Mesomelic Dysplasia, Savarirayan Type

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Classifications

Harrison's Part

ISDS Skeletal Nosology

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Inheritance

1

Autosomal dominant, often de novo HP:0000006

Heterozygous 6p22.3 rearrangements are associated with disease. De novo origin was confirmed for deletion alleles in patients 1 and 3 of the 2015 series and for the 2026 inversion. The parents of patient 2 in the 2015 series were unavailable for testing, so de novo origin cannot be assigned to every reported allele.

Autosomal dominant inheritance

Show evidence (2 references)

PMID:42069959 SUPPORT Human Clinical

"However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Documents the de novo origin of the inversion allele.

PMID:26032025 SUPPORT Human Clinical

"We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3."

The abstract summarizes the deletion series as de novo. The Results section specifies parental confirmation for patients 1 and 3 and states that the parents of patient 2 were unavailable for testing.

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Discussions and Knowledge Gaps

1

Has ID4 actually been shown to be misexpressed in the limb bud in this disorder, or is the attribution still entirely positional?

KNOWLEDGE GAP mdst_id4_misexpression_unmeasured

Attached to

pathophysiology#Enhancer Adoption by ID4 in the Limb Bud

Both papers state the model as a prediction from breakpoint position — "could result", "we predict", "likely to place" — and neither reports an expression measurement. The comparison case is instructive: at the HOXD locus the equivalent hypothesis was settled by an engineered mouse inversion plus an in-cis null rescue. Nothing equivalent exists here, and with five patients worldwide the route to it is a mouse model of the rearrangement rather than more human genetics.

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Pathophysiology

4

6p22.3 Deletion

Overlapping deletions remove MBOAT1, E2F3, CDKAL1 and SOX4 while retaining ID4. De novo origin was confirmed in two of the three patients in the 2015 series; parental samples were unavailable for the third.

Genetic context Variant type: deletion Genomic context: coding sequence Genomic context: intron Genomic context: intergenic region variant_origin: GERMLINE zygosity: HETEROZYGOUS

Downstream

Enhancer Adoption by ID4 in the Limb Bud Removal of regulatory boundaries is predicted to expose intact ID4 to limb enhancers; the proposed contact change has not been measured.

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4."

The deleted genes are distinct from the proposed regulatory target ID4. The Results and Table 2 document the individual deletion intervals and parental testing.

6p22.3 Inversion

A de novo inversion, accompanied by a breakpoint insertion, was identified by whole-genome sequencing after a negative array. ID4 coding sequence is retained. The junction details are recorded in the individual variant entry.

Genetic context Variant type: inversion variant_origin: DE_NOVO zygosity: HETEROZYGOUS

Downstream

Enhancer Adoption by ID4 in the Limb Bud Reorganization of regulatory boundaries is predicted to reposition ID4 relative to limb enhancers; the proposed contact change remains unmeasured.

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Establishes the inversion and its de novo origin. The linked LOVD record additionally describes the insertion at the inversion junction.

Enhancer Adoption by ID4 in the Limb Bud

Regulatory category: GOE (Hypothetical)

Both allele classes are predicted to disrupt topologically associating domains at 6p22.3 and place ID4 nearer to limb enhancers that normally cannot reach it. ID4 is an inhibitor-of-DNA-binding HLH protein — a dominant-negative regulator of bHLH transcription factors — so misexpressing it in the limb bud would be expected to interfere with, rather than augment, the differentiation programs those factors run. Both papers state this as a prediction from breakpoint position, not as a measured expression change.

ID4 hgnc:5363

Enhancer-driven regulation of ID4 transcription in the limb bud GO:0006357 ↕ DYSREGULATED limb development GO:0060173 ↕ DYSREGULATED

Downstream

Lower-Limb Mesomelic Shortening Proposed ID4 misexpression could disrupt limb differentiation and produce mesomelia; the intervening cellular changes have not been demonstrated.

Show evidence (3 references)

PMID:26032025 SUPPORT INDIRECT Human Clinical

"We identified a fourth patient with intellectual disability and an overlapping slightly larger do novo deletion also encompassing the flanking gene ID4. Given the fact that the fourth patient had no skeletal abnormalities and none of the genes in the deleted interval are known to be associated..."

