function sequence variants (frameshift and
      nonsense predominate; splice-site and missense also occur) and by 16q24.3
      copy-number deletions involving ANKRD11. In a ClinVar/literature synthesis,
      frameshift and nonsense were the most frequent of 583 pathogenic/likely
      pathogenic ANKRD11 variants. Inheritance is autosomal dominant; a large
      fraction of cases are de novo.
    inheritance:
      - name: Autosomal dominant
        inheritance_term:
          preferred_term: Autosomal dominant inheritance
          term:
            id: HP:0000006
            label: Autosomal dominant inheritance
        evidence:
          - reference: PMID:29258554
            reference_title: "KBG syndrome."
            supports: SUPPORT
            evidence_source: HUMAN_CLINICAL
            snippet: "Familial and de novo cases have been reported. Causative de novo variants occur approximately one third of the time. Transmission follows an autosomal dominant pattern."
            explanation: >
              Establishes autosomal dominant inheritance with a substantial de
              novo fraction.
    evidence:
      - reference: PMID:39135054
        reference_title: "Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Our investigation indicated that frameshift and nonsense were the most frequent types in 583 pathogenic or likely pathogenic variants identified in the ANKRD11 gene."
        explanation: >
          Quantifies the ANKRD11 variant spectrum, showing frameshift and
          nonsense (truncating) variants predominate.
      - reference: PMID:36446582
        reference_title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Both loss-of-function sequence variants and large deletions (copy number variations, CNVs) involving ANKRD11 cause KBG syndrome"
        explanation: >
          Confirms that both sequence variants and 16q24.3 CNVs involving ANKRD11
          cause KBG syndrome.

phenotypes:
  - category: Physical
    name: Macrodontia of upper central incisors
    description: >
      Macrodontia, especially of the upper (maxillary) permanent central
      incisors, is the most distinctive and characteristic feature of KBG
      syndrome.
    phenotype_term:
      preferred_term: Macrodontia of upper central incisors
      term:
        id: HP:0001572
        label: Macrodontia
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "KBG syndrome is typically characterized by macrodontia (especially of the upper central incisors)"
        explanation: >
          GeneReviews identifies macrodontia of the upper central incisors as a
          defining feature.
      - reference: PMID:36446582
        reference_title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures."
        explanation: >
          The 340-patient cohort lists macrodontia among the most prevalent
          features (reported ~79.6% in the cohort), supporting VERY_FREQUENT.

  - category: Physical
    name: Triangular face
    description: >
      A triangular facial shape is part of the characteristic KBG facial gestalt,
      together with broad/bushy eyebrows, prominent ears, prominent nasal bridge,
      and long philtrum.
    phenotype_term:
      preferred_term: Triangular face
      term:
        id: HP:0000325
        label: Triangular face
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "characteristic facial features (triangular face, brachycephaly, synophrys, widely spaced eyes, broad or bushy eyebrows, prominent ears, prominent nasal bridge, bulbous nose, anteverted nares, long philtrum, and thin vermilion of the upper lip)"
        explanation: >
          GeneReviews documents triangular face as part of the characteristic KBG
          facial features.

  - category: Physical
    name: Thick eyebrows
    description: >
      Broad or bushy (thick) eyebrows, sometimes with synophrys, are a frequent
      component of the KBG facial gestalt.
    phenotype_term:
      preferred_term: Thick / bushy eyebrows
      term:
        id: HP:0000574
        label: Thick eyebrow
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:29258554
        reference_title: "KBG syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "distinctive craniofacial features such as triangular face, prominent nasal bridge, thin upper lip and synophrys"
        explanation: >
          The Orphanet review documents the characteristic craniofacial features
          including synophrys (fused/bushy eyebrows).

  - category: Physical
    name: Long philtrum
    description: >
      A long philtrum is a recurrent dysmorphic facial feature in KBG syndrome.
    phenotype_term:
      preferred_term: Long philtrum
      term:
        id: HP:0000343
        label: Long philtrum
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "anteverted nares, long philtrum, and thin vermilion of the upper lip"
        explanation: >
          GeneReviews lists long philtrum among the characteristic facial
          features.

  - category: Physical
    name: Short stature
    description: >
      Postnatal short stature is a hallmark feature, present in roughly half of
      patients, and tends to be consistent over time. It is thought to relate to
      ANKRD11-mediated disruption of growth plate chondrocyte differentiation.
    phenotype_term:
      preferred_term: Short stature
      term:
        id: HP:0004322
        label: Short stature
    frequency: FREQUENT
    evidence:
      - reference: PMID:39135054
        reference_title: "Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Among the 245 KBGS patients with height data, approximately 50% displayed short stature."
        explanation: >
          Quantifies short stature in ~50% of KBGS patients with height data,
          consistent with FREQUENT.
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Short stature was consistent over time"
        explanation: >
          The European natural history cohort reports short stature is consistent
          over time, supporting it as a persistent feature.

  - category: Skeletal
    name: Brachydactyly
    description: >
      Hand anomalies including brachydactyly are common skeletal manifestations.
    phenotype_term:
      preferred_term: Brachydactyly
      term:
        id: HP:0001156
        label: Brachydactyly
    frequency: FREQUENT
    evidence:
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age"
        explanation: >
          The European cohort documents brachydactyly among the skeletal hand
          anomalies in KBG syndrome.

  - category: Skeletal
    name: Clinodactyly of the 5th finger
    description: >
      Fifth-finger clinodactyly is among the recurrent hand/skeletal anomalies.
    phenotype_term:
      preferred_term: Fifth finger clinodactyly
      term:
        id: HP:0004209
        label: Clinodactyly of the 5th finger
    frequency: FREQUENT
    evidence:
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "skeletal anomalies, such as brachydactyly, short fifth finger, fifth finger clinodactyly, pectus excavatum/carinatum, delayed bone age"
        explanation: >
          The European cohort documents fifth finger clinodactyly among the
          skeletal hand anomalies.

  - category: Skeletal
    name: Scoliosis and costovertebral anomalies
    description: >
      Skeletal anomalies in KBG syndrome include costovertebral (rib/vertebral)
      anomalies and scoliosis, alongside delayed bone age.
    phenotype_term:
      preferred_term: Scoliosis
      term:
        id: HP:0002650
        label: Scoliosis
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis)"
        explanation: >
          GeneReviews lists scoliosis among the skeletal anomalies of KBG
          syndrome.

  - category: Skeletal
    name: Large anterior fontanelle with delayed closure
    description: >
      A large anterior fontanelle with delayed closure is a recurrent cranial
      skeletal finding.
    phenotype_term:
      preferred_term: Large anterior fontanelle with delayed closure
      term:
        id: HP:0000239
        label: Large fontanelles
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "skeletal anomalies (brachydactyly, large anterior fontanelle with delayed closure, scoliosis)"
        explanation: >
          GeneReviews documents large anterior fontanelle with delayed closure.

  - category: Neurological
    name: Intellectual disability
    description: >
      Intellectual disability is a core neurodevelopmental feature, generally
      mild to moderate, though severe cases occur. It is reported in the large
      majority of patients.
    phenotype_term:
      preferred_term: Intellectual disability
      term:
        id: HP:0001249
        label: Intellectual disability
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Intellectual disability (ID) (82%) ranged from mild to moderate with severe ID identified in two patients."
        explanation: >
          The European natural history cohort reports ID in 82% of patients,
          typically mild to moderate, supporting VERY_FREQUENT.

  - category: Neurological
    name: Global developmental delay
    description: >
      Early developmental delay is a near-universal presenting feature and forms
      part of the proposed diagnostic framework for KBG syndrome.
    phenotype_term:
      preferred_term: Global developmental delay
      term:
        id: HP:0001263
        label: Global developmental delay
    frequency: VERY_FREQUENT
    evidence:
      - reference: PMID:36446582
        reference_title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Neurodevelopmental delay, macrodontia, triangular face, characteristic ears, nose and eyebrows were the most prevalentf (eatures."
        explanation: >
          The 340-patient cohort identifies neurodevelopmental delay as among the
          most prevalent features.

  - category: Neurological
    name: Delayed speech and language development
    description: >
      Language/speech delay is a common neurodevelopmental manifestation.
    phenotype_term:
      preferred_term: Language delay
      term:
        id: HP:0000750
        label: Delayed speech and language development
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "Surgical corrections and/or speech"
        explanation: >
          GeneReviews documents the need for speech therapy in KBG syndrome
          management, consistent with frequent speech/language involvement
          (reported ~72% in the 340-patient cohort).

