Cooks Syndrome

Mendelian MONDO:0007134 Pathograph 9 Show in embeddings browser Limb Development Disorders

Cooks syndrome is an isolated malformation of the apical structures of the digits: absent or dysplastic nails together with hypoplasia or absence of the distal phalanges, usually affecting more than half the digits of hands and feet, with thumbs that may look "digitalized". Despite the eponym it is not a multisystem syndrome — reported patients have normal stature, normal intellectual development, and no other skeletal abnormality — which is why the ISDS nosology places it with the isolated brachydactylies rather than the syndromic ones. Its mechanistic interest is out of proportion to its rarity. Cooks syndrome is caused not by a coding variant but by duplications at 17q24.3 that cross the boundary between the SOX9 topologically associating domain and the neighbouring KCNJ domain. Chromosome conformation capture showed that such a boundary-crossing duplication builds an entirely new chromatin domain — a neo-TAD — which captures KCNJ2 and exposes it to SOX9 limb enhancers, so KCNJ2 is misexpressed in the digit anlagen. The gene is an inward-rectifier potassium channel whose coding mutations cause Andersen-Tawil syndrome; here the channel is structurally normal and simply switched on in the wrong tissue, and affected individuals have none of the Andersen-Tawil phenotype. Cooks syndrome is therefore one of the clearest human demonstrations that where a gene is expressed, set by three-dimensional genome architecture, can be the disease mechanism.

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1
Inheritance
3
Pathophys.
5
Phenotypes
9
Pathograph
1
Genes
2
Medical Actions
3
References
🏷

Classifications

ISDS Skeletal Nosology
brachydactyly without extraskeletal manifestations
👪

Inheritance

1
Autosomal Dominant HP:0000006
Autosomal dominant transmission of a 17q24.3 duplication, documented over four generations in the largest reported family.
Autosomal dominant inheritance
Show evidence (2 references)
PMID:32583964 SUPPORT Human Clinical
"In this study, a large Chinese family with three members affected by brachydactyly-anonychia was investigated."
A multigenerational family with three living affected members establishes dominant transmission.
PMID:32583964 SUPPORT Human Clinical
"Remarkably, a 1.9 Mb duplication in chromosome 17q24.3"
Identifies the segregating copy-number variant in the affected members.

