Cooks Syndrome

Mendelian MONDO:0007134 Pathograph 12 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. A well-studied cause is a tandem duplication at 17q24.3 that includes KCNJ2 coding sequence and SOX9 regulatory sequence while sparing SOX9 itself. Boundary-crossing duplication forms a neo-TAD that exposes KCNJ2 to the duplicated SOX9 regulatory landscape. Patient-fibroblast chromatin contacts and engineered mouse limb-expression assays support this mechanism, with ectopic Kcnj2 expression in developing mouse digits. Thus the regulatory consequence is distinct from the coding overlap or copy-number gain. A complex 1;17 translocation has also been reported with a Cooks-like phenotype; its embryonic limb-expression consequence remains unresolved.

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1
Inheritance
5
Pathophys.
5
Phenotypes
12
Pathograph
1
Genes
1
Variants
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

5
Boundary-Crossing Duplication at 17q24.3
Boundary-crossing duplications at 17q24.3 copy KCNJ2 and neighboring noncoding regulatory sequence. The original Cooks duplications also include KCNJ16. Their regulatory consequence depends on the extent of the duplicated interval. In the experimental mouse series, duplicating Kcnj2 and Kcnj16 within their original TAD did not produce the digit phenotype, whereas incorporation of Kcnj2 into a neo-TAD with Sox9 regulatory sequence did. This distinguishes the pathogenic regulatory rearrangement from gene copy-number gain alone.
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.
Genetic context KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. Variant type: duplication Genomic context: coding sequence Genomic context: intergenic region variant_origin: GERMLINE
Tandem duplications include KCNJ2 coding sequence and intergenic SOX9 regulatory sequence, crossing the boundary between their TADs while sparing SOX9 coding sequence. The POSTRE Table 1 Nr3 interval is one reported example of this lesion class.
Downstream
Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact The boundary-crossing duplicated interval forms an insulated chromatin domain containing KCNJ2 and duplicated SOX9 regulatory sequence.
Show evidence (4 references)
PMID:32583964 SUPPORT Human Clinical
"which is involved in two coding regions of KCNJ2 and KCNJ16"
Defines the coding content of the independently reported Chinese-family duplication.
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."
The full experimental series distinguishes intra-TAD duplications from boundary-crossing duplications. Dup-K1 and Dup-K2 mice duplicate the Kcnj genes within their original domain without the Cooks digit phenotype.
+ 1 more reference
Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
Mechanism confidence: Established
The duplicated KCNJ2 gene occupies the neo-TAD together with part of the SOX9 regulatory landscape. Capture Hi-C and 4C-seq in engineered Dup-C mouse limb buds demonstrate new contacts within this domain; patient fibroblast 4C-seq also demonstrates ectopic KCNJ2 contacts with the duplicated SOX9 regulatory region. SOX9 itself remains outside the duplication. A gene-free neo-TAD in the Dup-L control is phenotypically silent, so domain formation alone is insufficient for the limb phenotype. The contact measurements are distinct from the expression assays below.
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.
KCNJ2 enhancer-promoter contacts within the neo-TAD GO:0140588 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal KCNJ2 enhancer-promoter contacts within the neo-TAD, annotated with chromatin looping (GO:0140588). GO:0140588 is a biological process from the Gene Ontology.
Downstream
Ectopic KCNJ2 Expression in Developing Digits Contact with the duplicated Sox9 regulatory landscape drives a Sox9-like Kcnj2 expression pattern in the developing digits of Dup-C mice.
Show evidence (2 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 engineered Dup-C mouse provides direct chromatin-contact evidence; the full paper separately reports corresponding 4C-seq contacts in cultured fibroblasts from an affected individual (Extended Data Figure 6).
PMID:27706140 SUPPORT Model Organism
"As a consequence of this insulation, inter-TAD duplications had no phenotypic effect."
The Dup-L control forms a neo-TAD without capturing Kcnj2 or Kcnj16 and has no digit phenotype; this does not describe the pathogenic Dup-C allele.
Ectopic KCNJ2 Expression in Developing Digits
Regulatory category: GOE (Established)
Whole-mount in situ hybridization in Dup-C mice shows Kcnj2 expression in the digit anlagen with a Sox9-like spatial pattern. Limb-bud RNA-seq at E12.5 and E17.5 also shows increased Kcnj2 expression, while Sox9 and Kcnj16 remain unchanged. The spatially ectopic expression supports GOE; the quantitative increase alone would not. A Dup-C2 allele including Kcnj2 but not Kcnj16 also produces the digit phenotype. These are model measurements, not direct expression measurements from human embryonic digits, and they do not demonstrate altered intrinsic channel activity.
