Brachydactyly Type A2

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Classifications

ISDS Skeletal Nosology

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Inheritance

1

Autosomal Dominant HP:0000006

BDA2 segregates as an autosomal dominant trait with variable expressivity, both for the BMPR1B and GDF5 coding variants and for the BMP2 enhancer duplications.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:14523231 SUPPORT Human Clinical

"Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes."

Two German pedigrees establish autosomal dominant transmission with variable expressivity.

PMID:19327734 SUPPORT Human Clinical

"Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5)."

Confirms dominant inheritance across the BMPR1B- and GDF5-associated forms.

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Pathophysiology

5

Dominant-Negative BMPR1B Receptor Signaling

BMPR1B is a type I transmembrane serine/threonine kinase that, with a type II receptor, transduces BMP and GDF5 signals to SMAD transcription factors. BDA2-associated missense variants fall either in the glycine/serine (GS) domain that must be transphosphorylated for receptor activation (I200K, kinase-deficient) or in a conserved region C-terminal to the kinase domain (R486W, kinase-competent). Both act on cartilage formation in a dominant-negative fashion rather than by simple haploinsufficiency, which is why two mechanistically different lesions produce the same digit phenotype.

Chondrocyte CL:0000138

BMPR1B hgnc:1077

BMP Signaling Pathway GO:0030509 ↓ DECREASED SMAD Protein Signal Transduction GO:0060395 ↓ DECREASED

Downstream

Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation A dominant-negative receptor lowers the BMP/GDF5 signal reaching SMADs in the condensing digital ray.

Show evidence (3 references)

PMID:14523231 SUPPORT Human Clinical

"In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor."

Locates the first BDA2 allele in the GS domain required for receptor activation.

PMID:14523231 SUPPORT In Vitro

"An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism."

Shows the two BDA2 alleles disable the receptor by different biochemical routes.

PMID:14523231 SUPPORT In Vitro

"These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner."

Establishes dominant-negative action rather than haploinsufficiency as the mechanism.

Defective proGDF5 Processing

GDF5 is the preferred ligand of BMPR1B and is synthesised as a precursor that must be cleaved at a dibasic site to release the mature growth factor from its prodomain. The BDA2-associated R380Q substitution sits at that processing site. The mutant protein is still secreted but is not cleaved by chondrogenic cells, and unprocessed proGDF5 is virtually inactive — so the lesion reduces the amount of active ligand available to BMPR1B without abolishing the gene product.

GDF5 hgnc:4220

Protein Processing GO:0016485 ↓ DECREASED BMP Signaling Pathway GO:0030509 ↓ DECREASED

Downstream

Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation Less mature GDF5 reaches BMPR1B, lowering pathway output in the digital ray.

Show evidence (2 references)

PMID:18203755 SUPPORT Human Clinical

"We investigated a family with a brachydactyly type A2 and identified a heterozygous arginine to glutamine (R380Q) substitution in the growth/differentiation factor 5 (GDF5) in all affected individuals."

Identifies the segregating GDF5 processing-site allele in a BDA2 family.

PMID:18203755 SUPPORT In Vitro

"Western blot analyses showed that wt GDF5 was processed by the chicken micromass cells, whereas the mutants were not, indicating that the mutations interfere with processing and that this leads to a strong reduction of biological activity."

Demonstrates that the variant blocks precursor cleavage and lowers ligand activity.

Altered BMP2 Enhancer Dosage in the Developing Limb

In BDA2 families without a BMPR1B or GDF5 coding variant, the lesion is a microduplication of a conserved noncoding element roughly 110 kb downstream of BMP2. A transgenic reporter shows the element drives limb expression overlapping endogenous Bmp2, identifying it as a limb-specific BMP2 enhancer. Duplicating it changes BMP2 dosage in the limb bud rather than altering any protein, so this is a regulatory route into the same pathway that the coding lesions disturb.

BMP2 hgnc:1069

BMP Signaling Pathway GO:0030509 ↕ DYSREGULATED Embryonic Limb Morphogenesis GO:0030326 ⚠ ABNORMAL

Downstream

Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation Altered limb-bud BMP2 dosage deregulates the same BMP/SMAD output that the receptor and ligand lesions reduce.

Show evidence (3 references)

PMID:19327734 SUPPORT Human Clinical

"A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected."

Identifies the noncoding duplication segregating in a mutation-negative BDA2 family.

PMID:19327734 SUPPORT Model Organism

"By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs."

Transgenic reporter assays establish the duplicated sequence as a limb enhancer.

PMID:19327734 SUPPORT Human Clinical

"Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb."

States the regulatory mechanism as a third route to BDA2.

Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation

Digital rays form from a continuous prechondrogenic mesenchymal condensation that segments into phalanges and metacarpals, with growth at the distal end. BMP/GDF5 signalling through BMPR1B controls both chondrocyte differentiation within the condensation and the position of the interphalangeal joints, which is why brachydactyly and abnormal interdigital joint formation travel together across types A-C. Lowering the signal shortens the segment that is forming when the deficit bites.