  - category: Behavioral
    name: Attention deficit hyperactivity disorder
    description: >
      ADHD diagnosis or symptoms are common behavioral comorbidities, reported in
      a majority of patients in large cohorts and targeted by ongoing
      methylphenidate trials.
    phenotype_term:
      preferred_term: Attention deficit hyperactivity disorder
      term:
        id: HP:0007018
        label: Attention deficit hyperactivity disorder
    frequency: FREQUENT
    evidence:
      - reference: PMID:36446582
        reference_title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants)"
        explanation: >
          The 340-patient cohort reports ADHD as part of the neurodevelopmental
          comorbidity profile (cohort ADHD ~63%).

  - category: Behavioral
    name: Autistic behavior
    description: >
      Autism spectrum disorder features are a recognized behavioral comorbidity.
    phenotype_term:
      preferred_term: Autism spectrum disorder features
      term:
        id: HP:0000729
        label: Autistic behavior
    frequency: FREQUENT
    evidence:
      - reference: PMID:36446582
        reference_title: "Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "the prevalence of intellectual disability/attention deficit hyperactivity disorder/autism spectrum disorder was lower in patients with the c.1903_1907del variant (70.4% vs 89.4% other variants)"
        explanation: >
          The 340-patient cohort reports autism spectrum disorder as part of the
          neurodevelopmental comorbidity profile (cohort ASD ~41.5%).

  - category: Neurological
    name: Seizures
    description: >
      Epilepsy/seizures occur in roughly a quarter to a third of patients and are
      heterogeneous in semiology, ranging from focal and generalized seizures to,
      rarely, severe drug-resistant epileptic (and even dyskinetic)
      encephalopathy. Presence of epilepsy is associated with poorer
      developmental outcome.
    phenotype_term:
      preferred_term: Seizures
      term:
        id: HP:0001250
        label: Seizure
    frequency: OCCASIONAL
    evidence:
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Epilepsy was present in 26.5%."
        explanation: >
          The European cohort reports epilepsy in 26.5% of patients, consistent
          with OCCASIONAL.
      - reference: PMID:38317675
        reference_title: "Epileptic dyskinetic encephalopathy in KBG syndrome: Expansion of the phenotype."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "This report expands the phenotype of ANKRD11-related KBG syndrome to include epileptic dyskinetic encephalopathy."
        explanation: >
          Documents the severe end of the KBG epilepsy spectrum (epileptic
          dyskinetic encephalopathy / Lennox-Gastaut syndrome).

  - category: Physical
    name: Hearing impairment
    description: >
      Hearing loss (conductive, mixed, or sensorineural) and recurrent otitis
      media are frequent, clinically actionable comorbidities. Ototoxic drugs
      should be avoided given the risk for hearing loss.
    phenotype_term:
      preferred_term: Hearing loss
      term:
        id: HP:0000365
        label: Hearing impairment
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "hearing loss (conductive, mixed, and sensorineural)"
        explanation: >
          GeneReviews documents conductive, mixed, and sensorineural hearing loss
          in KBG syndrome.

  - category: Physical
    name: Recurrent otitis media
    description: >
      Recurrent/chronic otitis media is a common ENT comorbidity contributing to
      conductive hearing loss.
    phenotype_term:
      preferred_term: Chronic otitis media
      term:
        id: HP:0000403
        label: Recurrent otitis media
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "for chronic otitis media"
        explanation: >
          GeneReviews documents chronic otitis media requiring management in KBG
          syndrome.

  - category: Physical
    name: Feeding difficulties
    description: >
      Feeding difficulties, particularly in infancy, are common and may require
      nasogastric tube feeding.
    phenotype_term:
      preferred_term: Feeding difficulties
      term:
        id: HP:0011968
        label: Feeding difficulties
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "feeding difficulties (particularly in infancy)"
        explanation: >
          GeneReviews documents feeding difficulties, particularly in infancy.

  - category: Physical
    name: Cryptorchidism
    description: >
      Undescended testis (cryptorchidism) is a frequent finding in affected
      males.
    phenotype_term:
      preferred_term: Cryptorchidism
      term:
        id: HP:0000028
        label: Cryptorchidism
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: PARTIAL
        evidence_source: HUMAN_CLINICAL
        snippet: "standard treatment of seizure disorder, undescended testis in"
        explanation: >
          GeneReviews documents undescended testis (cryptorchidism) among the
          manifestations requiring standard treatment in affected males.

  - category: Physical
    name: Congenital heart defect
    description: >
      Congenital heart defects are a recognized, clinically actionable
      comorbidity, reported in roughly a third of patients.
    phenotype_term:
      preferred_term: Congenital heart defect
      term:
        id: HP:0001627
        label: Abnormal heart morphology
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "congenital heart defects, strabismus / refractive errors, and"
        explanation: >
          GeneReviews documents congenital heart defects among the manifestations
          requiring treatment.

  - category: Physical
    name: Strabismus and refractive errors
    description: >
      Ophthalmologic involvement, including strabismus and refractive errors, is
      a clinically actionable feature requiring standard ophthalmologic treatment
      and routine vision monitoring per GeneReviews management recommendations.
    phenotype_term:
      preferred_term: Strabismus / refractive errors
      term:
        id: HP:0000486
        label: Strabismus
    frequency: FREQUENT
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "strabismus / refractive errors"
        explanation: >
          GeneReviews lists strabismus / refractive errors among the
          manifestations requiring standard treatment and recommends routine
          vision monitoring.

  - category: Physical
    name: Palatal anomalies
    description: >
      Palatal anomalies are a clinically actionable orofacial feature in KBG
      syndrome; GeneReviews management includes surgical correction and/or speech
      therapy for palatal anomalies.
    phenotype_term:
      preferred_term: Palatal anomalies
      term:
        id: HP:0000174
        label: Abnormal palate morphology
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "therapy for palatal anomalies"
        explanation: >
          GeneReviews management documents surgical correction and/or speech
          therapy for palatal anomalies.

  - category: Neurological
    name: Brain malformations
    description: >
      Structural brain (cerebral) anomalies are reported in a substantial
      proportion of patients and represent an important supportive diagnostic
      feature in the pediatric age.
    phenotype_term:
      preferred_term: Cerebral anomalies
      term:
        id: HP:0012443
        label: Abnormal brain morphology
    frequency: FREQUENT
    evidence:
      - reference: PMID:35861666
        reference_title: "Natural history of KBG syndrome in a large European cohort."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Cerebral anomalies, were identified in 56% of patients and thus represented the second most relevant clinical feature"
        explanation: >
          The European cohort reports cerebral anomalies in 56% of patients.

treatments:
  - name: Multidisciplinary Supportive Care
    description: >
      Management is multidisciplinary and symptomatic, addressing
      developmental/behavioral needs, feeding/nutrition, ENT/hearing,
      ophthalmology, cardiology, and urology. GeneReviews recommends routine
      surveillance of hearing, vision, growth, pubertal status, and cognitive
      development.
    treatment_term:
      preferred_term: supportive care
      term:
        id: MAXO:0000950
        label: supportive care
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Routine monitoring of hearing, vision,"
        explanation: >
          GeneReviews specifies routine multidisciplinary surveillance as the
          standard of care.

  - name: Growth Hormone Therapy
    description: >
      Recombinant human growth hormone (rhGH) is considered for short stature.
      Evidence is limited and non-randomized, but most reported treated children
      improved height SDS. GeneReviews lists consideration of growth hormone
      therapy for short stature.
    therapeutic_modality: PROTEIN_REPLACEMENT
    treatment_term:
      preferred_term: growth hormone therapy
      term:
        id: MAXO:0000283
        label: hormone modifying therapy
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "consideration of growth hormone therapy for short stature"
        explanation: >
          GeneReviews lists growth hormone therapy as a treatment consideration
          for short stature.
      - reference: PMID:39135054
        reference_title: "Insights into the ANKRD11 variants and short-stature phenotype through literature review and ClinVar database search."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Most patients showed a positive response to rhGH therapy, although the number of patients receiving treatment was limited."
        explanation: >
          The short-stature review reports a positive rhGH response in most
          treated patients while noting limited evidence.

  - name: Antiseizure Medication
    description: >
      Seizures are managed with individualized antiseizure medication. Responses
      vary; refractory epilepsy occurs in a subset. Lacosamide has shown benefit
      for focal seizures in some patients, and vagus nerve stimulation has helped
      selected severe refractory cases.
    treatment_term:
      preferred_term: antiseizure pharmacotherapy
      term:
        id: NCIT:C15986
        label: Pharmacotherapy
      therapeutic_agent:
        - preferred_term: anticonvulsant agent
          term:
            id: NCIT:C264
            label: Anticonvulsant Agent
        - preferred_term: lacosamide
          term:
            id: CHEBI:135939
            label: lacosamide
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "standard treatment of seizure disorder"
        explanation: >
          GeneReviews recommends standard treatment of the seizure disorder in
          KBG syndrome.