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.
gene expression GO:0010467 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased gene expression (GO:0010467). GO:0010467 is a biological process from the Gene Ontology.
Downstream
Apical Digit Malformation with Anonychia Ectopic Kcnj2 expression is associated with abnormal terminal phalanges and nail development in the duplication model. The intervening cellular mechanism remains unresolved.
Show evidence (2 references)
PMID:27706140 SUPPORT Model Organism
"consecutive misexpression of Kcnj2, and a limb malformation phenotype."
Figure 3 and the accompanying expression assays demonstrate ectopic Kcnj2 in developing digits, supporting regulatory GOE in the model.
PMID:32583964 SUPPORT INDIRECT BACKGROUND Model Organism
"17q24.3 duplications disrupt the boundary between SOX9 TAD and KCNJ TAD, leading to overexpression of Kcnj2 in the digit anlagen and limb buds"
This clinical report summarizes the earlier mouse mechanism; it is not an independent expression experiment in the Chinese family's limb tissue.
Alternative Translocation Affecting KCNJ2 Regulation
A reported complex 1;17 rearrangement is associated with a variant of Cooks syndrome and reduced KCNJ2 expression in blood cells and cultured skin fibroblasts. The expression effect in those accessible tissues does not establish the direction or spatial pattern in developing digits. This alternate lesion therefore does not refute the ectopic limb expression demonstrated in the duplication mouse model.
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.
Genetic context Variant type: translocation variant_origin: DE_NOVO
A complex de novo 1;17 rearrangement affects sequence 5' of KCNJ2; this is a distinct allele class from the boundary-crossing duplications.
Downstream
Apical Digit Malformation with Anonychia The rearrangement is associated with a Cooks-like developmental phenotype, but the limb-specific expression consequence and intervening pathway have not been established.
Show evidence (2 references)
PMID:34821995 SUPPORT Human Clinical
"Here, we report a unique case of CS associated with a de novo 1;17 translocation affecting the KCNJ2 locus."
Documents the alternate physical rearrangement in a human case.
PMID:34821995 SUPPORT In Vitro
"Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts."
This item supports the cultured fibroblast expression result. The source sentence also mentions patient blood; neither assay directly measures the developmental limb mechanism.
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 ⚠ ABNORMAL 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. Limb Morphogenesis GO:0035108 ⚠ ABNORMAL 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.
Downstream
Anonychia
Aplasia or Hypoplasia of the Distal Phalanges of the Hand
Aplasia or Hypoplasia of the Middle Phalanges of the Hand
Aplasia or Hypoplasia of the Distal Phalanges of the Toes
Brachydactyly
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.
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Phenotypes

5
Integument 1
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.
Limbs 4
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.
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.
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 gene page 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.
🔬

Variants

1
POSTRE Table 1 Nr3 17q24.3 duplication
Gene: KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. Regulatory target: KCNJ2 hgnc:6263 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant has a reported or proposed regulatory effect on this gene This variant has a reported or proposed regulatory effect on KCNJ2 (hgnc:6263). hgnc:6263 is a gene from the HUGO Gene Nomenclature Committee. duplication GOE
Genomic context: coding sequence intergenic region
Approximately 2.02 Mb duplication represented in POSTRE Table 1 patient Nr3 and Supplementary Data 3 as hg19 chr17:68020547-70038208, attributed there to the Cooks syndrome patient in Franke et al. (2016). These are POSTRE-reported interval bounds, not independently verified nucleotide-resolved junctions or a newly identified patient. The interval contains KCNJ2 and KCNJ16 coding sequence and intergenic regulatory sequence 5' of SOX9, while sparing SOX9 itself. KCNJ2 is both physically duplicated and the regulatory target. The pathogenic model is enhancer adoption within a neo-TAD, supported by patient-fibroblast chromatin contacts and corresponding engineered mouse alleles with ectopic digit expression. The GOE assignment uses the mouse spatial-expression evidence; it is not a claim that POSTRE experimentally measured this patient's expression.
Functional effects
Neo-TAD formation across the SOX9/KCNJ boundary Regulatory structural rearrangement TAD BOUNDARY
Duplicated parts of the adjacent regulatory domains form an insulated neo-TAD containing KCNJ2 and SOX9 regulatory sequence. This is domain reorganization rather than deletion of the boundary sequence.