The comparison motivates the enhancer-adoption hypothesis. It does not exclude variable expressivity or incomplete penetrance of effects from deleted genes.

PMID:26032025 SUPPORT INDIRECT Computational

"Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4. Thus, the deletion could result in the aberrant activation and misexpression of ID4 in the limb bud, thereby causing the mesomelic dysplasia."

States the enhancer-adoption model. The source says "could result", and no expression measurement is reported; genomic-position analysis supports the proposed expression mechanism indirectly.

PMID:42069959 SUPPORT INDIRECT Computational

"we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression"

The same model applied to the inversion allele, again explicitly as a prediction ("we predict", "likely", "could", "potentially").

Lower-Limb Mesomelic Shortening

Severe shortness of the middle segment of the lower limb, with hypoplastic triangular tibiae and hypoplastic or abnormally shaped fibulae. The predominance in the lower limb is characteristic; upper-limb findings vary and included short radii and ulnae in one patient in the defining series.

Downstream

Lower-Limb Mesomelia Shortening of the tibial and fibular segments produces lower-limb mesomelia.

Hypoplastic Triangular Tibia The triangular tibia is the characteristic radiographic form the shortened segment takes.

Fibular Hypoplasia The fibula is hypoplastic or abnormally shaped alongside the tibia.

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae."

Gives the defining radiographic phenotype.

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Pathograph

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Phenotypes

3

Lower-Limb Mesomelia VERY_FREQUENT Skeletal HP:0003027

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae."

Records the phenotype in all patients of the defining series and its lower-limb predominance.

Hypoplastic Triangular Tibia VERY_FREQUENT Skeletal HP:0005736

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"Our data indicate that the distinct deletion 6p22.3 is associated with mesomelic dysplasia Savarirayan type featuring hypoplastic, triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae."

Names the triangular hypoplastic tibia as a defining radiographic feature.

Fibular Hypoplasia VERY_FREQUENT Skeletal HP:0003038

Show evidence (1 reference)

PMID:26032025 SUPPORT Human Clinical

"All patients showed mesomelia of the lower limbs with hypoplastic tibiae and fibulae."

Records fibular hypoplasia in all patients of the defining series.

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Genetic Associations

1

ID4 (6p22.3 regulatory landscape)

Gene: ID4 hgnc:5363 gene page relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4."

Names the genes actually removed, which are not the gene the disorder is attributed to.

PMID:42069959 SUPPORT Human Clinical

"Thus, this case broadens the genetic spectrum in MDST and provides further support to the role of ID4 dysregulation as the main underlying molecular mechanism of this ultra-rare skeletal disorder."

States the ID4-dysregulation attribution, at the strength the source gives it ("further support", not proof).

Variants (3)

6p22.3 deletion spanning hg19 chr6:19974194-22013061

Regulatory target: ID4 hgnc:5363 deletion

Genomic context: coding sequence intron intergenic region

Heterozygous deletion reported as arr[hg19] 6p22.3 (19974194-22013061)x1 in the 2015 series. These coordinates are the outermost deleted probes, not nucleotide-resolved breakpoints; Table 2 gives flanking normal probes at chr6:19965294 and chr6:22016585. The interval removes MBOAT1, E2F3, CDKAL1 and SOX4, including coding, intronic and intervening intergenic sequence, while retaining ID4. ID4 is the proposed regulatory target, not a deleted coding gene. Parental samples were unavailable, so origin is unconfirmed for this allele despite the abstract's collective de novo wording.

Functional effects

Spatial regulation of ID4 expression during limb development predicted enhancer adoption TAD BOUNDARY

The proposed outcome is gain of ectopic ID4 expression in limb buds. This remains a positional hypothesis; expression was not measured.

Mechanism: Deletion of regulatory boundaries is predicted to expose intact ID4 to normally insulated limb enhancers.

Developmental stage: embryonic limb development

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4."

Establishes the coding-gene content of the disease-associated deletions. The Results and Table 2 identify this allele as patient 2 and give the hg19 probe limits and unavailable parental testing.