  - name: Avoid Ototoxic Drugs
    description: >
      Ototoxic drugs should be avoided in KBG syndrome because of the risk for
      hearing loss (GeneReviews "Agents/Circumstances to Avoid").
    treatment_term:
      preferred_term: supportive care
      term:
        id: MAXO:0000950
        label: supportive care
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "Ototoxic drugs should be avoided because of the risk for hearing loss."
        explanation: >
          GeneReviews drug-safety warning: ototoxic drugs should be avoided given
          the risk for hearing loss.

  - name: ENT Surgical Management for Chronic Otitis Media
    description: >
      Pressure-equalizing tubes and/or tonsillectomy/adenoidectomy are used for
      chronic otitis media.
    treatment_term:
      preferred_term: surgical procedure
      term:
        id: MAXO:0000004
        label: surgical procedure
    evidence:
      - reference: PMID:29565525
        reference_title: "KBG Syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "tubes and/or tonsillectomy/adenoidectomy for chronic otitis media"
        explanation: >
          GeneReviews documents ENT surgical interventions for chronic otitis
          media.

clinical_trials:
  - name: NCT06465641
    phase: NOT_APPLICABLE
    status: RECRUITING
    description: >
      Methylphenidate in KBG Syndrome: N-of-1 Series (Radboud University Medical
      Center). A randomized, quadruple-masked crossover N-of-1 series evaluating
      methylphenidate for ADHD-like symptoms in molecularly confirmed KBG
      syndrome, with the SDQ ADHD subscale as the primary endpoint.
    target_phenotypes:
      - preferred_term: Attention deficit hyperactivity disorder
        term:
          id: HP:0007018
          label: Attention deficit hyperactivity disorder
    evidence:
      - reference: clinicaltrials:NCT06465641
        reference_title: "Effectiveness of Methylphenidate in Children and Adolescents With KBG Syndrome: An N-of-1 Series"
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "What is the effectiveness of methylphenidate on attention deficit and ADHD-related symptoms in children and adolescents with KBG syndrome?"
        explanation: >
          ClinicalTrials.gov registration confirms an interventional N-of-1
          series evaluating methylphenidate for ADHD-related symptoms in KBG
          syndrome.

diagnosis:
  - name: ANKRD11 DNA methylation episignature
    description: >
      KBG syndrome has a recognizable blood DNA methylation (DNAm) episignature.
      A 95-CpG signature distinguishes individuals with pathogenic ANKRD11
      variants from controls, is shared by 16q24.3 microdeletion cases, and can
      be applied via a machine-learning classifier to reclassify variants of
      uncertain significance, providing a functional diagnostic biomarker.
    diagnosis_term:
      preferred_term: DNA methylation episignature analysis
      term:
        id: MAXO:0000003
        label: diagnostic procedure
    evidence:
      - reference: PMID:36440975
        reference_title: "ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "We identified 95"
        explanation: >
          Awamleh et al. identified a 95-CpG DNAm signature distinguishing KBG
          syndrome individuals with pathogenic ANKRD11 variants from typically
          developing controls.
      - reference: PMID:36440975
        reference_title: "ANKRD11 pathogenic variants and 16q24.3 microdeletions share an altered DNA methylation signature in patients with KBG syndrome."
        supports: SUPPORT
        evidence_source: HUMAN_CLINICAL
        snippet: "diagnostic utility of the new KBGS signature by classifying the DNAm profiles of"
        explanation: >
          The study demonstrates the diagnostic utility of the KBG syndrome DNAm
          signature for classifying methylation profiles, including VUS
          reclassification.

datasets: []
📚

References & Deep Research

References

3
PMID:29565525
KBG Syndrome.
No top-level findings curated for this source.
PMID:29258554
KBG syndrome.
No top-level findings curated for this source.
PMID:36446582
Clinical description, molecular delineation and genotype-phenotype correlation in 340 patients with KBG syndrome: addition of 67 new patients.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
KBG Syndrome (ANKRD11-related): Disease Characteristics Research Report
Edison Scientific Literature 44 citations 2026-06-04T15:38:08.160574

KBG Syndrome (ANKRD11-related): Disease Characteristics Research Report

Target disease

  • Disease name: KBG syndrome
  • Category: Mendelian (monogenic, autosomal dominant)
  • Primary gene: ANKRD11 (chromosome 16q24.3)
  • MONDO ID: Not located in the retrieved sources in this run (not asserted).

Evidence summary table

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. (loberti2022naturalhistoryof pages 1-2, swols2017kbgsyndrome pages 1-2) OMIM 148050; >100 patients reported by 2017 review; 49-patient European natural history cohort. (loberti2022naturalhistoryof pages 1-2, swols2017kbgsyndrome pages 1-2) 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. (swols2017kbgsyndrome pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 21-23) ~1/3 de novo in 2017 review; 86% de novo in 2023 cohort subset. (swols2017kbgsyndrome pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 21-23) 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. (he2024insightsintothe pages 1-2, wei2024functionalinvestigationof pages 6-9, bestetti2022expandingthemolecular pages 10-11, iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7) 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. (he2024insightsintothe pages 1-2, wei2024functionalinvestigationof pages 6-9) 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. (gao2022geneticandphenotypic pages 9-11, bestetti2022expandingthemolecular pages 10-11, iwataotsubo202516q24.3microdeletionsdisrupting pages 7-9) Molecular diagnosis in 22/33 (67%) clinically suspected cases using multi-test strategy in one study; 16q24.3 microdeletion review summarized 68 cases. (bestetti2022expandingthemolecular pages 10-11, li2026clinicalfeaturesand pages 1-2) 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. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23, martinezcayuelas2023clinicaldescriptionmolecular pages 5-7) Low et al. criteria reportedly met by 70% of patients in the 2023 analysis. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23) 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. (martinezcayuelas2023clinicaldescriptionmolecular pages 1-5, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2) 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). (martinezcayuelas2023clinicaldescriptionmolecular pages 1-5, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14) 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. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23, martinezcayuelas2023clinicaldescriptionmolecular pages 18-21, donnellan2024epilepticdyskineticencephalopathy pages 1-2) 2023 cohort: ID 82.1%, language delay 72%, ADHD 63.3%, ASD 41.5%. European cohort: ID 82%. (martinezcayuelas2023clinicaldescriptionmolecular pages 10-12, loberti2022naturalhistoryof pages 1-2) 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. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2) 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%. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2) 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. (donnellan2024epilepticdyskineticencephalopathy pages 1-2, donnellan2024epilepticdyskineticencephalopathy pages 2-4, liu2026heterogeneityofepileptic pages 1-3) 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%. (loberti2022naturalhistoryof pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, donnellan2024epilepticdyskineticencephalopathy pages 1-2, liu2026heterogeneityofepileptic pages 1-3, liu2026heterogeneityofepileptic pages 6-7) 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. (donnellan2024epilepticdyskineticencephalopathy pages 2-4, liu2026heterogeneityofepileptic pages 3-4, liu2026heterogeneityofepileptic pages 6-7) 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%. (liu2026heterogeneityofepileptic pages 3-4, liu2026heterogeneityofepileptic pages 6-7) 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. (he2024insightsintothe pages 1-2, he2024insightsintothe pages 10-11, he2024insightsintothe pages 3-6) 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. (he2024insightsintothe pages 3-6, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2) 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. (he2024insightsintothe pages 6-8, he2024insightsintothe pages 8-10, li2026clinicalfeaturesand pages 1-2) 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. (he2024insightsintothe pages 6-8, he2024insightsintothe pages 8-10, li2026clinicalfeaturesand pages 2-3, li2026clinicalfeaturesand pages 1-2) 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. (awamleh2023ankrd11pathogenicvariants pages 1-2, awamleh2023ankrd11pathogenicvariants pages 2-2, awamleh2023ankrd11pathogenicvariants pages 4-5) 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. (awamleh2023ankrd11pathogenicvariants pages 1-2, awamleh2023ankrd11pathogenicvariants pages 2-2, awamleh2023ankrd11pathogenicvariants pages 4-5, awamleh2023ankrd11pathogenicvariants media 9f6c7c1b) 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. (loberti2022naturalhistoryof pages 1-2, swols2017kbgsyndrome pages 6-7, donnellan2024epilepticdyskineticencephalopathy pages 1-2) 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. (loberti2022naturalhistoryof pages 1-2, swols2017kbgsyndrome pages 6-7) 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.