Prechondrogenic Mesenchymal Cell CL:0008019 Chondrocyte CL:0000138

Chondrocyte Differentiation GO:0002062 ↓ DECREASED Embryonic Digit Morphogenesis GO:0042733 ⚠ ABNORMAL

Downstream

Hypoplasia of the Index and Fifth Middle Phalanges Reduced chondrogenic output in the second (and fifth) digital ray leaves a rudimentary, often triangular middle phalanx.

Show evidence (3 references)

PMID:14523231 SUPPORT Other

"The digital rays are thought to be formed from spatially continuous prechondrogenic condensations that subsequently segment into individual skeletal elements, i.e., the phalanges and the metacarpals."

Describes the developmental substrate on which the reduced BMP signal acts.

PMID:14523231 SUPPORT Other

"Thus, BD types A-C have certain overlapping features including hypoplasia/aplasia of phalanges and abnormal interdigital joint formation, suggesting that the formation of joints and phalanges are linked on a developmental and molecular basis."

Supports a shared segmentation/joint-formation effector for the type A-C brachydactylies.

PMID:19790289 SUPPORT Other

"These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway."

Places the BMP pathway at the centre of the brachydactyly disease family.

Hypoplasia of the Index and Fifth Middle Phalanges

The realised malformation: a hypoplastic, aplastic, or triangular ("delta") middle phalanx of the index finger and, less consistently, the fifth finger, with lateral deviation of the affected digit. Because the same patterning program is reused in the hindlimb autopod, the first and second toes are involved in roughly half of affected individuals.

Limb Morphogenesis GO:0035108 ⚠ ABNORMAL

Downstream

Type A2 Brachydactyly

Short Middle Phalanx of the Second Finger

Triangular Middle Phalanx of the Second Finger

Short Middle Phalanx of the Fifth Finger

Ulnar or Radial Deviation of the Index Finger

Clinodactyly of the Fifth Finger

Short Second Toe

Medially Deviated Second Toe

Short Broad Hallux

Cutaneous Syndactyly of Toes

Camptodactyly

Show evidence (2 references)

PMID:14523231 SUPPORT Human Clinical

"In this article we describe the molecular cause of BDA2, a hand malformation characterized by hypoplasia/aplasia of the middle phalanx of the second and sometimes the fifth fingers"

Defines the cardinal digital malformation of BDA2.

PMID:14523231 SUPPORT Human Clinical

"Approximately half of them also had foot involvement such as deviation and shortening of the first or second toes, cutaneous syndactyly between the second and third toes, and camptodactyly."

Quantifies hindlimb involvement in the two molecularly solved families.

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Pathograph

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Phenotypes

11

Limbs 1

Short Broad Hallux FREQUENT HP:0010055

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"(D) Short, broad, and laterally deviated first toe and medial deviation of the second toe."

Photographic documentation of the short, broad, laterally deviated hallux.

Musculoskeletal 1

Camptodactyly OCCASIONAL HP:0012385

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"cutaneous syndactyly between the second and third toes, and camptodactyly"

Lists camptodactyly among the observed findings in the two BDA2 families.

Other 9

Type A2 Brachydactyly OBLIGATE HP:0009372

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"All affected individuals had the characteristic BDA2 hand phenotype consisting of medially deviated or shortened index fingers"

The hand phenotype was present in every affected individual in both families.

Short Middle Phalanx of the Second Finger Short middle phalanx of the 2nd finger HP:0009577

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"(B) Radiograph of the triangular-shaped middle phalanx of the second finger (Right) and missing middle phalanx of the second finger (Left)."

Radiographic documentation of the triangular or absent index middle phalanx.

Short Middle Phalanx of the Fifth Finger FREQUENT Short middle phalanx of the 5th finger HP:0004220

Show evidence (1 reference)

PMID:19327734 SUPPORT Human Clinical

"Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers"

Fifth-finger middle-phalanx hypoplasia is part of the defining description.

Ulnar or Radial Deviation of the Index Finger Ulnar deviation of the 2nd finger HP:0009464

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"(AandC) Short and medially deviated second fingers and clinodactyly of the fifth fingers."

Documents index-finger deviation and fifth-finger clinodactyly in affected individuals.

Short Second Toe FREQUENT Short 2nd toe HP:0001885

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"Approximately half of them also had foot involvement such as deviation and shortening of the first or second toes, cutaneous syndactyly between the second and third toes, and camptodactyly."

Quantifies foot involvement in two molecularly confirmed BDA2 families.

Cutaneous Syndactyly of Toes OCCASIONAL 2-3 toe cutaneous syndactyly HP:0005709

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"cutaneous syndactyly between the second and third toes"

Lists 2-3 toe cutaneous syndactyly among the observed foot findings.