PMID:26032025 SUPPORT INDIRECT Computational

"Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4."

Genomic-position analysis supports the enhancer-adoption hypothesis, not a directly observed ID4 expression change.

6p22.3 deletion spanning hg19 chr6:19849280-21604600

Regulatory target: ID4 hgnc:5363 deletion

Genomic context: coding sequence intron intergenic region

De novo heterozygous deletion reported as arr[hg19] 6p22.3 (19849280-21604600)x1 in the 2015 series. These are the outermost deleted probes; Table 2 gives flanking normal probes at chr6:19840492 and chr6:21630684. The approximately 1.76 Mb minimum interval removes MBOAT1, E2F3, CDKAL1 and SOX4, including coding, intronic and intervening intergenic sequence, but leaves the proposed target ID4 intact. The deletion and its de novo origin were confirmed by qPCR.

Functional effects

Spatial regulation of ID4 expression during limb development predicted enhancer adoption TAD BOUNDARY

Ectopic ID4 expression is proposed to explain the limb phenotype; neither the expression change nor the causal enhancer contacts were measured in this allele.

Mechanism: Removal of regulatory boundaries is predicted to place limb enhancers in the regulatory domain of ID4 without deleting its coding sequence.

Developmental stage: embryonic limb development

Show evidence (2 references)

PMID:26032025 SUPPORT Human Clinical

"We performed array comparative genomic hybridisation in three unrelated patients with mesomelic dysplasia Savarirayan type and identified 2 Mb overlapping de novo microdeletions on chromosome 6p22.3."

The abstract summarizes the overlapping deletions. The Results and Table 2 identify this smaller allele as patient 3, give its hg19 probe limits and document parental qPCR confirmation of de novo origin.

PMID:26032025 SUPPORT INDIRECT Computational

"Analysis of the genomic region showed that the deletion removes two regulatory boundaries and brings several potential limb enhancers into close proximity of ID4."

The preserved ID4 coding sequence and altered regulatory boundaries support a predicted expression effect rather than ID4 haploinsufficiency.

6p22.3 inversion with a breakpoint insertion

Regulatory target: ID4 hgnc:5363 inversion

De novo inversion identified by whole-genome sequencing after a negative array in the 2026 report. The author-deposited LOVD record gives the hg38 genomic description on chromosome 6 as g.19066060_21763046delins[CGAATTAACTGT;19066051_21763045inv]. Supplementary Figure 2 documents a templated insertion at the telomeric breakpoint, so this is not represented as a completely balanced simple inversion. ID4 is a predicted regulatory target whose coding sequence is retained. Genomic contexts are omitted because the accessed abstract and supplement do not establish transcript-specific breakpoint overlaps.

Functional effects

Spatial regulation of ID4 expression during limb development predicted enhancer adoption TAD BOUNDARY

The proposed gain of ectopic expression is supported by genomic position and POSTRE prediction, not by direct measurement of ID4 RNA or protein in developing limb tissue.

Mechanism: The inversion is predicted to alter TAD organization and reposition intact ID4 relative to telomeric limb enhancers.

Developmental stage: embryonic limb development

External assertions

LOVD 6p22.3 inversion record 0001070241

Global Variome shared LOVD author-deposited variant record 0001070241

Variant linked from individual 00474045 in the publication's data availability statement. The record includes hg19 and hg38 descriptions and resolves the associated inversion junction insertion.

Show evidence (2 references)

PMID:42069959 SUPPORT Human Clinical

"No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Establishes the observed SV class and de novo origin. Supplementary Figure 2 and the linked LOVD deposition provide junction detail.

PMID:42069959 SUPPORT INDIRECT Computational

"we predict that the structural variant disrupts several topologically associated domains (TADs) in the region and is likely to place ID4 in closer proximity to more telomerically located limb enhancers, which could result in enhancer adoption and potentially lead to ID4 limb misexpression"

The authors predict altered enhancer access. This is mechanistic support by inference, not confirmation of an ectopic-expression phenotype.