1. Disease information

1.1 Concise overview (current understanding)

KBG syndrome is a rare, multisystem neurodevelopmental disorder classically characterized by macrodontia of the upper permanent incisors, characteristic facial gestalt, postnatal short stature, skeletal anomalies, and developmental delay/intellectual disability with frequent behavioral comorbidity. It is most often caused by heterozygous loss-of-function (LoF) variants in ANKRD11 or by copy-number variants (CNVs)/microdeletions at 16q24.3 involving ANKRD11, with ANKRD11 dosage sensitivity as the predominant mechanism. (swols2017kbgsyndrome pages 1-2, loberti2022naturalhistoryof pages 1-2)

A large 2023 international/literature-integrated analysis emphasized high phenotypic variability and reported high prevalence of neurodevelopmental involvement (ID/ADHD/ASD features) alongside dysmorphology and frequent medical comorbidities (hearing/otitis, cardiac defects, seizures, feeding problems, vision issues, cryptorchidism). (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, martinezcayuelas2023clinicaldescriptionmolecular pages 21-23)

1.2 Key identifiers

  • OMIM: KBG syndrome, MIM #148050. (loberti2022naturalhistoryof pages 1-2)
  • Orphanet / ICD-10 / ICD-11 / MeSH / MONDO: Not present in the retrieved full-text evidence in this run; therefore not asserted.

1.3 Synonyms / alternative names

The retrieved sources consistently use “KBG syndrome.” The acronym derives from initial affected families described historically (not re-verified here beyond secondary description). (swols2017kbgsyndrome pages 1-2)

1.4 Evidence provenance (patient-level vs aggregated)

The current evidence base includes: - Large aggregated cohorts integrating literature cases (e.g., n=340 analysis) (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14) - Multi-center natural history cohort (n=49) (loberti2022naturalhistoryof pages 1-2) - Focused mechanistic/functional studies in vitro and transcriptomics in patient-derived cell lines (wei2024functionalinvestigationof pages 6-9, iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7) - Reviews and case series (swols2017kbgsyndrome pages 1-2, he2024insightsintothe pages 6-8)

2. Etiology

2.1 Disease causal factors

Primary cause: heterozygous disruption of ANKRD11 (sequence variants and CNVs/microdeletions affecting ANKRD11) producing ANKRD11 dosage reduction and downstream transcriptional dysregulation. (swols2017kbgsyndrome pages 1-2, loberti2022naturalhistoryof pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)

Variant classes implicated: nonsense, frameshift, splice-site variants leading to premature termination; intragenic deletions/duplications; larger 16q24.3 deletions; and regulatory/non-coding deletions that reduce ANKRD11 expression. (gao2022geneticandphenotypic pages 9-11, bestetti2022expandingthemolecular pages 10-11, iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7)

2.2 Risk factors

As a Mendelian disorder, the principal risk factor is carrying a pathogenic ANKRD11 variant or an ANKRD11-involving 16q24.3 CNV. De novo occurrence is common; in the 2023 cohort subset summarized in evidence, most ANKRD11 variants were de novo (86%). (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23)

No environmental susceptibility factors or gene–environment interactions were identified in the retrieved evidence for KBG syndrome.

2.3 Protective factors

No genetic or environmental protective factors were identified in the retrieved evidence.

3. Phenotypes (with suggested HPO terms)

3.1 Most prevalent phenotypes and frequencies (2023–2024 prioritized)

A large 2023 cohort analysis (n=340 combined; 67 newly assessed) provides granular frequencies (note denominators vary by feature, reflecting heterogeneous reporting). Key features include: macrodontia (79.6%, 211/265), bushy/thick 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), and short stature ≤10th centile (57.9%, 150/259). (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)

Comorbidities are frequent: feeding difficulties (43.2%, 70/162), cryptorchidism (44.2%, 42/95), congenital heart defects (35.7%, 71/199), seizures (33.8%, 73/216), sleep problems (36.2%, 25/69). (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)

A European natural-history cohort (n=49) reported intellectual disability (82%), epilepsy (26.5%), cerebral anomalies (56%), and dental anomalies including macrodontia/oligodontia/dental agenesis (53%). (loberti2022naturalhistoryof pages 1-2)

3.2 Neurodevelopmental and behavioral phenotype

In the 2023 cohort subset summarized in evidence, neurodevelopmental diagnoses/symptoms were very common: intellectual disability 82.1%, language delay 72%, ADHD diagnosis/symptoms 63.3%, ASD diagnosis/symptoms 41.5%. (martinezcayuelas2023clinicaldescriptionmolecular pages 18-21, martinezcayuelas2023clinicaldescriptionmolecular pages 10-12)

3.3 Epilepsy phenotype

Epilepsy is heterogeneous in semiology and severity. A 2024 report summarizing prior cohort data described generalized, focal, and mixed seizure types with median onset about 3–4 years, frequent seizure remission but with an estimated ~quarter drug-resistant in some analyses. (donnellan2024epilepticdyskineticencephalopathy pages 1-2)

Severe epileptic encephalopathy phenotypes have been reported, including Lennox–Gastaut syndrome with refractory seizures and profound neurodevelopmental impairment; in one case, a vagal nerve stimulator reduced motor seizures and status epilepticus frequency. (donnellan2024epilepticdyskineticencephalopathy pages 2-4)

3.4 Suggested HPO terms (examples; not exhaustive)

Based on the reported phenotype spectrum: - Macrodontia of permanent maxillary central incisors: HP:0001572 (macrodontia) - Triangular face: HP:0000325 - Thick/bushy eyebrows / synophrys: HP:0000574 / HP:0000664 - Long philtrum: HP:0000343 - Short stature: HP:0004322 - Brachydactyly / clinodactyly: HP:0001156 / HP:0000031 - Developmental delay / Intellectual disability: HP:0001263 / HP:0001249 - ADHD: HP:0007018 - Autism spectrum disorder: HP:0000729 - Hearing loss / recurrent otitis media: HP:0000365 / HP:0000403 - Seizures / abnormal EEG: HP:0001250 / HP:0002353 - Cryptorchidism: HP:0000028 - Congenital heart defect (broad): HP:0001627 - Feeding difficulties: HP:0011968

(martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, martinezcayuelas2023clinicaldescriptionmolecular pages 10-12, loberti2022naturalhistoryof pages 1-2)

3.5 Quality of life impact

Direct QoL instrument data (e.g., EQ-5D/SF-36) were not present in the retrieved evidence. However, the condition’s burden is expected to derive from neurodevelopmental disability (ID/ADHD/ASD), epilepsy, feeding problems, hearing impairment, and multisystem medical follow-up needs. (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, donnellan2024epilepticdyskineticencephalopathy pages 2-4)

4. Genetic / molecular information

4.1 Causal gene(s)

  • ANKRD11 is the principal disease gene. (swols2017kbgsyndrome pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)

4.2 Variant spectrum and classification

  • Pathogenic variants include truncating variants (frameshift, nonsense, splice leading to PTC), missense variants, intragenic deletions/duplications, promoter/regulatory region deletions, and larger 16q24.3 microdeletions involving ANKRD11. (gao2022geneticandphenotypic pages 9-11, bestetti2022expandingthemolecular pages 10-11, iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7)
  • A 2024 ClinVar/literature synthesis reported 583 pathogenic/likely pathogenic ANKRD11 variants, with frameshift and nonsense being the most frequent classes. (he2024insightsintothe pages 1-2)

4.3 Functional consequences and mechanism (current models)

Haploinsufficiency model: KBG syndrome is widely described as resulting from ANKRD11 haploinsufficiency (dosage reduction), consistent with the high prevalence of truncating variants and pathogenic deletions. (swols2017kbgsyndrome pages 1-2, he2024insightsintothe pages 1-2)

Transcription/chromatin regulator role: ANKRD11 functions as a transcriptional regulator associated with chromatin-modifying complexes; it can recruit HDACs and interacts with acetylation-related complexes, supporting classification among “chromatinopathies.” (he2024insightsintothe pages 1-2, parenti2021ankrd11variantskbg pages 11-12)

Transcriptome evidence for downstream dysregulation: Upstream non-coding deletions involving ANKRD11 exon 1 and its upstream region reduce ANKRD11 transcript level and are associated with broad differential gene expression in patient-derived lymphoblastoid cell lines, consistent with global transcriptional alteration downstream of reduced ANKRD11 dosage. (iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7)