Triangular Middle Phalanx of the Second Finger FREQUENT Triangular shaped middle phalanx of the 2nd finger HP:0009575

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"(B) Radiograph of the triangular-shaped middle phalanx of the second finger (Right) and missing middle phalanx of the second finger (Left)."

Radiographic documentation of the triangular index middle phalanx alongside the aplastic form.

Clinodactyly of the Fifth Finger FREQUENT Clinodactyly of the 5th finger HP:0004209

Show evidence (2 references)

PMID:14523231 SUPPORT Human Clinical

"(AandC) Short and medially deviated second fingers and clinodactyly of the fifth fingers."

Documents fifth-finger clinodactyly in the molecularly solved families.

PMID:36064339 SUPPORT Other

"BDA2112,600Short middle phalanx with clinodactyly of the index fingers and second toes"

A recent review tabulates clinodactyly as part of the defining BDA2 description, independent of the original family series.

Medially Deviated Second Toe FREQUENT HP:0008096

Show evidence (1 reference)

PMID:14523231 SUPPORT Human Clinical

"(D) Short, broad, and laterally deviated first toe and medial deviation of the second toe."

Documents medial deviation of the second toe in affected individuals.

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Genetic Associations

3

BMPR1B Pathogenic Variants (Causative)

Gene: BMPR1B hgnc:1077 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:14523231 SUPPORT Human Clinical

"We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25."

Maps the BDA2 locus to the interval containing BMPR1B.

PMID:14523231 SUPPORT Human Clinical

"In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain."

Identifies the second BDA2 allele in an independent family.

GDF5 Pathogenic Variants (Causative)

Gene: GDF5 hgnc:4220 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:18203755 SUPPORT Human Clinical

"The observed mutation is located at the processing site of the protein, at which the GDF5 precursor is thought to be cleaved releasing the mature molecule from the prodomain."

Places the BDA2 allele at the precursor cleavage site.

PMID:19327734 SUPPORT Human Clinical

"has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5)"

Independent confirmation that GDF5 is an established BDA2 gene.

BMP2 Limb-Enhancer Microduplication (Causative)

Gene: BMP2 hgnc:1069 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:19327734 SUPPORT Human Clinical

"A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2)."

Establishes the third BDA2 locus in coding-variant-negative families.

PMID:19327734 SUPPORT Human Clinical

"Screening of other patients by qPCR revealed a similar duplication in a second family."

Replication of the duplication in an independent family.

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Medical Actions

3

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling for autosomal dominant transmission with variable expressivity, including the possibility of a regulatory (copy-number) rather than coding lesion in the family.

Show evidence (1 reference)

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 for isolated brachydactyly.

Function- or Cosmesis-Directed Hand Surgery

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Surgery is reserved for meaningful impairment of hand function or selected cosmetic indications, and is usually not required in isolated brachydactyly.

Show evidence (1 reference)

PMID:18554391 SUPPORT Other

"Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed."

Defines the limited surgical indications in isolated brachydactyly.

Hand Function Rehabilitation

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical and occupational therapy where digital shortening limits function.

Show evidence (1 reference)

PMID:18554391 SUPPORT Other

"Physical therapy and ergotherapy may ameliorate hand function."

Supports function-directed rehabilitation.

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Diagnosis

1

Clinical-radiographic and molecular diagnosis

Diagnosis rests on the clinical and radiographic pattern of a hypoplastic, absent, or triangular middle phalanx of the index finger with lateral deviation, confirmed where possible by finding a BMPR1B or GDF5 variant or, in coding-negative families, a BMP2 enhancer duplication on array CGH or qPCR. Sequencing alone will miss the regulatory form.

genetic testing NCIT:C15709

Results: Triangular or absent middle phalanx of the second (and sometimes fifth) finger on hand radiographs, with a causal BMPR1B or GDF5 variant or a 20p12.3 noncoding duplication when molecularly solved.

Show evidence (2 references)

PMID:18554391 SUPPORT Other

"Diagnosis is clinical, anthropometric and radiological."

Establishes the clinical-radiographic basis of brachydactyly diagnosis.

PMID:19327734 SUPPORT Human Clinical

"No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed."

Shows why copy-number analysis is needed: the regulatory form is invisible to sequencing of the coding region.

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Prevalence

1

Reported pedigrees worldwide

Cases In Literature Unknown

No population-based estimate exists. Isolated BDA2 is known from a small number of multigenerational pedigrees; the general review literature places every isolated brachydactyly except types A3 and D in the rare category.

Show evidence (1 reference)

PMID:18554391 SUPPORT Other

"The various types of isolated brachydactyly are rare, except for types A3 and D."

Places isolated BDA2 among the rare brachydactylies rather than the common ones.