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Diagnosis

2

Radiographic Recognition

Suspected from severe lower-limb mesomelia with hypoplastic triangular tibiae and hypoplastic or abnormally shaped fibulae. Upper-limb involvement is variable. The radiographic picture is characteristic enough that the 2026 inversion case was recognized clinically before any variant was found.

diagnostic radiography NCIT:C17369

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"a 9 year-old female with severe mesomelic lower limb shortening and characteristic radiographic findings, highly resembling those identified in previous MDST patients"

Supports radiographic recognizability: the diagnosis was made on imaging resemblance to prior cases.

Structural-Variant Analysis of 6p22.3

Array CGH identifies the microdeletion alleles. A negative array does not exclude the diagnosis: the fifth reported patient had a normal array and a de novo inversion found only on whole-genome sequencing. In a radiographically typical case with a negative array, WGS is the next step.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"No deletion was identified by array. However, whole genome sequencing (WGS) revealed a de novo inversion at 6p22.3."

Directly supports the recommendation to proceed to WGS after a negative array.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Five reported patients as of the 2026 inversion case: four with 6p22.3 microdeletions and one with an inversion. No denominator-based estimate exists.

Show evidence (1 reference)

PMID:42069959 SUPPORT Human Clinical

"Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions. To date, only four cases have been reported. Here, we report a fifth case"

Gives the cumulative case count directly, the basis for the ULTRA_RARE band.

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Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Mesomelic Dysplasia, Savarirayan Type:

Mesomelic dysplasia, Kantaputra type

Overlapping Features The same class of lesion — enhancer adoption after a structural rearrangement — at a different locus (HOXD, 2q31), with all four limbs affected and carpal and tarsal synostoses. The mechanistic parallel is close enough that the two disorders are best read together.

KINSSHIP syndrome

Overlapping Features Named in the KINSSHIP acronym for its Savarirayan-like limb radiographs, but a different condition per the nosology's own comment: AFF3-related, and with horseshoe kidney, seizures, and intellectual disability that this disorder does not produce.

Langer mesomelic dysplasia

Overlapping Features Biallelic SHOX deficiency, which affects the forearms as well as the lower legs and has no 6p22.3 lesion.