Mechanism: Boundary-crossing tandem duplication and neo-TAD formation
Ectopic KCNJ2 expression in developing digits Regulatory gain of ectopic expression GOE ENHANCER
Kcnj2 adopts a Sox9-like digit expression pattern in the corresponding mouse duplication model. Expression and phenotype controls distinguish this effect from an extra Kcnj2 copy within its original regulatory domain; no altered intrinsic potassium-channel activity is established.
Mechanism: Enhancer adoption from the duplicated SOX9 regulatory landscape
Developmental stage: Embryonic digit development; mouse limb assays at E12.5 and E17.5
Show evidence (2 references)
PMID:36999617 SUPPORT Other
"The coordinates of the SVs in positive control patients (Table 1 and Table 2)"
Table 1 Nr3, Supplementary Data 3 Table1_SVs, and the authors' testFiles/Table1_LongRange_SVs.tsv agree on the hg19 interval chr17:68020547-70038208, duplication, KCNJ2, limb phenotype, and Franke et al. source. POSTRE is the secondary coordinate and case index here, not the source of experimental proof.
PMID:27706140 SUPPORT INDIRECT 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."
Primary experimental evidence supports the mechanism of the corresponding duplication class. The mouse Dup-C and Dup-C2 alleles are engineered models, not the human hg19 allele; patient fibroblast 4C-seq separately supports the ectopic contacts. The paper's main text does not resolve the POSTRE coordinate pair to nucleotide-level human junctions.
💊

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
Platform: Behavioral / lifestyle
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
Platform: Behavioral / lifestyle
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.

  A well-studied cause is a tandem duplication at 17q24.3 that includes KCNJ2
  coding sequence and SOX9 regulatory sequence while sparing SOX9 itself.
  Boundary-crossing duplication forms a neo-TAD that exposes KCNJ2 to the
  duplicated SOX9 regulatory landscape. Patient-fibroblast chromatin contacts
  and engineered mouse limb-expression assays support this mechanism, with
  ectopic Kcnj2 expression in developing mouse digits. Thus the regulatory
  consequence is distinct from the coding overlap or copy-number gain.
  A complex 1;17 translocation has also been reported with a Cooks-like
  phenotype; its embryonic limb-expression consequence remains unresolved.
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
  genetic_context:
    gene:
      preferred_term: KCNJ2
      term:
        id: hgnc:6263
        label: KCNJ2
    variant_type: duplication
    genomic_contexts:
    - coding sequence
    - intergenic region
    variant_origin: GERMLINE
    description: >-
      Tandem duplications include KCNJ2 coding sequence and intergenic SOX9
      regulatory sequence, crossing the boundary between their TADs while
      sparing SOX9 coding sequence. The POSTRE Table 1 Nr3 interval is one
      reported example of this lesion class.
  description: >-
    Boundary-crossing duplications at 17q24.3 copy KCNJ2 and neighboring
    noncoding regulatory sequence. The original Cooks duplications also
    include KCNJ16. Their regulatory consequence depends on the extent of
    the duplicated interval. In the experimental mouse series, duplicating
    Kcnj2 and Kcnj16 within their original TAD did not produce the digit
    phenotype, whereas incorporation of Kcnj2 into a neo-TAD with Sox9
    regulatory sequence did. This distinguishes the pathogenic regulatory
    rearrangement from gene copy-number gain alone.
  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 coding content of the independently reported Chinese-family duplication.
  - 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: >-
      The full experimental series distinguishes intra-TAD duplications from
      boundary-crossing duplications. Dup-K1 and Dup-K2 mice duplicate the
      Kcnj genes within their original domain without the Cooks digit phenotype.
  - 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 associated with Cooks syndrome.
  downstream:
  - target: Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
    description: >-
      The boundary-crossing duplicated interval forms an insulated chromatin
      domain containing KCNJ2 and duplicated SOX9 regulatory sequence.
    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: Capture Hi-C in engineered mouse limb buds demonstrates neo-TAD formation.
- name: Neo-TAD Formation and Ectopic KCNJ2 Enhancer Contact
  role: central_effector
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The duplicated KCNJ2 gene occupies the neo-TAD together with part of the
    SOX9 regulatory landscape. Capture Hi-C and 4C-seq in engineered Dup-C
    mouse limb buds demonstrate new contacts within this domain; patient
    fibroblast 4C-seq also demonstrates ectopic KCNJ2 contacts with the
    duplicated SOX9 regulatory region. SOX9 itself remains outside the
    duplication. A gene-free neo-TAD in the Dup-L control is phenotypically
    silent, so domain formation alone is insufficient for the limb phenotype.