Functional in vitro evidence (2024): A 2024 Heliyon study of a segregating ANKRD11 frameshift (NM_013275.6 c.2280_2281delGT, p.Tyr761Glnfs*20) reported escape from nonsense-mediated decay with production of a truncated protein (~85 kDa). The mutant protein showed altered subcellular distribution (predominantly nuclear) and reduced CDKN1A/P21 promoter luciferase activation relative to wild type; endogenous CDKN1A/P21 mRNA was reduced, interpreted as impaired transcriptional regulatory function and a possible dominant-negative effect for that allele. (wei2024functionalinvestigationof pages 6-9)

4.4 Modifier genes / blended phenotypes

The retrieved evidence mentions phenotypic overlap with other chromatinopathy syndromes and the possibility of additional molecular diagnoses contributing to phenotypic variability, but does not provide validated modifier genes for KBG syndrome. (parenti2021ankrd11variantskbg pages 11-12)

4.5 Epigenetic information: DNA methylation signature (2023 development)

A 2023 Human Molecular Genetics study established a blood DNA methylation (DNAm) signature for KBG syndrome: - Profiling in whole blood using Illumina EPIC arrays included 21 individuals with ANKRD11 variants, 2 with 16q24.3 microdeletions, and 28 typically developing controls. (awamleh2023ankrd11pathogenicvariants pages 1-2) - A discovery analysis of 14 cases vs 28 controls identified 95 differentially methylated CpG sites (FDR thresholding and effect-size criteria described). (awamleh2023ankrd11pathogenicvariants pages 2-2) - A supervised classifier achieved 100% sensitivity in a validation set (7 affected individuals) and 100% specificity in controls (n=150). (awamleh2023ankrd11pathogenicvariants pages 4-5) - The DNAm profiles of 16q24.3 microdeletion cases were reported as indistinguishable from those with pathogenic ANKRD11 variants, supporting shared downstream epigenomic effects. (awamleh2023ankrd11pathogenicvariants pages 1-2)

Visual evidence (figures): The 95-CpG separation of cases vs controls and model performance are shown in the cropped figure panels retrieved from the paper. (awamleh2023ankrd11pathogenicvariants media 9f6c7c1b, awamleh2023ankrd11pathogenicvariants media 554a6258)

5. Environmental information

No specific environmental, lifestyle, or infectious contributors were identified in the retrieved evidence for KBG syndrome.

6. Mechanism / pathophysiology

6.1 Proposed causal chain (from gene disruption to phenotype)

  1. Primary trigger: germline heterozygous ANKRD11 LoF variant or ANKRD11-involving CNV/microdeletion at 16q24.3. (swols2017kbgsyndrome pages 1-2, martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)
  2. Molecular consequence: reduced ANKRD11 dosage and/or altered ANKRD11 protein function, affecting transcriptional regulation and chromatin-associated processes via HDAC recruitment and acetylation-linked complexes. (he2024insightsintothe pages 1-2, parenti2021ankrd11variantskbg pages 11-12)
  3. Downstream transcriptional effects: global gene expression changes observed in patient-derived cell lines, with predominance of downregulated genes in some transcriptomic comparisons. (iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7)
  4. Systems-level developmental effects: neurodevelopmental impairment (developmental delay/ID/ADHD/ASD), craniofacial and dental anomalies, skeletal anomalies (including short stature), and multisystem comorbidities such as seizures/epilepsy, hearing loss/otitis media, and congenital heart defects. (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2)

6.2 Pathways and processes (suggested GO terms)

Grounded in ANKRD11’s transcription/chromatin role and observed downstream effects: - GO:0006355 regulation of transcription, DNA-templated (broad) - GO:0006338 chromatin remodeling - GO:0016570 histone modification - GO:0007049 cell cycle (via CDKN1A/P21 involvement in functional assays) - GO:0007399 nervous system development (high-level mechanistic interpretation)

(These are ontology suggestions; the evidence supports transcription/chromatin involvement and p21 regulatory effects but does not enumerate GO IDs.) (he2024insightsintothe pages 1-2, wei2024functionalinvestigationof pages 6-9)

6.3 Cell types (suggested CL terms)

Direct disease cell-type specificity was not established in the retrieved evidence. For mechanistic annotation consistent with reported hypotheses: - Growth plate chondrocyte (CL:0000138) as a candidate key cell type for short stature mechanisms. (he2024insightsintothe pages 10-11) - Neuronal lineages broadly (e.g., “neuronal cell”) for neurodevelopmental phenotype.

7. Anatomical structures affected (suggested UBERON terms)

From dominant phenotype domains: - Central nervous system / brain (UBERON:0000955) including structural anomalies on MRI (loberti2022naturalhistoryof pages 1-2, liu2026heterogeneityofepileptic pages 7-8) - Teeth (UBERON:0001091) / dentition (macrodontia, dental anomalies) (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, loberti2022naturalhistoryof pages 1-2) - Skeleton / bone (UBERON:0002481) including hand bones/spine and growth plate effects (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, he2024insightsintothe pages 10-11) - Ear (UBERON:0001690) related to hearing loss/otitis media (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14) - Heart (UBERON:0000948) related to congenital heart defects (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14) - Testis / male reproductive system (UBERON:0000473) related to cryptorchidism (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14)

8. Temporal development

8.1 Onset

KBG syndrome is typically a pediatric-onset neurodevelopmental disorder with early developmental delay and evolving recognizability of dysmorphic/skeletal/dental features over time. (loberti2022naturalhistoryof pages 1-2)

8.2 Progression and course

  • In the European natural history cohort, short stature was consistent over time, while head circumference tended to normalize from a median −0.88 SD at birth. (loberti2022naturalhistoryof pages 1-2)
  • Epilepsy onset in summarized cohorts is commonly in early childhood (median ~3–4 years), with many patients achieving remission but a subset having drug-resistant epilepsy and severe outcomes. (donnellan2024epilepticdyskineticencephalopathy pages 1-2, donnellan2024epilepticdyskineticencephalopathy pages 2-4)

9. Inheritance and population

9.1 Inheritance

Autosomal dominant inheritance is consistently reported. De novo variants are common; in one 2023 cohort subset, 86% were de novo. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23)

9.2 Epidemiology

Robust incidence/prevalence estimates were not identified in the retrieved evidence. A 2024 review attempted indirect prevalence reasoning using short-stature cohorts; it reported pathogenic ANKRD11 variant frequencies in some short stature cohorts (~0.35–0.55%) and extrapolated an estimated ANKRD11 population prevalence of ~0.0105–0.0165% based on ~3% population short stature, but this is an indirect estimate with substantial assumptions. (he2024insightsintothe pages 6-8)

9.3 Sex ratio / demographics

No stable population sex ratio for KBG syndrome overall was established from the retrieved evidence. Some sub-analyses show male predominance in epilepsy-focused literature; interpret cautiously due to ascertainment. (liu2026heterogeneityofepileptic pages 1-3)

10. Diagnostics

10.1 Clinical diagnostic criteria (recent developments)

A 2023 large cohort analysis proposed updated diagnostic framing based on neurodevelopmental involvement plus characteristic features and/or comorbidities. Specifically, the authors proposed diagnosis when there is neurodevelopmental delay or ID/ADHD/ASD plus (i) ≥3 phenotypic features, or (ii) fewer phenotypic features combined with ≥1 of seven main comorbidities. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23)

The same work summarized prior criteria systems using major/minor features and thresholds (e.g., macrodontia/characteristic gestalt, short stature, otitis/hearing loss, family history as major features; seizures, cryptorchidism, feeding/palate problems, ASD, wide fontanelle as minor features). (martinezcayuelas2023clinicaldescriptionmolecular pages 5-7)

10.2 Genetic testing strategy (real-world implementation)

  • Clinical diagnosis should be confirmed by identifying a pathogenic ANKRD11 variant or ANKRD11-involving CNV/microdeletion; approaches include targeted panels, exome/genome sequencing, and chromosomal microarray for CNVs. (swols2017kbgsyndrome pages 1-2)
  • Multi-test diagnostic strategies can increase yield and detect regulatory-region alterations (e.g., promoter/exon 1 deletions) via transcript quantification (RT-qPCR) in selected cases. (bestetti2022expandingthemolecular pages 10-11)

10.3 Epigenomic testing as an emerging diagnostic adjunct

The 2023 DNAm signature work supports peripheral-blood DNAm profiling as a tool for variant interpretation and VUS classification in ANKRD11, with high performance in reported validation sets. (awamleh2023ankrd11pathogenicvariants pages 4-5, awamleh2023ankrd11pathogenicvariants media 9f6c7c1b)

10.4 Differential diagnosis

The retrieved evidence supports that ANKRD11-related phenotypes overlap with other chromatinopathy syndromes (e.g., Cornelia de Lange-like presentations and other epigenetic regulator disorders), potentially complicating purely clinical diagnosis. (parenti2021ankrd11variantskbg pages 11-12)

11. Outcome / prognosis

11.1 Neurodevelopmental outcomes

Intellectual disability is typically mild to moderate in the European cohort (82% ID; severe in 2 individuals), and no regression was emphasized in review-level summaries. (loberti2022naturalhistoryof pages 1-2, swols2017kbgsyndrome pages 6-7)

11.2 Epilepsy-related prognosis

Epilepsy is associated with poorer developmental outcomes in summarized cohorts and can be severe and refractory in some individuals (e.g., developmental and epileptic encephalopathy phenotypes). (donnellan2024epilepticdyskineticencephalopathy pages 1-2, donnellan2024epilepticdyskineticencephalopathy pages 2-4)

11.3 Mortality / survival

No disease-specific survival or mortality rates were identified in the retrieved evidence.