{ }

Source YAML

click to show

name: Brachydactyly Type A2
synonyms:
- BDA2
- Mohr-Wriedt type brachydactyly
- Brachymesophalangy type 2
creation_date: '2026-08-27T00:00:00Z'
category: Mendelian
description: >
  Brachydactyly type A2 (BDA2) is an autosomal dominant isolated hand and foot
  malformation in which the middle phalanx of the index finger — and, less
  consistently, of the fifth finger — is hypoplastic, rudimentary, or absent.
  The hypoplastic middle phalanx is characteristically triangular ("delta"
  phalanx), so that the index finger deviates laterally; the second toe is
  affected at least as consistently as the index finger. Unlike brachydactyly
  type A1, which arises from Indian hedgehog signalling defects, BDA2 is a
  disorder of the BMP/GDF5-BMPR1B-SMAD axis that patterns and segments the
  digital ray. Three distinct molecular routes converge on the same phenotype:
  dominant-negative missense variants in the type I BMP receptor BMPR1B,
  variants in its ligand GDF5 that block proteolytic maturation of the
  precursor, and microduplications of a limb enhancer downstream of BMP2 that
  alter BMP2 dosage in the developing limb.
disease_term:
  preferred_term: brachydactyly type A2
  term:
    id: MONDO:0007216
    label: brachydactyly type A2
parents:
- Limb Development Disorders
inheritance:
- name: Autosomal Dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    BDA2 segregates as an autosomal dominant trait with variable expressivity,
    both for the BMPR1B and GDF5 coding variants and for the BMP2 enhancer
    duplications.
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brachydactyly (BD) type A2 is an autosomal dominant hand malformation characterized by shortening and lateral deviation of the index fingers and, to a variable degree, shortening and deviation of the first and second toes."
    explanation: Two German pedigrees establish autosomal dominant transmission with variable expressivity.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers, has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5)."
    explanation: Confirms dominant inheritance across the BMPR1B- and GDF5-associated forms.
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 the
      isolated brachydactyly type A2 entity (OMIM 112600; BMPR1B, BMP2, GDF5).
      The 2019 revision (PMID:31633310) placed the same entity 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 pedigrees worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: UNKNOWN
  notes: >-
    No population-based estimate exists. Isolated BDA2 is known from a small
    number of multigenerational pedigrees; the general review literature places
    every isolated brachydactyly except types A3 and D in the rare category.
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The various types of isolated brachydactyly are rare, except for types A3 and D."
    explanation: Places isolated BDA2 among the rare brachydactylies rather than the common ones.
pathophysiology:
- name: Dominant-Negative BMPR1B Receptor Signaling
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    BMPR1B is a type I transmembrane serine/threonine kinase that, with a type II
    receptor, transduces BMP and GDF5 signals to SMAD transcription factors.
    BDA2-associated missense variants fall either in the glycine/serine (GS)
    domain that must be transphosphorylated for receptor activation (I200K,
    kinase-deficient) or in a conserved region C-terminal to the kinase domain
    (R486W, kinase-competent). Both act on cartilage formation in a
    dominant-negative fashion rather than by simple haploinsufficiency, which is
    why two mechanistically different lesions produce the same digit phenotype.
  gene:
    preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  biological_processes:
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  - preferred_term: SMAD Protein Signal Transduction
    term:
      id: GO:0060395
      label: SMAD protein signal transduction
    modifier: DECREASED
  cell_types:
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In one family, we identified a T599 --> A mutation changing an isoleucine into a lysine residue (I200K) within the glycine/serine (GS) domain of BMPR1B, a region involved in phosphorylation of the receptor."
    explanation: Locates the first BDA2 allele in the GS domain required for receptor activation.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "An in vitro kinase assay showed that the I200K mutation is kinase-deficient, whereas the R486W mutation has normal kinase activity, indicating a different pathogenic mechanism."
    explanation: Shows the two BDA2 alleles disable the receptor by different biochemical routes.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These findings imply that both mutations identified in human BMPR1B affect cartilage formation in a dominant-negative manner."
    explanation: Establishes dominant-negative action rather than haploinsufficiency as the mechanism.
  downstream:
  - target: Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation
    description: >-
      A dominant-negative receptor lowers the BMP/GDF5 signal reaching SMADs in
      the condensing digital ray.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:14523231
      reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Functional analyses with a micromass culture system revealed a strong inhibition of chondrogenesis by both mutant receptors."
      explanation: Micromass assays link the mutant receptors directly to suppressed chondrogenesis.
- name: Defective proGDF5 Processing
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    GDF5 is the preferred ligand of BMPR1B and is synthesised as a precursor that
    must be cleaved at a dibasic site to release the mature growth factor from
    its prodomain. The BDA2-associated R380Q substitution sits at that processing
    site. The mutant protein is still secreted but is not cleaved by chondrogenic