    The contact measurements are distinct from the expression assays below.
  gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  biological_processes:
  - preferred_term: KCNJ2 enhancer-promoter contacts within the neo-TAD
    term:
      id: GO:0140588
      label: chromatin looping
    modifier: ABNORMAL
  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 engineered Dup-C mouse provides direct chromatin-contact evidence;
      the full paper separately reports corresponding 4C-seq contacts in
      cultured fibroblasts from an affected individual (Extended Data Figure 6).
  - 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 Dup-L control forms a neo-TAD without capturing Kcnj2 or Kcnj16
      and has no digit phenotype; this does not describe the pathogenic Dup-C allele.
  downstream:
  - target: Ectopic KCNJ2 Expression in Developing Digits
    description: >-
      Contact with the duplicated Sox9 regulatory landscape drives a Sox9-like
      Kcnj2 expression pattern in the developing digits of Dup-C mice.
    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: "ectopic contacts of Kcnj2 with the duplicated part of the Sox9 regulatory region, consecutive misexpression of Kcnj2"
      explanation: >-
        Chromatin-contact assays and whole-mount in situ hybridization link
        the new regulatory contacts to ectopic digit expression in the mouse model.
- name: Ectopic KCNJ2 Expression in Developing Digits
  role: central_effector
  biological_scale: MOLECULAR
  regulatory_category: GOE
  mechanism_confidence: ESTABLISHED
  description: >-
    Whole-mount in situ hybridization in Dup-C mice shows Kcnj2 expression
    in the digit anlagen with a Sox9-like spatial pattern. Limb-bud RNA-seq
    at E12.5 and E17.5 also shows increased Kcnj2 expression, while Sox9 and
    Kcnj16 remain unchanged. The spatially ectopic expression supports GOE;
    the quantitative increase alone would not. A Dup-C2 allele including
    Kcnj2 but not Kcnj16 also produces the digit phenotype. These are model
    measurements, not direct expression measurements from human embryonic
    digits, and they do not demonstrate altered intrinsic channel activity.
  gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  biological_processes:
  - preferred_term: gene expression
    term:
      id: GO:0010467
      label: gene expression
    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: "consecutive misexpression of Kcnj2, and a limb malformation phenotype."
    explanation: >-
      Figure 3 and the accompanying expression assays demonstrate ectopic
      Kcnj2 in developing digits, supporting regulatory GOE in the model.
  - reference: PMID:32583964
    reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    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: >-
      This clinical report summarizes the earlier mouse mechanism; it is not
      an independent expression experiment in the Chinese family's limb tissue.
  downstream:
  - target: Apical Digit Malformation with Anonychia
    description: >-
      Ectopic Kcnj2 expression is associated with abnormal terminal phalanges
      and nail development in the duplication model. The intervening cellular
      mechanism remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27706140
      reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "consecutive misexpression of Kcnj2, and a limb malformation phenotype."
      explanation: >-
        Dup-C and Dup-C2 models recapitulate the digital phenotype, supporting
        the regulatory mechanism without identifying all downstream intermediates.
    - reference: PMID:32583964
      reference_title: A 17q24.3 duplication identified in a large Chinese family with brachydactyly-anonychia.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "our findings suggest that 17q24.3 duplication is the genetic cause of brachydactyly-anonychia in this family"
      explanation: >-
        Human genotype-phenotype association supports the disease endpoint;
        this family did not undergo embryonic limb expression assays.
- name: Alternative Translocation Affecting KCNJ2 Regulation
  role: trigger
  biological_scale: MOLECULAR
  genetic_context:
    variant_type: translocation
    variant_origin: DE_NOVO
    description: >-
      A complex de novo 1;17 rearrangement affects sequence 5' of KCNJ2;
      this is a distinct allele class from the boundary-crossing duplications.
  description: >-
    A reported complex 1;17 rearrangement is associated with a variant of
    Cooks syndrome and reduced KCNJ2 expression in blood cells and cultured
    skin fibroblasts. The expression effect in those accessible tissues
    does not establish the direction or spatial pattern in developing digits.
    This alternate lesion therefore does not refute the ectopic limb
    expression demonstrated in the duplication mouse model.
  gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  evidence:
  - 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: Documents the alternate physical rearrangement in a human case.