12. Treatment

12.1 Supportive, multidisciplinary care (standard of care)

Management is generally multidisciplinary and symptomatic, addressing developmental/behavioral needs, feeding/nutrition, ENT/hearing, ophthalmology, cardiology when indicated, and urologic issues such as cryptorchidism. (swols2017kbgsyndrome pages 6-7, li2026clinicalfeaturesand pages 1-2)

12.2 Epilepsy management

Anti-seizure medication (ASM) strategies are individualized; seizure phenotypes and responses are variable. Evidence from an epilepsy-focused case series/literature review suggests: - Overall ASM response is often favorable, but refractory epilepsy can occur (~27.8% in one pooled analysis). (liu2026heterogeneityofepileptic pages 1-3) - Lacosamide may be effective for focal seizures in some KBG patients; two reported patients achieved seizure control with lacosamide in one series. (liu2026heterogeneityofepileptic pages 3-4) - Severe refractory cases may require multiple ASMs and advanced therapies; VNS showed benefit in one severe case. (donnellan2024epilepticdyskineticencephalopathy pages 2-4)

MAXO suggestions: - Antiseizure therapy (e.g., MAXO:0000058 drug therapy; concept-level) - Vagus nerve stimulation (concept-level)

12.3 Short stature: recombinant human growth hormone (rhGH)

A 2024 Orphanet Journal of Rare Diseases review focused on short stature in ANKRD11/KBG reported: - Short stature prevalence around half (e.g., 47.35% [116/245] in an expanded height dataset). (he2024insightsintothe pages 3-6) - Limited rhGH-treated cases (n=9 summarized) show height SDS gains ranging roughly +0.14 to +1.87 over ~0.58–3 years, suggesting potential benefit in selected individuals though evidence is sparse and non-randomized. (he2024insightsintothe pages 8-10)

In a 16q24.3 microdeletion KBG report/review, two children treated with rhGH had catch-up growth of +1.66 SD and +0.68 SD in height. (li2026clinicalfeaturesand pages 1-2)

MAXO suggestions: - Growth hormone therapy (concept-level) - Endocrinology evaluation (concept-level; includes bone age assessment, GH stimulation testing, IGF-1)

12.4 Recent clinical trial activity (real-world implementation)

A registered interventional study targets ADHD-like symptoms in KBG syndrome: - NCT06465641, “Methylphenidate in KBG Syndrome: N-of-1 Series” (Radboud University Medical Center; registry year 2024): randomized crossover, quadruple-masked N-of-1 series; estimated enrollment 15; primary endpoint SDQ ADHD subscale; includes multiple secondary outcomes and adverse effects monitoring; eligibility includes molecularly confirmed ANKRD11 pathogenic variant or 16q24 deletion including ANKRD11. (NCT06465641 chunk 1)

13. Prevention

Primary prevention is not applicable for established Mendelian disease except through reproductive options. The retrieved evidence did not include formal prevention guidelines.

14. Other species / natural disease

No naturally occurring KBG-like disease in non-human species was identified in the retrieved evidence.

15. Model organisms

Direct model-organism primary papers were not retrieved in full-text here; however, mechanistic summaries in a 2024 review cite mouse models (e.g., Ankrd11-mutant “Yoda” and conditional knockout contexts) supporting roles in neurodevelopment and skeletal growth, consistent with the short stature mechanism hypothesis (growth-plate chondrocyte differentiation disruption). (he2024insightsintothe pages 8-10, he2024insightsintothe pages 1-2)

2023–2024 “latest research” highlights (curated)

  1. Largest genotype–phenotype and diagnostic-criteria update: n=340 cohort analysis proposing updated diagnostic framing and reporting detailed frequencies and genotype–phenotype correlations. Publication: 2023-11; DOI: https://doi.org/10.1136/jmg-2022-108632. (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14, martinezcayuelas2023clinicaldescriptionmolecular pages 21-23)
  2. Epigenomic biomarker development: discovery/validation of a KBG-specific whole-blood DNAm signature (95 CpGs) with machine-learning classification showing 100% sensitivity and specificity in reported validations; includes VUS interpretation use case. Publication: 2023-11; DOI: https://doi.org/10.1093/hmg/ddac289. (awamleh2023ankrd11pathogenicvariants pages 4-5, awamleh2023ankrd11pathogenicvariants media 9f6c7c1b)
  3. Short stature focused synthesis and rhGH evidence: short stature prevalence quantified (~47–49% depending on dataset) and a small rhGH-treated case synthesis suggesting potential benefit; mechanistic hypothesis linking ANKRD11 deficiency to growth plate chondrocyte differentiation disruption. Publication: 2024-08; DOI: https://doi.org/10.1186/s13023-024-03301-y. (he2024insightsintothe pages 3-6, he2024insightsintothe pages 8-10)
  4. Expanded epilepsy phenotype: severe epileptic-dyskinetic encephalopathy/Lennox–Gastaut cases and synthesis that epilepsy is linked with poorer outcomes in subsets. Publication: 2024-01; DOI: https://doi.org/10.1016/j.ebr.2024.100647. (donnellan2024epilepticdyskineticencephalopathy pages 2-4, donnellan2024epilepticdyskineticencephalopathy pages 1-2)
  5. Interventional trial for ADHD symptoms: NCT06465641 methylphenidate N-of-1 series for KBG. Registry year: 2024; URL: https://clinicaltrials.gov/study/NCT06465641. (NCT06465641 chunk 1)

Notes on limitations of this run

  • Several requested identifiers (Orphanet ORPHA code, ICD-10/ICD-11 code, MeSH term, MONDO ID) and PMIDs were not present in the retrieved evidence snippets; therefore they are not asserted here.
  • Some recent high-impact papers referenced in retrieved bibliographies (e.g., 2023 Genetics in Medicine missense-mechanism paper; 2023 Epilepsia Open epilepsy outcome paper) were listed as unobtainable in this run; thus detailed extraction from those sources was not possible.

References

  1. (loberti2022naturalhistoryof pages 1-2): Lorenzo Loberti, Lucia Pia Bruno, Stefania Granata, Gabriella Doddato, Sara Resciniti, Francesca Fava, Michele Carullo, Elisa Rahikkala, Guillaume Jouret, Leonie A Menke, Damien Lederer, Pascal Vrielynck, Lukáš Ryba, Nicola Brunetti-Pierri, Amaia Lasa-Aranzasti, Anna Maria Cueto-González, Laura Trujillano, Irene Valenzuela, Eduardo F Tizzano, Alessandro Mauro Spinelli, Irene Bruno, Aurora Currò, Franco Stanzial, Francesco Benedicenti, Diego Lopergolo, Filippo Maria Santorelli, Constantia Aristidou, George A Tanteles, Isabelle Maystadt, Tinatin Tkemaladze, Tiia Reimand, Helen Lokke, Katrin Õunap, Maria K Haanpää, Andrea Holubová, Veronika Zoubková, Martin Schwarz, Riina Žordania, Kai Muru, Laura Roht, Annika Tihveräinen, Rita Teek, Ulvi Thomson, Isis Atallah, Andrea Superti-Furga, Sabrina Buoni, Roberto Canitano, Valeria Scandurra, Annalisa Rossetti, Salvatore Grosso, Roberta Battini, Margherita Baldassarri, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Mirella Bruttini, Francesca Mari, Francesca Ariani, Alessandra Renieri, and Anna Maria Pinto. Natural history of kbg syndrome in a large european cohort. Human Molecular Genetics, 31:4131-4142, Jul 2022. URL: https://doi.org/10.1093/hmg/ddac167, doi:10.1093/hmg/ddac167. This article has 33 citations and is from a domain leading peer-reviewed journal.