Pathophysiology

3
Boundary-Crossing Duplication at 17q24.3
The causal lesion is a tandem duplication of roughly 1-2 Mb at 17q24.3 that contains the coding sequences of KCNJ2 and KCNJ16 together with noncoding regulatory sequence 5' of SOX9. What matters is not the extra copy of any gene but where the duplication starts and stops: it spans the boundary between the SOX9 TAD and the neighbouring KCNJ TAD. Duplications confined within the SOX9 TAD produce a different disease (sex reversal), and duplications that stay inside a single boundary can be phenotypically silent — so the pathogenicity is a property of the breakpoints relative to TAD architecture, not of dosage. In-tandem duplication is not the only route: a de novo 1;17 translocation affecting the KCNJ2 locus produces the same phenotype, which widens the lesion class to any rearrangement that reorganises this boundary.
KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (5 references)
PMID:32583964 SUPPORT Human Clinical
"which is involved in two coding regions of KCNJ2 and KCNJ16"
Defines the gene content of the duplicated interval.
PMID:32583964 SUPPORT Human Clinical
"To further verify the potential pathogenicity of this CNV, we conducted qPCR analysis to screen for this duplicated region in 500 normal controls and no one carried this variation."
Control screening supports the duplication as pathogenic rather than a common variant.
PMID:27706140 SUPPORT Model Organism
"Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure."
Establishes that a duplication contained within the SOX9 TAD gives a different phenotype, so breakpoint position relative to the boundary is what matters.
+ 2 more references
Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
Inside the neo-TAD, KCNJ2 comes to lie in the same insulated compartment as the duplicated portion of the SOX9 regulatory landscape. Capture Hi-C and 4C-seq show ectopic contacts between KCNJ2 and those enhancers. The consequence is tissue-specific misexpression: KCNJ2 is switched on in the digit anlagen and limb buds, where SOX9 enhancers are active and where KCNJ2 is normally silent. A neo-TAD that does not capture a gene has no phenotypic effect, which is the control that identifies gene capture, rather than domain formation itself, as the pathogenic step.
SOX9 hgnc:11204 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SOX9 (hgnc:11204). hgnc:11204 is a gene from the HUGO Gene Nomenclature Committee.
Regulation of Transcription by RNA Polymerase II GO:0006357 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves dysregulated Regulation of Transcription by RNA Polymerase II (GO:0006357). GO:0006357 is a biological process from the Gene Ontology. ↕ DYSREGULATED
Inward Rectifier Potassium Channel Activity GO:0005242 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves increased Inward Rectifier Potassium Channel Activity (GO:0005242). GO:0005242 is a molecular function from the Gene Ontology. ↑ INCREASED
Show evidence (5 references)
PMID:27706140 SUPPORT Model Organism
"However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype."
The central mechanistic result — gene capture into the neo-TAD drives KCNJ2 misexpression and limb malformation.
PMID:27706140 SUPPORT Model Organism
"As a consequence of this insulation, inter-TAD duplications had no phenotypic effect."
The negative control: forming a neo-TAD without capturing a gene produces no phenotype, isolating gene capture as the pathogenic step.
PMID:32583964 SUPPORT Human Clinical
"17q24.3 duplications disrupt the boundary between SOX9 TAD and KCNJ TAD, leading to overexpression of Kcnj2 in the digit anlagen and limb buds"
Restates the boundary-disruption-to-misexpression mechanism for the human duplication.
+ 2 more references
Apical Digit Malformation with Anonychia
The realised malformation is confined to the apical digital structures: hypoplasia or absence of distal phalanges with absent or dystrophic nails, typically in more than half the digits of both hands and feet, and thumbs that may appear digitalized. Because the terminal phalanx and the nail unit develop together, the anonychia is part of the same apical lesion rather than a separate ectodermal defect. Nothing outside the autopod is affected — no short stature, no developmental delay, no other skeletal abnormality, and none of the Andersen-Tawil phenotype that KCNJ2 coding mutations produce.
Embryonic Digit Morphogenesis GO:0042733 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Embryonic Digit Morphogenesis (GO:0042733). GO:0042733 is a biological process from the Gene Ontology. ⚠ ABNORMAL Limb Morphogenesis GO:0035108 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Limb Morphogenesis (GO:0035108). GO:0035108 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Show evidence (2 references)
PMID:32583964 SUPPORT Human Clinical
"had the normal stature as well as intellectual development and no other skeletal abnormality"
Confirms the malformation is confined to the digits.
PMID:32583964 SUPPORT Human Clinical
"brachydactyly-anonychia but no any phenotypes related to Andersen"
Affected individuals lack the Andersen-Tawil phenotype, consistent with a tissue-restricted misexpression mechanism rather than altered channel function everywhere.

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cooks 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

5
Limbs 1
Brachydactyly OBLIGATE HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32583964 SUPPORT Human Clinical
"Brachydactyly (BD) is a rare autosomal dominant inherited disease characterized by shortness of the fingers and/or toes"
Establishes digital shortening as the phenotype under investigation.
Other 4
Anonychia OBLIGATE HP:0001798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Anonychia (HP:0001798). HP:0001798 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32583964 SUPPORT Human Clinical
"reported seven affected individuals representing BD as well as absent nails in all digits"
Absent nails in all digits in the original case series.
Aplasia or Hypoplasia of the Distal Phalanges of the Hand OBLIGATE Aplasia/Hypoplasia of the distal phalanges of the hand HP:0009835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the distal phalanges of the hand (HP:0009835). HP:0009835 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32583964 SUPPORT Human Clinical
"our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
Radiographic documentation of absent phalanges in the affected rays.
Aplasia or Hypoplasia of the Distal Phalanges of the Toes VERY_FREQUENT Aplasia/Hypoplasia of the distal phalanges of the toes HP:0010185 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the distal phalanges of the toes (HP:0010185). HP:0010185 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32583964 SUPPORT Human Clinical
"our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
The same ray distribution is documented in the upper and lower extremities.
Aplasia or Hypoplasia of the Middle Phalanges of the Hand FREQUENT Aplasia/Hypoplasia of the middle phalanges of the hand HP:0009843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aplasia/Hypoplasia of the middle phalanges of the hand (HP:0009843). HP:0009843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32583964 SUPPORT Human Clinical
"our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
Radiographic absence of middle phalanges in all three affected family members.
🧬