    cells, and unprocessed proGDF5 is virtually inactive — so the lesion reduces
    the amount of active ligand available to BMPR1B without abolishing the gene
    product.
  gene:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  biological_processes:
  - preferred_term: Protein Processing
    term:
      id: GO:0016485
      label: protein processing
    modifier: DECREASED
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:18203755
    reference_title: Brachydactyly type A2 associated with a defect in proGDF5 processing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We investigated a family with a brachydactyly type A2 and identified a heterozygous arginine to glutamine (R380Q) substitution in the growth/differentiation factor 5 (GDF5) in all affected individuals."
    explanation: Identifies the segregating GDF5 processing-site allele in a BDA2 family.
  - reference: PMID:18203755
    reference_title: Brachydactyly type A2 associated with a defect in proGDF5 processing.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blot analyses showed that wt GDF5 was processed by the chicken micromass cells, whereas the mutants were not, indicating that the mutations interfere with processing and that this leads to a strong reduction of biological activity."
    explanation: Demonstrates that the variant blocks precursor cleavage and lowers ligand activity.
  downstream:
  - target: Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation
    description: >-
      Less mature GDF5 reaches BMPR1B, lowering pathway output in the digital ray.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:18203755
      reference_title: Brachydactyly type A2 associated with a defect in proGDF5 processing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Both mutants were secreted from chicken micromass cultures, but showed diminished biological activity."
      explanation: Ties the processing defect to reduced biological signalling activity.
- name: Altered BMP2 Enhancer Dosage in the Developing Limb
  conforms_to: "limb_digit_patterning_serial_homology#Limb Patterning Signal Perturbation"
  role: trigger
  biological_scale: MOLECULAR
  description: >
    In BDA2 families without a BMPR1B or GDF5 coding variant, the lesion is a
    microduplication of a conserved noncoding element roughly 110 kb downstream
    of BMP2. A transgenic reporter shows the element drives limb expression
    overlapping endogenous Bmp2, identifying it as a limb-specific BMP2 enhancer.
    Duplicating it changes BMP2 dosage in the limb bud rather than altering any
    protein, so this is a regulatory route into the same pathway that the coding
    lesions disturb.
  gene:
    preferred_term: BMP2
    term:
      id: hgnc:1069
      label: BMP2
  biological_processes:
  - preferred_term: BMP Signaling Pathway
    term:
      id: GO:0030509
      label: BMP signaling pathway
    modifier: DYSREGULATED
  - preferred_term: Embryonic Limb Morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A microduplication of approximately 5.5 kb in a noncoding sequence approximately 110 kb downstream of BMP2 was detected."
    explanation: Identifies the noncoding duplication segregating in a mutation-negative BDA2 family.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By using a transgenic mouse model we can show that this sequence is able to drive expression of a X-Gal reporter construct in the limbs."
    explanation: Transgenic reporter assays establish the duplicated sequence as a limb enhancer.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our results reveal an additional functional mechanism for the pathogenesis of BDA2, which is duplication of a regulatory element that affects the expression of BMP2 in the developing limb."
    explanation: States the regulatory mechanism as a third route to BDA2.
  downstream:
  - target: Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation
    description: >-
      Altered limb-bud BMP2 dosage deregulates the same BMP/SMAD output that the
      receptor and ligand lesions reduce.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:19327734
      reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "The almost complete overlap with endogenous Bmp2 expression indicates that a limb-specific enhancer of Bmp2 is located within the identified duplication."
      explanation: >-
        Supports altered limb BMP2 expression as the proximate consequence. The
        sentence interprets the transgenic mouse reporter experiment reported in
        the same abstract, comparing the reporter domain with endogenous murine
        Bmp2, so the finding reaches the human duplication through the mouse
        enhancer assay. The quantitative effect on downstream SMAD output in the
        human digital ray was not measured either, so the reduction in BMP/SMAD
        signalling is inferred rather than shown.
- name: Reduced BMP/SMAD Output in the Digital Chondrogenic Condensation
  conforms_to: "limb_digit_patterning_serial_homology#Disrupted Digit Number and Identity Specification"
  role: central_effector
  biological_scale: CELLULAR
  description: >
    Digital rays form from a continuous prechondrogenic mesenchymal condensation
    that segments into phalanges and metacarpals, with growth at the distal end.
    BMP/GDF5 signalling through BMPR1B controls both chondrocyte differentiation
    within the condensation and the position of the interphalangeal joints, which
    is why brachydactyly and abnormal interdigital joint formation travel
    together across types A-C. Lowering the signal shortens the segment that is
    forming when the deficit bites.
  biological_processes:
  - preferred_term: Chondrocyte Differentiation
    term:
      id: GO:0002062
      label: chondrocyte differentiation
    modifier: DECREASED
  - preferred_term: Embryonic Digit Morphogenesis
    term:
      id: GO:0042733
      label: embryonic digit morphogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Prechondrogenic Mesenchymal Cell