{ }

Source YAML

click to show

name: Mesomelic Dysplasia, Savarirayan Type
synonyms:
- Mesomelic dysplasia (Savarirayan type), ID4-related
- MDST
- mesomelic dysplasia with absent fibulae and triangular tibiae
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Mesomelic dysplasia of the Savarirayan type is an ultra-rare skeletal
  dysplasia in which the middle segment of the lower limb is severely short,
  with hypoplastic triangular tibiae and hypoplastic or abnormally shaped
  fibulae. Lower-limb involvement predominates, although upper-limb abnormalities
  also occur. Associated structural variants at 6p22.3 include microdeletions
  and an inversion, with de novo origin confirmed in several cases. The proposed
  mechanism is disruption of regulatory boundaries followed by enhancer adoption
  and ectopic ID4 expression in the limb bud. The deletions encompass coding
  genes, but overlapping larger deletions that also remove ID4 can lack the
  characteristic skeletal phenotype. This comparison and the inversion support
  a regulatory mechanism; ID4 misexpression has not been demonstrated directly.
disease_term:
  preferred_term: mesomelic dysplasia, Savarirayan type
  term:
    id: MONDO:0011530
    label: mesomelic dysplasia, Savarirayan type
parents:
- Skeletal Dysplasia
- Mesomelic Dysplasia
notes: >-
  The gene attribution here needs reading carefully. ID4 is named in the ISDS
  row and in the disorder's dyadic name, but no ID4 coding variant has been
  reported in any patient: ID4 lies outside the smallest deleted interval, and
  its involvement is inferred from the position of the rearrangement breakpoints
  relative to limb enhancers and topological boundaries. The 2026 inversion case
  strengthens that inference because it produces the characteristic phenotype
  without an array-detectable deletion. Its breakpoint insertion does not
  establish a gene-dosage mechanism. The proposed ID4 expression consequence
  remains unmeasured. GOE classifies the proposed ectopic-expression mechanism
  on the HYPOTHETICAL pathophysiology node.
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian skeletal dysplasia associated with structural variants;
      tagged on the genetics axis.
  isds_skeletal_category:
  - classification_value: mesomelic_and_rhizomesomelic_dysplasias
    notes: >-
      ISDS Nosology of Genetic Skeletal Disorders, 2023 revision (Unger et al.,
      PMID:36779427), group 15 "Mesomelic and rhizo-mesomelic dysplasias", row
      NOS 15-0150, listed as "Mesomelic dysplasia (Savarirayan type),
      ID4-related" (MIM 605274, AD), with the row's own comment recording the
      cause as microdeletions on 6p22.3. The KINSSHIP row in the same group
      (NOS 15-0160) names this type in its acronym but carries an explicit
      comment that it is a different condition. The 2019 revision (Mortier et
      al., PMID:31633310) numbered the same group 17.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Five reported patients as of the 2026 inversion case: four with 6p22.3
    microdeletions and one with an inversion. No denominator-based estimate
    exists.
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mesomelic dysplasia Savarirayan-type or ID4-related (MDST) is an
      ultra-rare skeletal dysplasia caused by chromosome 6p22.3 microdeletions.
      To date, only four cases have been reported. Here, we report a fifth case
    explanation: >-
      Gives the cumulative case count directly, the basis for the ULTRA_RARE
      band.
inheritance:
- name: Autosomal dominant, often de novo
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Heterozygous 6p22.3 rearrangements are associated with disease. De novo
    origin was confirmed for deletion alleles in patients 1 and 3 of the 2015
    series and for the 2026 inversion. The parents of patient 2 in the 2015
    series were unavailable for testing, so de novo origin cannot be assigned
    to every reported allele.
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, whole genome sequencing (WGS) revealed a de novo inversion at
      6p22.3.
    explanation: >-
      Documents the de novo origin of the inversion allele.
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed array comparative genomic hybridisation in three unrelated
      patients with mesomelic dysplasia Savarirayan type and identified 2 Mb
      overlapping de novo microdeletions on chromosome 6p22.3.
    explanation: >-
      The abstract summarizes the deletion series as de novo. The Results
      section specifies parental confirmation for patients 1 and 3 and states
      that the parents of patient 2 were unavailable for testing.
pathophysiology:
- name: 6p22.3 Deletion
  biological_scale: MOLECULAR
  genetic_context:
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    - intron
    - intergenic region
    zygosity: HETEROZYGOUS
    variant_origin: GERMLINE
  description: >-
    Overlapping deletions remove MBOAT1, E2F3, CDKAL1 and SOX4 while retaining
    ID4. De novo origin was confirmed in two of the three patients in the
    2015 series; parental samples were unavailable for the third.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4.
    explanation: >-
      The deleted genes are distinct from the proposed regulatory target ID4.
      The Results and Table 2 document the individual deletion intervals and
      parental testing.
  downstream:
  - target: Enhancer Adoption by ID4 in the Limb Bud
    causal_link_type: DIRECT
    description: >-
      Removal of regulatory boundaries is predicted to expose intact ID4 to
      limb enhancers; the proposed contact change has not been measured.
- name: 6p22.3 Inversion
  biological_scale: MOLECULAR
  genetic_context:
    variant_type: inversion
    zygosity: HETEROZYGOUS
    variant_origin: DE_NOVO
  description: >-