Genetic Associations

1
17q24.3 Boundary-Crossing Duplication (Causative)
Gene: KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (3 references)
PMID:32583964 SUPPORT Human Clinical
"Both whole-exome sequencing and microarray-based comparative genomic hybridization (CGH) were performed on this family and the results of copy number variation (CNV) were verified by quantitative real-time PCR (qPCR)."
Documents the testing strategy that identified the copy-number lesion.
PMID:32583964 SUPPORT Human Clinical
"However, through whole-exome sequencing (WES), we detected no pathogenic mutations in genes conferred to bone development."
Explains why sequencing alone does not diagnose this disorder.
PMID:32583964 SUPPORT Human Clinical
"In summary, our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly-anonychia in this family, which support the prior report that brachydactyly-anonychia is associated with 17q24.3 duplication, and further indicates the pathogenic correlation between BD and CNVs."
Independent replication of the 17q24.3 duplication as the cause.
💊

Medical Actions

2
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for autosomal dominant transmission of a copy-number variant, including the point that the phenotype is confined to the digits and carries no Andersen-Tawil cardiac or neuromuscular risk despite involving KCNJ2.
Show evidence (2 references)
PMID:32583964 SUPPORT Human Clinical
"brachydactyly-anonychia but no any phenotypes related to Andersen"
Supports counseling that the KCNJ2-associated cardiac phenotype does not accompany this duplication.
PMID:18554391 SUPPORT Other
"The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
Supports inheritance- and phenotype-specific counseling.
Function-Directed Hand Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Management is supportive and directed at hand function and nail-bed care; there is no disease-specific treatment.
Show evidence (2 references)
PMID:18554391 SUPPORT Other
"There is no specific management or treatment that is applicable to all forms of brachydactyly."
Supports symptom-directed rather than disease-specific management.
PMID:18554391 SUPPORT Other
"Physical therapy and ergotherapy may ameliorate hand function."
Supports function-directed rehabilitation.
🔬

Diagnosis

1
Copy-number diagnosis after a negative exome
Recognised clinically by absent nails with hypoplastic or absent distal phalanges across most digits of hands and feet in an otherwise normal child. Confirmation requires copy-number analysis — chromosomal microarray or array CGH, verified by qPCR — because the lesion is a noncoding-boundary duplication that exome sequencing does not detect. A negative gene panel is expected and should not stop the workup.
array comparative genomic hybridization NCIT:C198497 NCI Thesaurus (NCIT)
Results: A 17q24.3 duplication spanning the SOX9/KCNJ TAD boundary, with normal exome sequencing.
Show evidence (2 references)
PMID:32583964 SUPPORT Human Clinical
"Because some CNVs, including deletions and duplications, cannot be readily detected by WES, we also employed comparative genomic hybridization (CGH) for CNV analysis on this family."
States why copy-number analysis is required after a negative exome.
PMID:32583964 SUPPORT Human Clinical
"We next confirmed this duplication by qPCR"
Documents qPCR as the confirmatory step for the array finding.
📊

Prevalence

1
Reported families worldwide
Cases In Literature Unknown
Extremely rare. Seven affected individuals in four families were reported in the original genomic series in 2009, with essentially no further reports until a single Chinese family in 2020.
Show evidence (3 references)
PMID:32583964 SUPPORT Human Clinical
"reported seven affected individuals representing BD as well as absent nails in all digits"
Records the size of the original case series.
PMID:32583964 SUPPORT Human Clinical
"Since then, no other studies have reported this disease any more."
States the near-absence of further reports in the intervening decade.
PMID:34821995 SUPPORT Human Clinical
"To date, six CS families were resolved at the molecular level."
Gives the running total of molecularly resolved Cooks syndrome families as of 2022.
{ }