    term:
      id: CL:0008019
      label: mesenchymal cell
  - preferred_term: Chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The digital rays are thought to be formed from spatially continuous prechondrogenic condensations that subsequently segment into individual skeletal elements, i.e., the phalanges and the metacarpals."
    explanation: Describes the developmental substrate on which the reduced BMP signal acts.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Thus, BD types A-C have certain overlapping features including hypoplasia/aplasia of phalanges and abnormal interdigital joint formation, suggesting that the formation of joints and phalanges are linked on a developmental and molecular basis."
    explanation: Supports a shared segmentation/joint-formation effector for the type A-C brachydactylies.
  - reference: PMID:19790289
    reference_title: "The brachydactylies: a molecular disease family."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway."
    explanation: Places the BMP pathway at the centre of the brachydactyly disease family.
  downstream:
  - target: Hypoplasia of the Index and Fifth Middle Phalanges
    description: >-
      Reduced chondrogenic output in the second (and fifth) digital ray leaves a
      rudimentary, often triangular middle phalanx.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - suppressed chondrogenesis in the prechondrogenic condensation
    - mispositioned interphalangeal joint segmentation
    evidence:
    - reference: PMID:14523231
      reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Overexpression of mutant chBmpR1b in vivo in chick embryos by using a retroviral system resulted either in a BD phenotype with shortening and/or missing phalanges similar to the human phenotype or in severe hypoplasia of the entire limb."
      explanation: >-
        In vivo misexpression of the mutant receptor reproduces the shortened or
        missing phalanges seen in patients.
- name: Hypoplasia of the Index and Fifth Middle Phalanges
  conforms_to: "limb_digit_patterning_serial_homology#Serially Homologous Autopod Malformation"
  role: consequence
  biological_scale: TISSUE
  description: >
    The realised malformation: a hypoplastic, aplastic, or triangular
    ("delta") middle phalanx of the index finger and, less consistently, the
    fifth finger, with lateral deviation of the affected digit. Because the same
    patterning program is reused in the hindlimb autopod, the first and second
    toes are involved in roughly half of affected individuals.
  biological_processes:
  - preferred_term: Limb Morphogenesis
    term:
      id: GO:0035108
      label: limb morphogenesis
    modifier: ABNORMAL
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this article we describe the molecular cause of BDA2, a hand malformation characterized by hypoplasia/aplasia of the middle phalanx of the second and sometimes the fifth fingers"
    explanation: Defines the cardinal digital malformation of BDA2.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately half of them also had foot involvement such as deviation and shortening of the first or second toes, cutaneous syndactyly between the second and third toes, and camptodactyly."
    explanation: Quantifies hindlimb involvement in the two molecularly solved families.
  downstream:
  - target: Type A2 Brachydactyly
    causal_link_type: DIRECT
  - target: Short Middle Phalanx of the Second Finger
    causal_link_type: DIRECT
  - target: Triangular Middle Phalanx of the Second Finger
    causal_link_type: DIRECT
  - target: Short Middle Phalanx of the Fifth Finger
    causal_link_type: DIRECT
  - target: Ulnar or Radial Deviation of the Index Finger
    causal_link_type: DIRECT
  - target: Clinodactyly of the Fifth Finger
    causal_link_type: DIRECT
  - target: Short Second Toe
    causal_link_type: DIRECT
  - target: Medially Deviated Second Toe
    causal_link_type: DIRECT
  - target: Short Broad Hallux
    causal_link_type: DIRECT
  - target: Cutaneous Syndactyly of Toes
    causal_link_type: DIRECT
  - target: Camptodactyly
    causal_link_type: DIRECT
phenotypes:
- category: Skeletal
  name: Type A2 Brachydactyly
  description: >
    The defining digital pattern: hypoplasia or aplasia of the middle phalanx of
    the index finger, variably of the fifth finger, with lateral deviation of the
    affected digit.
  phenotype_term:
    preferred_term: Type A2 brachydactyly
    term:
      id: HP:0009372
      label: Type A2 brachydactyly
  frequency: OBLIGATE
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All affected individuals had the characteristic BDA2 hand phenotype consisting of medially deviated or shortened index fingers"
    explanation: The hand phenotype was present in every affected individual in both families.
- category: Skeletal
  name: Short Middle Phalanx of the Second Finger
  description: >
    Shortening or absence of the index-finger middle phalanx is the core skeletal
    lesion; radiographs show either a triangular middle phalanx or none at all.
  phenotype_term:
    preferred_term: Short middle phalanx of the 2nd finger
    term:
      id: HP:0009577
      label: Short middle phalanx of the 2nd finger
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(B) Radiograph of the triangular-shaped middle phalanx of the second finger (Right) and missing middle phalanx of the second finger (Left)."
    explanation: Radiographic documentation of the triangular or absent index middle phalanx.
- category: Skeletal
  name: Short Middle Phalanx of the Fifth Finger
  description: >
    Fifth-finger involvement is less consistent than index involvement and is
    often expressed as clinodactyly.
  phenotype_term:
    preferred_term: Short middle phalanx of the 5th finger
    term:
      id: HP:0004220
      label: Short middle phalanx of the 5th finger
  frequency: FREQUENT
  evidence:
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autosomal-dominant brachydactyly type A2 (BDA2), a limb malformation characterized by hypoplastic middle phalanges of the second and fifth fingers"
    explanation: Fifth-finger middle-phalanx hypoplasia is part of the defining description.
- category: Skeletal
  name: Ulnar or Radial Deviation of the Index Finger
  description: >
    A triangular middle phalanx grows preferentially along one side, so the
    distal segment of the index finger deviates rather than lengthening.
  phenotype_term:
    preferred_term: Ulnar deviation of the 2nd finger
    term:
      id: HP:0009464
      label: Ulnar deviation of the 2nd finger
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(AandC) Short and medially deviated second fingers and clinodactyly of the fifth fingers."
    explanation: Documents index-finger deviation and fifth-finger clinodactyly in affected individuals.
- category: Skeletal
  name: Short Second Toe
  description: >
    Hindlimb involvement mirrors the hand: deviation and shortening of the first
    or second toes occurred in about half of the affected individuals in the
    original molecular series, and the review literature treats second-toe
    deformity as at least as consistent as index-finger deformity.
  phenotype_term:
    preferred_term: Short 2nd toe
    term:
      id: HP:0001885
      label: Short 2nd toe
  frequency: FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Approximately half of them also had foot involvement such as deviation and shortening of the first or second toes, cutaneous syndactyly between the second and third toes, and camptodactyly."
    explanation: Quantifies foot involvement in two molecularly confirmed BDA2 families.
- category: Skeletal
  name: Cutaneous Syndactyly of Toes
  description: >
    Soft-tissue syndactyly between the second and third toes is a recurring minor
    feature of the BDA2 foot.
  phenotype_term:
    preferred_term: 2-3 toe cutaneous syndactyly
    term:
      id: HP:0005709
      label: 2-3 toe cutaneous syndactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cutaneous syndactyly between the second and third toes"
    explanation: Lists 2-3 toe cutaneous syndactyly among the observed foot findings.
- category: Skeletal
  name: Triangular Middle Phalanx of the Second Finger
  description: >
    Where the index middle phalanx is present rather than absent it is
    characteristically triangular - the "delta phalanx". Its epiphysis runs
    along the shortened side, so growth can only push the digit sideways, which
    is why the deviation and the shortening are one finding rather than two.
  phenotype_term:
    preferred_term: Triangular shaped middle phalanx of the 2nd finger
    term:
      id: HP:0009575
      label: Triangular shaped middle phalanx of the 2nd finger
  frequency: FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(B) Radiograph of the triangular-shaped middle phalanx of the second finger (Right) and missing middle phalanx of the second finger (Left)."
    explanation: Radiographic documentation of the triangular index middle phalanx alongside the aplastic form.
- category: Skeletal
  name: Clinodactyly of the Fifth Finger
  description: >
    Fifth-finger involvement in BDA2 is usually expressed as clinodactyly rather
    than as frank absence of the middle phalanx.
  phenotype_term:
    preferred_term: Clinodactyly of the 5th finger
    term:
      id: HP:0004209
      label: Clinodactyly of the 5th finger
  frequency: FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(AandC) Short and medially deviated second fingers and clinodactyly of the fifth fingers."
    explanation: Documents fifth-finger clinodactyly in the molecularly solved families.
  - reference: PMID:36064339
    reference_title: "A novel variant in the ROR2 gene underlying brachydactyly type B: a case report."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "BDA2112,600Short middle phalanx with clinodactyly of the index fingers and second toes"
    explanation: >-
      A recent review tabulates clinodactyly as part of the defining BDA2
      description, independent of the original family series.
- category: Skeletal
  name: Short Broad Hallux
  description: >
    The great toe is short and broad with lateral deviation of its distal
    phalanx, reflecting malformation of the hallux proximal phalanx.
  phenotype_term:
    preferred_term: Broad hallux
    term:
      id: HP:0010055
      label: Broad hallux
  frequency: FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(D) Short, broad, and laterally deviated first toe and medial deviation of the second toe."
    explanation: Photographic documentation of the short, broad, laterally deviated hallux.
- category: Skeletal
  name: Medially Deviated Second Toe
  description: >
    Medial deviation of the second toe accompanies its shortening and is at
    least as consistent a finding as the index-finger deformity.
  phenotype_term:
    preferred_term: Medially deviated second toe
    term:
      id: HP:0008096
      label: Medially deviated second toe
  frequency: FREQUENT
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "(D) Short, broad, and laterally deviated first toe and medial deviation of the second toe."
    explanation: Documents medial deviation of the second toe in affected individuals.
- category: Skeletal
  name: Camptodactyly
  description: >
    Flexion contracture of one or more digits was noted among the foot findings
    in the original molecular series.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "cutaneous syndactyly between the second and third toes, and camptodactyly"
    explanation: Lists camptodactyly among the observed findings in the two BDA2 families.
genetic:
- name: BMPR1B Pathogenic Variants
  gene_term:
    preferred_term: BMPR1B
    term:
      id: hgnc:1077
      label: BMPR1B
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Heterozygous missense variants at the BDA2 locus on 4q21-q25. I200K lies in