  2. (swols2017kbgsyndrome pages 1-2): Dayna Morel Swols, Joseph Foster, and Mustafa Tekin. Kbg syndrome. Orphanet Journal of Rare Diseases, Dec 2018. URL: https://doi.org/10.1186/s13023-017-0736-8, doi:10.1186/s13023-017-0736-8. This article has 64 citations and is from a peer-reviewed journal.

  3. (martinezcayuelas2023clinicaldescriptionmolecular pages 21-23): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  4. (he2024insightsintothe pages 1-2): Dongye He, Mei Zhang, Yanying Li, Fupeng Liu, and Bo Ban. Insights into the ankrd11 variants and short-stature phenotype through literature review and clinvar database search. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03301-y, doi:10.1186/s13023-024-03301-y. This article has 11 citations and is from a peer-reviewed journal.

  5. (wei2024functionalinvestigationof pages 6-9): Shuoshuo Wei, Yanying Li, Wanling Yang, Shuxiong Chen, Fupeng Liu, Mei Zhang, Bo Ban, and Dongye He. Functional investigation of a novel ankrd11 frameshift variant identified in a chinese family with kbg syndrome. Heliyon, 10:e28082, Mar 2024. URL: https://doi.org/10.1016/j.heliyon.2024.e28082, doi:10.1016/j.heliyon.2024.e28082. This article has 2 citations.

  6. (bestetti2022expandingthemolecular pages 10-11): Ilaria Bestetti, Milena Crippa, Alessandra Sironi, Francesca Tumiatti, Maura Masciadri, Marie Falkenberg Smeland, Swati Naik, Oliver Murch, Maria Teresa Bonati, Alice Spano, Elisa Cattaneo, Milena Mariani, Fabio Gotta, Francesca Crosti, Pietro Cavalli, Chiara Pantaleoni, Federica Natacci, Maria Francesca Bedeschi, Donatella Milani, Silvia Maitz, Angelo Selicorni, Luigina Spaccini, Angela Peron, Silvia Russo, Lidia Larizza, Karen Low, and Palma Finelli. Expanding the molecular spectrum of ankrd11 gene defects in 33 patients with a clinical presentation of kbg syndrome. International Journal of Molecular Sciences, 23:5912, May 2022. URL: https://doi.org/10.3390/ijms23115912, doi:10.3390/ijms23115912. This article has 11 citations.

  7. (iwataotsubo202516q24.3microdeletionsdisrupting pages 5-7): Aiko Iwata-Otsubo, Alyssa L. Rippert, Jorune Balciuniene, Sarah K. Fiordaliso, Robert Chen, Preetha Markose, Cara M. Skraban, Christopher Gray, Elaine H. Zackai, Holly A Dubbs, Matthew A. Deardorff, Laura K. Conlin, and Kosuke Izumi. 16q24.3 microdeletions disrupting upstream non-coding region of ankrd11 cause kbg syndrome. Genes, 16:136, Jan 2025. URL: https://doi.org/10.3390/genes16020136, doi:10.3390/genes16020136. This article has 1 citations.

  8. (gao2022geneticandphenotypic pages 9-11): Fenqi Gao, Xiu Zhao, Bingyan Cao, Xin Fan, Xiaoqiao Li, Lele Li, Shengbin Sui, Zhe Su, and Chunxiu Gong. Genetic and phenotypic spectrum of kbg syndrome: a report of 13 new chinese cases and a review of the literature. Journal of Personalized Medicine, 12:407, Mar 2022. URL: https://doi.org/10.3390/jpm12030407, doi:10.3390/jpm12030407. This article has 17 citations.

  9. (iwataotsubo202516q24.3microdeletionsdisrupting pages 7-9): Aiko Iwata-Otsubo, Alyssa L. Rippert, Jorune Balciuniene, Sarah K. Fiordaliso, Robert Chen, Preetha Markose, Cara M. Skraban, Christopher Gray, Elaine H. Zackai, Holly A Dubbs, Matthew A. Deardorff, Laura K. Conlin, and Kosuke Izumi. 16q24.3 microdeletions disrupting upstream non-coding region of ankrd11 cause kbg syndrome. Genes, 16:136, Jan 2025. URL: https://doi.org/10.3390/genes16020136, doi:10.3390/genes16020136. This article has 1 citations.

  10. (li2026clinicalfeaturesand pages 1-2): Miaomiao Li, Shiqi Wang, Guimei Pan, Zixia Zhang, Xi Wang, Jiaqian Hu, Mengqin Wang, Mengmeng Du, Haiyan Wei, and Yongxing Chen. Clinical features and management of 16q24.3 microdeletion kbg syndrome: literature review. Frontiers in Pediatrics, Feb 2026. URL: https://doi.org/10.3389/fped.2026.1742479, doi:10.3389/fped.2026.1742479. This article has 0 citations.

  11. (martinezcayuelas2023clinicaldescriptionmolecular pages 5-7): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  12. (martinezcayuelas2023clinicaldescriptionmolecular pages 1-5): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  13. (martinezcayuelas2023clinicaldescriptionmolecular pages 12-14): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  14. (martinezcayuelas2023clinicaldescriptionmolecular pages 18-21): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  15. (donnellan2024epilepticdyskineticencephalopathy pages 1-2): Eoin P. Donnellan, Kathleen M. Gorman, Amre Shahwan, and Nicholas M. Allen. Epileptic dyskinetic encephalopathy in kbg syndrome: expansion of the phenotype. Epilepsy & Behavior Reports, 25:100647, Jan 2024. URL: https://doi.org/10.1016/j.ebr.2024.100647, doi:10.1016/j.ebr.2024.100647. This article has 7 citations and is from a peer-reviewed journal.

  16. (martinezcayuelas2023clinicaldescriptionmolecular pages 10-12): Elena Martinez-Cayuelas, Fiona Blanco-Kelly, Fermina Lopez-Grondona, Saoud Tahsin Swafiri, Rosario Lopez-Rodriguez, Rebeca Losada-Del Pozo, Ignacio Mahillo-Fernandez, Beatriz Moreno, Maria Rodrigo-Moreno, Didac Casas-Alba, Aitor Lopez-Gonzalez, Sixto García-Miñaúr, Maria Ángeles Mori, Marta Pacio-Minguez, Emi Rikeros-Orozco, Fernando Santos-Simarro, Jaime Cruz-Rojo, Juan Francisco Quesada-Espinosa, Maria Teresa Sanchez-Calvin, Jaime Sanchez-del Pozo, Raquel Bernado Fonz, Maria Isidoro-Garcia, Irene Ruiz-Ayucar, Maria Isabel Alvarez-Mora, Raquel Blanco-Lago, Begoña De Azua, Jesus Eiris, Juan Jose Garcia-Peñas, Belen Gil-Fournier, Carmen Gomez-Lado, Nadia Irazabal, Vanessa Lopez-Gonzalez, Irene Madrigal, Ignacio Malaga, Beatriz Martinez-Menendez, Soraya Ramiro-Leon, Maria Garcia-Hoyos, Pablo Prieto-Matos, Javier Lopez-Pison, Sergio Aguilera-Albesa, Sara Alvarez, Alberto Fernández-Jaén, Isabel Llano-Rivas, Blanca Gener-Querol, Carmen Ayuso, Ana Arteche-Lopez, Maria Palomares-Bralo, Anna Cueto-González, Irene Valenzuela, Antonio Martinez-Monseny, Isabel Lorda-Sanchez, and Berta Almoguera. Clinical description, molecular delineation and genotype–phenotype correlation in 340 patients with kbg syndrome: addition of 67 new patients. Journal of Medical Genetics, 60:644-654, Nov 2023. URL: https://doi.org/10.1136/jmg-2022-108632, doi:10.1136/jmg-2022-108632. This article has 23 citations and is from a domain leading peer-reviewed journal.

  17. (donnellan2024epilepticdyskineticencephalopathy pages 2-4): Eoin P. Donnellan, Kathleen M. Gorman, Amre Shahwan, and Nicholas M. Allen. Epileptic dyskinetic encephalopathy in kbg syndrome: expansion of the phenotype. Epilepsy & Behavior Reports, 25:100647, Jan 2024. URL: https://doi.org/10.1016/j.ebr.2024.100647, doi:10.1016/j.ebr.2024.100647. This article has 7 citations and is from a peer-reviewed journal.

  18. (liu2026heterogeneityofepileptic pages 1-3): Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li, and Fang Chen. Heterogeneity of epileptic phenotypes in kbg syndrome: a series of four cases and literature review. Unknown journal, Feb 2026. URL: https://doi.org/10.21203/rs.3.rs-8780749/v1, doi:10.21203/rs.3.rs-8780749/v1.