Source YAML

click to show
name: Cooks Syndrome
synonyms:
- Brachydactyly-anonychia
- Anonychia-onychodystrophy with hypoplasia or absence of distal phalanges
- ODP
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Cooks syndrome is an isolated malformation of the apical structures of the
  digits: absent or dysplastic nails together with hypoplasia or absence of the
  distal phalanges, usually affecting more than half the digits of hands and
  feet, with thumbs that may look "digitalized". Despite the eponym it is not a
  multisystem syndrome — reported patients have normal stature, normal
  intellectual development, and no other skeletal abnormality — which is why the
  ISDS nosology places it with the isolated brachydactylies rather than the
  syndromic ones.

  Its mechanistic interest is out of proportion to its rarity. Cooks syndrome is
  caused not by a coding variant but by duplications at 17q24.3 that cross the
  boundary between the SOX9 topologically associating domain and the neighbouring
  KCNJ domain. Chromosome conformation capture showed that such a
  boundary-crossing duplication builds an entirely new chromatin domain — a
  neo-TAD — which captures KCNJ2 and exposes it to SOX9 limb enhancers, so KCNJ2
  is misexpressed in the digit anlagen. The gene is an inward-rectifier potassium
  channel whose coding mutations cause Andersen-Tawil syndrome; here the channel
  is structurally normal and simply switched on in the wrong tissue, and affected
  individuals have none of the Andersen-Tawil phenotype. Cooks syndrome is
  therefore one of the clearest human demonstrations that where a gene is
  expressed, set by three-dimensional genome architecture, can be the disease
  mechanism.
disease_term:
  preferred_term: Cooks syndrome
  term:
    id: MONDO:0007134
    label: Cooks syndrome
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Autosomal dominant transmission of a 17q24.3 duplication, documented over
    four generations in the largest reported family.
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, a large Chinese family with three members affected by brachydactyly-anonychia was investigated."
    explanation: A multigenerational family with three living affected members establishes dominant transmission.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, a 1.9 Mb duplication in chromosome 17q24.3"
    explanation: Identifies the segregating copy-number variant in the affected members.
classifications:
  isds_skeletal_category:
  - classification_value: brachydactyly_without_extraskeletal_manifestations
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 18 "Brachydactylies (isolated)", which lists
      brachydactyly with anonychia (Cooks syndrome, KCNJ2). The placement in the
      "isolated" rather than the "as part of syndromes" group is deliberate
      despite the eponym: the phenotype is confined to the apical digital
      structures, with normal stature, normal development, and no other skeletal
      abnormality. Anonychia here is part of the apical digit malformation — nail
      and terminal phalanx form as one unit — not an extraskeletal feature. The
      2019 revision (PMID:31633310) placed it in group 37 "Brachydactylies
      (without extraskeletal manifestations)". Per-row re-verification against
      the 2023 Table 1 is tracked in monarch-initiative/dismech#7867.
prevalence:
- population: Reported families worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    Extremely rare. Seven affected individuals in four families were reported in
    the original genomic series in 2009, with essentially no further reports
    until a single Chinese family in 2020.
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reported seven affected individuals representing BD as well as absent nails in all digits"
    explanation: Records the size of the original case series.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Since then, no other studies have reported this disease any more."
    explanation: States the near-absence of further reports in the intervening decade.
  - reference: PMID:34821995
    reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, six CS families were resolved at the molecular level."
    explanation: Gives the running total of molecularly resolved Cooks syndrome families as of 2022.
pathophysiology:
- name: Boundary-Crossing Duplication at 17q24.3
  role: trigger
  biological_scale: MOLECULAR
  description: >
    The causal lesion is a tandem duplication of roughly 1-2 Mb at 17q24.3 that
    contains the coding sequences of KCNJ2 and KCNJ16 together with noncoding
    regulatory sequence 5' of SOX9. What matters is not the extra copy of any
    gene but where the duplication starts and stops: it spans the boundary
    between the SOX9 TAD and the neighbouring KCNJ TAD. Duplications confined
    within the SOX9 TAD produce a different disease (sex reversal), and
    duplications that stay inside a single boundary can be phenotypically silent
    — so the pathogenicity is a property of the breakpoints relative to TAD
    architecture, not of dosage. In-tandem duplication is not the only route: a