    the GS domain and abolishes kinase activity; R486W lies C-terminal to the
    kinase domain and retains it. Both act as dominant negatives on
    chondrogenesis.
  evidence:
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed linkage analysis in two unrelated German families and mapped a locus for BD type A2 to 4q21-q25."
    explanation: Maps the BDA2 locus to the interval containing BMPR1B.
  - reference: PMID:14523231
    reference_title: Mutations in bone morphogenetic protein receptor 1B cause brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the other family we identified a C1456 --> T mutation leading to an arginine-to-tryptophan amino acid change (R486W) in a highly conserved region C-terminal of the BMPR1B kinase domain."
    explanation: Identifies the second BDA2 allele in an independent family.
- name: GDF5 Pathogenic Variants
  gene_term:
    preferred_term: GDF5
    term:
      id: hgnc:4220
      label: GDF5
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Variants in the GDF5 precursor processing site (R380Q) cause BDA2 by
    preventing release of the mature ligand. GDF5 is also the BDC gene and a
    BDA1 gene, so allele-specific effect — not gene identity — determines which
    brachydactyly type results.
  evidence:
  - reference: PMID:18203755
    reference_title: Brachydactyly type A2 associated with a defect in proGDF5 processing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The observed mutation is located at the processing site of the protein, at which the GDF5 precursor is thought to be cleaved releasing the mature molecule from the prodomain."
    explanation: Places the BDA2 allele at the precursor cleavage site.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "has been shown to be due to mutations in the Bone morphogenetic protein receptor 1B (BMPR1B) or in its ligand Growth and differentiation factor 5 (GDF5)"
    explanation: Independent confirmation that GDF5 is an established BDA2 gene.
- name: BMP2 Limb-Enhancer Microduplication
  gene_term:
    preferred_term: BMP2
    term:
      id: hgnc:1069
      label: BMP2
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    A tandem microduplication of roughly 5.5 kb of conserved noncoding sequence
    about 110 kb downstream of BMP2 on 20p12.3, found in two families with no
    BMPR1B or GDF5 coding variant. The duplicated interval behaves as a
    limb-specific BMP2 enhancer in transgenic mice.
  evidence:
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A linkage analysis performed in a mutation-negative family identified a novel locus for BDA2 on chromosome 20p12.3 that incorporates the gene for Bone morphogenetic protein 2 (BMP2)."
    explanation: Establishes the third BDA2 locus in coding-variant-negative families.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Screening of other patients by qPCR revealed a similar duplication in a second family."
    explanation: Replication of the duplication in an independent family.
diagnosis:
- name: Clinical-radiographic and molecular diagnosis
  description: >-
    Diagnosis rests on the clinical and radiographic pattern of a hypoplastic,
    absent, or triangular middle phalanx of the index finger with lateral
    deviation, confirmed where possible by finding a BMPR1B or GDF5 variant or,
    in coding-negative families, a BMP2 enhancer duplication on array CGH or
    qPCR. Sequencing alone will miss the regulatory form.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: >-
    Triangular or absent middle phalanx of the second (and sometimes fifth)
    finger on hand radiographs, with a causal BMPR1B or GDF5 variant or a 20p12.3
    noncoding duplication when molecularly solved.
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Diagnosis is clinical, anthropometric and radiological."
    explanation: Establishes the clinical-radiographic basis of brachydactyly diagnosis.
  - reference: PMID:19327734
    reference_title: Duplications involving a conserved regulatory element downstream of BMP2 are associated with brachydactyly type A2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No point mutation was identified in BMP2, so a high-density array CGH analysis covering the critical interval of approximately 1.3 Mb was performed."
    explanation: >-
      Shows why copy-number analysis is needed: the regulatory form is invisible
      to sequencing of the coding region.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for autosomal dominant transmission with variable expressivity,
    including the possibility of a regulatory (copy-number) rather than coding
    lesion in the family.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - 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 for isolated brachydactyly.
- name: Function- or Cosmesis-Directed Hand Surgery
  description: >-
    Surgery is reserved for meaningful impairment of hand function or selected
    cosmetic indications, and is usually not required in isolated brachydactyly.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:18554391
    reference_title: Brachydactyly.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed."
    explanation: Defines the limited surgical indications in isolated brachydactyly.
- name: Hand Function Rehabilitation
  description: >-
    Physical and occupational therapy where digital shortening limits function.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - 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:19790289
  title: "The brachydactylies: a molecular disease family."
- reference: PMID:18554391
  title: Brachydactyly.

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2

PMID:19790289

The brachydactylies: a molecular disease family.

No top-level findings curated for this source.

PMID:18554391

Brachydactyly.

No top-level findings curated for this source.

Brachydactyly Type A2

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