  19. (liu2026heterogeneityofepileptic pages 6-7): Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li, and Fang Chen. Heterogeneity of epileptic phenotypes in kbg syndrome: a series of four cases and literature review. Unknown journal, Feb 2026. URL: https://doi.org/10.21203/rs.3.rs-8780749/v1, doi:10.21203/rs.3.rs-8780749/v1.

  20. (liu2026heterogeneityofepileptic pages 3-4): Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li, and Fang Chen. Heterogeneity of epileptic phenotypes in kbg syndrome: a series of four cases and literature review. Unknown journal, Feb 2026. URL: https://doi.org/10.21203/rs.3.rs-8780749/v1, doi:10.21203/rs.3.rs-8780749/v1.

  21. (he2024insightsintothe pages 10-11): Dongye He, Mei Zhang, Yanying Li, Fupeng Liu, and Bo Ban. Insights into the ankrd11 variants and short-stature phenotype through literature review and clinvar database search. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03301-y, doi:10.1186/s13023-024-03301-y. This article has 11 citations and is from a peer-reviewed journal.

  22. (he2024insightsintothe pages 3-6): Dongye He, Mei Zhang, Yanying Li, Fupeng Liu, and Bo Ban. Insights into the ankrd11 variants and short-stature phenotype through literature review and clinvar database search. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03301-y, doi:10.1186/s13023-024-03301-y. This article has 11 citations and is from a peer-reviewed journal.

  23. (he2024insightsintothe pages 6-8): Dongye He, Mei Zhang, Yanying Li, Fupeng Liu, and Bo Ban. Insights into the ankrd11 variants and short-stature phenotype through literature review and clinvar database search. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03301-y, doi:10.1186/s13023-024-03301-y. This article has 11 citations and is from a peer-reviewed journal.

  24. (he2024insightsintothe pages 8-10): Dongye He, Mei Zhang, Yanying Li, Fupeng Liu, and Bo Ban. Insights into the ankrd11 variants and short-stature phenotype through literature review and clinvar database search. Orphanet Journal of Rare Diseases, Aug 2024. URL: https://doi.org/10.1186/s13023-024-03301-y, doi:10.1186/s13023-024-03301-y. This article has 11 citations and is from a peer-reviewed journal.

  25. (li2026clinicalfeaturesand pages 2-3): Miaomiao Li, Shiqi Wang, Guimei Pan, Zixia Zhang, Xi Wang, Jiaqian Hu, Mengqin Wang, Mengmeng Du, Haiyan Wei, and Yongxing Chen. Clinical features and management of 16q24.3 microdeletion kbg syndrome: literature review. Frontiers in Pediatrics, Feb 2026. URL: https://doi.org/10.3389/fped.2026.1742479, doi:10.3389/fped.2026.1742479. This article has 0 citations.

  26. (awamleh2023ankrd11pathogenicvariants pages 1-2): Zain Awamleh, Sanaa Choufani, Cheryl Cytrynbaum, Fowzan S Alkuraya, Stephen Scherer, Sofia Fernandes, Catarina Rosas, Pedro Louro, Patricia Dias, Mariana Tomásio Neves, Sérgio B Sousa, and Rosanna Weksberg. Ankrd11 pathogenic variants and 16q24.3 microdeletions share an altered dna methylation signature in patients with kbg syndrome. Human Molecular Genetics, 32:1429-1438, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac289, doi:10.1093/hmg/ddac289. This article has 24 citations and is from a domain leading peer-reviewed journal.

  27. (awamleh2023ankrd11pathogenicvariants pages 2-2): Zain Awamleh, Sanaa Choufani, Cheryl Cytrynbaum, Fowzan S Alkuraya, Stephen Scherer, Sofia Fernandes, Catarina Rosas, Pedro Louro, Patricia Dias, Mariana Tomásio Neves, Sérgio B Sousa, and Rosanna Weksberg. Ankrd11 pathogenic variants and 16q24.3 microdeletions share an altered dna methylation signature in patients with kbg syndrome. Human Molecular Genetics, 32:1429-1438, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac289, doi:10.1093/hmg/ddac289. This article has 24 citations and is from a domain leading peer-reviewed journal.

  28. (awamleh2023ankrd11pathogenicvariants pages 4-5): Zain Awamleh, Sanaa Choufani, Cheryl Cytrynbaum, Fowzan S Alkuraya, Stephen Scherer, Sofia Fernandes, Catarina Rosas, Pedro Louro, Patricia Dias, Mariana Tomásio Neves, Sérgio B Sousa, and Rosanna Weksberg. Ankrd11 pathogenic variants and 16q24.3 microdeletions share an altered dna methylation signature in patients with kbg syndrome. Human Molecular Genetics, 32:1429-1438, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac289, doi:10.1093/hmg/ddac289. This article has 24 citations and is from a domain leading peer-reviewed journal.

  29. (awamleh2023ankrd11pathogenicvariants media 9f6c7c1b): Zain Awamleh, Sanaa Choufani, Cheryl Cytrynbaum, Fowzan S Alkuraya, Stephen Scherer, Sofia Fernandes, Catarina Rosas, Pedro Louro, Patricia Dias, Mariana Tomásio Neves, Sérgio B Sousa, and Rosanna Weksberg. Ankrd11 pathogenic variants and 16q24.3 microdeletions share an altered dna methylation signature in patients with kbg syndrome. Human Molecular Genetics, 32:1429-1438, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac289, doi:10.1093/hmg/ddac289. This article has 24 citations and is from a domain leading peer-reviewed journal.

  30. (swols2017kbgsyndrome pages 6-7): Dayna Morel Swols, Joseph Foster, and Mustafa Tekin. Kbg syndrome. Orphanet Journal of Rare Diseases, Dec 2018. URL: https://doi.org/10.1186/s13023-017-0736-8, doi:10.1186/s13023-017-0736-8. This article has 64 citations and is from a peer-reviewed journal.

  31. (parenti2021ankrd11variantskbg pages 11-12): Ilaria Parenti, Mark B. Mallozzi, Irina Hüning, Cristina Gervasini, Alma Kuechler, Emanuele Agolini, Beate Albrecht, Carolina Baquero‐Montoya, Axel Bohring, Nuria C. Bramswig, Andreas Busche, Andreas Dalski, Yiran Guo, Britta Hanker, Yorck Hellenbroich, Denise Horn, A. Micheil Innes, Chiara Leoni, Yun R. Li, Sally Ann Lynch, Milena Mariani, Livija Medne, Barbara Mikat, Donatella Milani, Roberta Onesimo, Xilma Ortiz‐Gonzalez, Eva Christina Prott, Heiko Reutter, Eva Rossier, Angelo Selicorni, Peter Wieacker, Alisha Wilkens, Dagmar Wieczorek, Elaine H. Zackai, Giuseppe Zampino, Birgit Zirn, Hakon Hakonarson, Matthew A. Deardorff, Gabriele Gillessen‐Kaesbach, and Frank J. Kaiser. ankrd11 variants: kbg syndrome and beyond. Clinical Genetics, 100:187-200, May 2021. URL: https://doi.org/10.1111/cge.13977, doi:10.1111/cge.13977. This article has 48 citations and is from a peer-reviewed journal.

  32. (awamleh2023ankrd11pathogenicvariants media 554a6258): Zain Awamleh, Sanaa Choufani, Cheryl Cytrynbaum, Fowzan S Alkuraya, Stephen Scherer, Sofia Fernandes, Catarina Rosas, Pedro Louro, Patricia Dias, Mariana Tomásio Neves, Sérgio B Sousa, and Rosanna Weksberg. Ankrd11 pathogenic variants and 16q24.3 microdeletions share an altered dna methylation signature in patients with kbg syndrome. Human Molecular Genetics, 32:1429-1438, Nov 2023. URL: https://doi.org/10.1093/hmg/ddac289, doi:10.1093/hmg/ddac289. This article has 24 citations and is from a domain leading peer-reviewed journal.

  33. (liu2026heterogeneityofepileptic pages 7-8): Xuefang Liu, Jingjie Li, Jing Zhang, Lingyu Pang, Panhui Yu, Fan Feng, Hongru Lu, Liyao Ma, Xin Li, and Fang Chen. Heterogeneity of epileptic phenotypes in kbg syndrome: a series of four cases and literature review. Unknown journal, Feb 2026. URL: https://doi.org/10.21203/rs.3.rs-8780749/v1, doi:10.21203/rs.3.rs-8780749/v1.

  34. (NCT06465641 chunk 1): Methylphenidate in KBG Syndrome: N-of-1 Series. Radboud University Medical Center. 2024. ClinicalTrials.gov Identifier: NCT06465641

Artifacts