    de novo 1;17 translocation affecting the KCNJ2 locus produces the same
    phenotype, which widens the lesion class to any rearrangement that
    reorganises this boundary.
  gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which is involved in two coding regions of KCNJ2 and KCNJ16"
    explanation: Defines the gene content of the duplicated interval.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To further verify the potential pathogenicity of this CNV, we conducted qPCR analysis to screen for this duplicated region in 500 normal controls and no one carried this variation."
    explanation: Control screening supports the duplication as pathogenic rather than a common variant.
  - reference: PMID:27706140
    reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Duplications of non-coding DNA within the mouse Sox9 TAD (intra-TAD) that cause female to male sex reversal in humans, showed increased contact of the duplicated regions within the TAD, but no change in the overall TAD structure."
    explanation: >-
      Establishes that a duplication contained within the SOX9 TAD gives a
      different phenotype, so breakpoint position relative to the boundary is
      what matters.
  - reference: PMID:34821995
    reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cooks syndrome (CS) is an ultrarare limb malformation due to in tandem microduplications involving KCNJ2 and extending to the 5' regulatory element of SOX9."
    explanation: Independent statement of the duplication class that defines Cooks syndrome.
  - reference: PMID:34821995
    reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus."
    explanation: >-
      A non-duplication rearrangement producing the same phenotype. It widens
      the lesion class this node describes, showing that in-tandem duplication
      is not the only route to Cooks syndrome.
  downstream:
  - target: Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
    description: >-
      A duplication extending past the TAD boundary reorganises the local
      chromatin into a new self-contained domain.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27706140
      reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, overlapping duplications that extended over the next boundary into the neighbouring TAD (inter-TAD), resulted in the formation of a new chromatin domain (neo-TAD) that was isolated from the rest of the genome."
      explanation: Shows boundary-crossing duplications generate a neo-TAD.
- name: Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
  role: central_effector
  biological_scale: MOLECULAR
  description: >
    Inside the neo-TAD, KCNJ2 comes to lie in the same insulated compartment as
    the duplicated portion of the SOX9 regulatory landscape. Capture Hi-C and
    4C-seq show ectopic contacts between KCNJ2 and those enhancers. The
    consequence is tissue-specific misexpression: KCNJ2 is switched on in the
    digit anlagen and limb buds, where SOX9 enhancers are active and where KCNJ2
    is normally silent. A neo-TAD that does not capture a gene has no phenotypic
    effect, which is the control that identifies gene capture, rather than
    domain formation itself, as the pathogenic step.
  gene:
    preferred_term: SOX9
    term:
      id: hgnc:11204
      label: SOX9
  biological_processes:
  - preferred_term: Regulation of Transcription by RNA Polymerase II
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: Inward Rectifier Potassium Channel Activity
    term:
      id: GO:0005242
      label: inward rectifier potassium channel activity
    modifier: INCREASED
  evidence:
  - reference: PMID:27706140
    reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, incorporation of the next flanking gene, Kcnj2, in the neo-TAD resulted in ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2, and a limb malformation phenotype."
    explanation: >-
      The central mechanistic result — gene capture into the neo-TAD drives
      KCNJ2 misexpression and limb malformation.
  - reference: PMID:27706140
    reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "As a consequence of this insulation, inter-TAD duplications had no phenotypic effect."
    explanation: >-
      The negative control: forming a neo-TAD without capturing a gene produces
      no phenotype, isolating gene capture as the pathogenic step.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "17q24.3 duplications disrupt the boundary between SOX9 TAD and KCNJ TAD, leading to overexpression of Kcnj2 in the digit anlagen and limb buds"
    explanation: Restates the boundary-disruption-to-misexpression mechanism for the human duplication.
  - reference: PMID:34821995
    reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts."
    explanation: >-
      Cuts against this node's INCREASED direction: in the translocation case
      KCNJ2 was *down*-regulated, with the breakpoint separating KCNJ2 from a
      putative enhancer. What the finding establishes is that a rearrangement
      giving the Cooks phenotype can reduce rather than raise KCNJ2 output, so
      increased expression is not a necessary feature of the lesion class and