  - 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: IN_VITRO
    snippet: "Gene expression analysis demonstrated downregulation of KCNJ2 in both patient's blood cells and cultured skin fibroblasts."
    explanation: >-
      This item supports the cultured fibroblast expression result. The source
      sentence also mentions patient blood; neither assay directly measures
      the developmental limb mechanism.
  downstream:
  - target: Apical Digit Malformation with Anonychia
    description: >-
      The rearrangement is associated with a Cooks-like developmental
      phenotype, but the limb-specific expression consequence and intervening
      pathway have not been established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34821995
      reference_title: A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
      supports: SUPPORT
      directness: INDIRECT
      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 propose phenotypic convergence without measuring embryonic digit expression.
- 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.
variants:
- name: POSTRE Table 1 Nr3 17q24.3 duplication
  variant_type: duplication
  genomic_contexts:
  - coding sequence
  - intergenic region
  gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  regulatory_target_gene:
    preferred_term: KCNJ2
    term:
      id: hgnc:6263
      label: KCNJ2
  regulatory_category: GOE
  description: >-
    Approximately 2.02 Mb duplication represented in POSTRE Table 1 patient
    Nr3 and Supplementary Data 3 as hg19 chr17:68020547-70038208, attributed
    there to the Cooks syndrome patient in Franke et al. (2016). These are
    POSTRE-reported interval bounds, not independently verified
    nucleotide-resolved junctions or a newly identified patient. The interval contains
    KCNJ2 and KCNJ16 coding sequence and intergenic regulatory sequence 5'
    of SOX9, while sparing SOX9 itself. KCNJ2 is both physically duplicated
    and the regulatory target. The pathogenic model is enhancer adoption
    within a neo-TAD, supported by patient-fibroblast chromatin contacts and
    corresponding engineered mouse alleles with ectopic digit expression.
    The GOE assignment uses the mouse spatial-expression evidence; it is
    not a claim that POSTRE experimentally measured this patient's expression.
  evidence:
  - reference: PMID:36999617
    reference_title: 'POSTRE: a tool to predict the pathological effects of human structural variants.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The coordinates of the SVs in positive control patients (Table 1 and Table 2)"
    explanation: >-
      Table 1 Nr3, Supplementary Data 3 Table1_SVs, and the authors'
      testFiles/Table1_LongRange_SVs.tsv agree on the hg19 interval
      chr17:68020547-70038208, duplication, KCNJ2, limb phenotype, and
      Franke et al. source. POSTRE is the secondary coordinate and case
      index here, not the source of experimental proof.
  - reference: PMID:27706140
    reference_title: Formation of new chromatin domains determines pathogenicity of genomic duplications.
    supports: SUPPORT
    directness: INDIRECT
    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: >-
      Primary experimental evidence supports the mechanism of the corresponding
      duplication class. The mouse Dup-C and Dup-C2 alleles are engineered
      models, not the human hg19 allele; patient fibroblast 4C-seq separately
      supports the ectopic contacts. The paper's main text does not resolve
      the POSTRE coordinate pair to nucleotide-level human junctions.
  functional_effects:
  - function: Neo-TAD formation across the SOX9/KCNJ boundary
    type: Regulatory structural rearrangement
    regulatory_element_type: TAD_BOUNDARY
    regulatory_mechanism: Boundary-crossing tandem duplication and neo-TAD formation
    description: >-
      Duplicated parts of the adjacent regulatory domains form an insulated
      neo-TAD containing KCNJ2 and SOX9 regulatory sequence. This is domain
      reorganization rather than deletion of the boundary sequence.
  - function: Ectopic KCNJ2 expression in developing digits
    type: Regulatory gain of ectopic expression
    regulatory_category: GOE
    regulatory_element_type: ENHANCER
    affected_developmental_stage: Embryonic digit development; mouse limb assays at E12.5 and E17.5
    regulatory_mechanism: Enhancer adoption from the duplicated SOX9 regulatory landscape
    description: >-
      Kcnj2 adopts a Sox9-like digit expression pattern in the corresponding
      mouse duplication model. Expression and phenotype controls distinguish
      this effect from an extra Kcnj2 copy within its original regulatory
      domain; no altered intrinsic potassium-channel activity is established.
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
PMID:34821995
A novel complex genomic rearrangement affecting the KCNJ2 regulatory region causes a variant of Cooks syndrome.
No top-level findings curated for this source.
PMID:19639023
Duplications of noncoding elements 5' of SOX9 are associated with brachydactyly-anonychia.
No top-level findings curated for this source.
PMID:18554391
Brachydactyly.
No top-level findings curated for this source.