      the direction that matters for the limb is unsettled. Graded INDIRECT
      because the measurement was made in blood and cultured fibroblasts rather
      than the digit anlagen, so it reaches the limb claim only through the
      inference that accessible tissues report on limb-bud expression.
  - reference: PMID:34821995
    reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that a complex rearrangement falling in the 5' of KCNJ2 may mimic the developmental consequences of in tandem duplications affecting the SOX9-KCNJ2/Sox9-Kcnj2 locus."
    explanation: >-
      The authors converge on the same conclusion by a different lesion: what
      matters is disturbance of the KCNJ2 regulatory landscape.
  downstream:
  - target: Apical Digit Malformation with Anonychia
    description: >-
      Ectopic KCNJ2 activity in the digit anlagen disturbs formation of the
      terminal phalanx and its nail unit.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:32583964
      reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly-anonychia in this family"
      explanation: Links the duplication to the digital phenotype in an independent family.
- name: Apical Digit Malformation with Anonychia
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation is confined to the apical digital structures:
    hypoplasia or absence of distal phalanges with absent or dystrophic nails,
    typically in more than half the digits of both hands and feet, and thumbs
    that may appear digitalized. Because the terminal phalanx and the nail unit
    develop together, the anonychia is part of the same apical lesion rather than
    a separate ectodermal defect. Nothing outside the autopod is affected — no
    short stature, no developmental delay, no other skeletal abnormality, and
    none of the Andersen-Tawil phenotype that KCNJ2 coding mutations produce.
  biological_processes:
  - preferred_term: Embryonic Digit Morphogenesis
    term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    modifier: ABNORMAL
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "had the normal stature as well as intellectual development and no other skeletal abnormality"
    explanation: Confirms the malformation is confined to the digits.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brachydactyly-anonychia but no any phenotypes related to Andersen"
    explanation: >-
      Affected individuals lack the Andersen-Tawil phenotype, consistent with a
      tissue-restricted misexpression mechanism rather than altered channel
      function everywhere.
  downstream:
  - target: Anonychia
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Middle Phalanges of the Hand
    causal_link_type: DIRECT
  - target: Aplasia or Hypoplasia of the Distal Phalanges of the Toes
    causal_link_type: DIRECT
  - target: Brachydactyly
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Anonychia
  description: >
    Absent or severely dystrophic nails on the affected digits, the feature that
    names the phenotype.
  phenotype_term:
    preferred_term: Anonychia
    term:
      id: HP:0001798
      label: Anonychia
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "reported seven affected individuals representing BD as well as absent nails in all digits"
    explanation: Absent nails in all digits in the original case series.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Distal Phalanges of the Hand
  description: >
    Hypoplasia or absence of the terminal phalanges of the fingers; in the
    Chinese family the middle phalanges of fingers II-V were absent
    radiographically.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the hand
    term:
      id: HP:0009835
      label: Aplasia/Hypoplasia of the distal phalanges of the hand
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
    explanation: Radiographic documentation of absent phalanges in the affected rays.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Distal Phalanges of the Toes
  description: >
    The feet are affected in the same distribution as the hands.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the distal phalanges of the toes
    term:
      id: HP:0010185
      label: Aplasia/Hypoplasia of the distal phalanges of the toes
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
    explanation: The same ray distribution is documented in the upper and lower extremities.
- category: Skeletal
  name: Brachydactyly
  description: >
    Short digits follow from the missing terminal skeletal segments.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly (BD) is a rare autosomal dominant inherited disease characterized by shortness of the fingers and/or toes"
    explanation: Establishes digital shortening as the phenotype under investigation.
- category: Skeletal
  name: Aplasia or Hypoplasia of the Middle Phalanges of the Hand
  description: >
    In the Chinese family the radiographic lesion was absence of the middle
    phalanges of fingers and toes II-V, not only of the terminal segments,
    showing that the deficiency can extend one joint further proximally than the
    classic "apical structures" description implies.
  phenotype_term:
    preferred_term: Aplasia/Hypoplasia of the middle phalanges of the hand
    term:
      id: HP:0009843
      label: Aplasia/Hypoplasia of the middle phalanges of the hand
  frequency: FREQUENT
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "our clinical data described a BD characterized by complete absence of middle phalanges of finger/toes II"
    explanation: Radiographic absence of middle phalanges in all three affected family members.
genetic:
- name: 17q24.3 Boundary-Crossing Duplication
  gene_term:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    A tandem duplication at 17q24.3 spanning the SOX9/KCNJ TAD boundary and
    including the KCNJ2 and KCNJ16 coding sequences plus SOX9 upstream
    regulatory sequence. Four overlapping duplications in an approximately 2 Mb
    interval were reported in the original four families, and a 1.9 Mb
    duplication in a later Chinese family. Because the lesion is a copy-number
    variant with a regulatory mechanism, exome sequencing is negative — the
    Chinese family was solved only after array CGH. KCNJ2 coding mutations cause
    Andersen-Tawil syndrome, an unrelated phenotype.
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both whole-exome sequencing and microarray-based comparative genomic hybridization (CGH) were performed on this family and the results of copy number variation (CNV) were verified by quantitative real-time PCR (qPCR)."
    explanation: Documents the testing strategy that identified the copy-number lesion.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, through whole-exome sequencing (WES), we detected no pathogenic mutations in genes conferred to bone development."
    explanation: Explains why sequencing alone does not diagnose this disorder.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In summary, our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly-anonychia in this family, which support the prior report that brachydactyly-anonychia is associated with 17q24.3 duplication, and further indicates the pathogenic correlation between BD and CNVs."
    explanation: Independent replication of the 17q24.3 duplication as the cause.
diagnosis:
- name: Copy-number diagnosis after a negative exome
  description: >-
    Recognised clinically by absent nails with hypoplastic or absent distal
    phalanges across most digits of hands and feet in an otherwise normal child.
    Confirmation requires copy-number analysis — chromosomal microarray or array
    CGH, verified by qPCR — because the lesion is a noncoding-boundary
    duplication that exome sequencing does not detect. A negative gene panel is
    expected and should not stop the workup.
  diagnosis_term:
    preferred_term: array comparative genomic hybridization
    term:
      id: NCIT:C198497
      label: Array-based Comparative Genomic Hybridization
  results: >-
    A 17q24.3 duplication spanning the SOX9/KCNJ TAD boundary, with normal
    exome sequencing.
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because some CNVs, including deletions and duplications, cannot be readily detected by WES, we also employed comparative genomic hybridization (CGH) for CNV analysis on this family."
    explanation: States why copy-number analysis is required after a negative exome.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We next confirmed this duplication by qPCR"
    explanation: Documents qPCR as the confirmatory step for the array finding.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission of a copy-number variant,
    including the point that the phenotype is confined to the digits and carries
    no Andersen-Tawil cardiac or neuromuscular risk despite involving KCNJ2.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brachydactyly-anonychia but no any phenotypes related to Andersen"
    explanation: Supports counseling that the KCNJ2-associated cardiac phenotype does not accompany this duplication.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms."
    explanation: Supports inheritance- and phenotype-specific counseling.
- name: Function-Directed Hand Care
  description: >-
    Management is supportive and directed at hand function and nail-bed care;
    there is no disease-specific treatment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "There is no specific management or treatment that is applicable to all forms of brachydactyly."
    explanation: Supports symptom-directed rather than disease-specific management.
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Physical therapy and ergotherapy may ameliorate hand function."
    explanation: Supports function-directed rehabilitation.
references:
- reference: PMID:34821995
  title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
- reference: PMID:19639023
  title: Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia.
- reference: PMID:18554391
  title: Brachydactyly.
📚

References & Deep Research

References

3
A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
No top-level findings curated for this source.
Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia.
No top-level findings curated for this source.
Brachydactyly.
No top-level findings curated for this source.