    A de novo inversion, accompanied by a breakpoint insertion, was identified
    by whole-genome sequencing after a negative array. ID4 coding sequence is
    retained. The junction details are recorded in the individual variant entry.
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No deletion was identified by array. However, whole genome sequencing
      (WGS) revealed a de novo inversion at 6p22.3.
    explanation: >-
      Establishes the inversion and its de novo origin. The linked LOVD record
      additionally describes the insertion at the inversion junction.
  downstream:
  - target: Enhancer Adoption by ID4 in the Limb Bud
    causal_link_type: DIRECT
    description: >-
      Reorganization of regulatory boundaries is predicted to reposition ID4
      relative to limb enhancers; the proposed contact change remains unmeasured.
- name: Enhancer Adoption by ID4 in the Limb Bud
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  regulatory_category: GOE
  gene:
    preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
  description: >-
    Both allele classes are predicted to disrupt topologically associating
    domains at 6p22.3 and place ID4 nearer to limb enhancers that normally
    cannot reach it. ID4 is an inhibitor-of-DNA-binding HLH protein — a
    dominant-negative regulator of bHLH transcription factors — so misexpressing
    it in the limb bud would be expected to interfere with, rather than augment,
    the differentiation programs those factors run. Both papers state this as a
    prediction from breakpoint position, not as a measured expression change.
  biological_processes:
  - preferred_term: Enhancer-driven regulation of ID4 transcription in the limb bud
    modifier: DYSREGULATED
    term:
      id: GO:0006357
      label: regulation of transcription by RNA polymerase II
  - preferred_term: limb development
    modifier: DYSREGULATED
    term:
      id: GO:0060173
      label: limb development
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a fourth patient with intellectual disability and an
      overlapping slightly larger do novo deletion also encompassing the
      flanking gene ID4. Given the fact that the fourth patient had no skeletal
      abnormalities and none of the genes in the deleted interval are known to
      be associated with abnormalities in skeletal development, other mutational
      mechanisms than loss of function of the deleted genes have to be
      considered.
    explanation: >-
      The comparison motivates the enhancer-adoption hypothesis. It does not
      exclude variable expressivity or incomplete penetrance of effects from
      deleted genes.
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      Analysis of the genomic region showed that the deletion removes two
      regulatory boundaries and brings several potential limb enhancers into
      close proximity of ID4. Thus, the deletion could result in the aberrant
      activation and misexpression of ID4 in the limb bud, thereby causing the
      mesomelic dysplasia.
    explanation: >-
      States the enhancer-adoption model. The source says "could result", and no
      expression measurement is reported; genomic-position analysis supports
      the proposed expression mechanism indirectly.
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: COMPUTATIONAL
    snippet: >-
      we predict that the structural variant disrupts several topologically
      associated domains (TADs) in the region and is likely to place ID4 in
      closer proximity to more telomerically located limb enhancers, which could
      result in enhancer adoption and potentially lead to ID4 limb misexpression
    explanation: >-
      The same model applied to the inversion allele, again explicitly as a
      prediction ("we predict", "likely", "could", "potentially").
  downstream:
  - target: Lower-Limb Mesomelic Shortening
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed ID4 misexpression could disrupt limb differentiation and produce
      mesomelia; the intervening cellular changes have not been demonstrated.
- name: Lower-Limb Mesomelic Shortening
  biological_scale: ORGANISM
  description: >-
    Severe shortness of the middle segment of the lower limb, with hypoplastic
    triangular tibiae and hypoplastic or abnormally shaped fibulae. The
    predominance in the lower limb is characteristic; upper-limb findings vary
    and included short radii and ulnae in one patient in the defining series.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the distinct deletion 6p22.3 is associated with
      mesomelic dysplasia Savarirayan type featuring hypoplastic,
      triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.
    explanation: >-
      Gives the defining radiographic phenotype.
  downstream:
  - target: Lower-Limb Mesomelia
    causal_link_type: DIRECT
    description: >-
      Shortening of the tibial and fibular segments produces lower-limb
      mesomelia.
  - target: Hypoplastic Triangular Tibia
    causal_link_type: DIRECT
    description: >-
      The triangular tibia is the characteristic radiographic form the shortened
      segment takes.
  - target: Fibular Hypoplasia
    causal_link_type: DIRECT
    description: >-
      The fibula is hypoplastic or abnormally shaped alongside the tibia.
phenotypes:
- category: Skeletal
  name: Lower-Limb Mesomelia
  description: >-
    Severe mesomelic shortening predominantly affects the lower limbs;
    upper-limb abnormalities are variable rather than uniformly absent.
  phenotype_term:
    preferred_term: Mesomelia
    term:
      id: HP:0003027
      label: Mesomelia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed mesomelia of the lower limbs with hypoplastic tibiae
      and fibulae.
    explanation: >-
      Records the phenotype in all patients of the defining series and its
      lower-limb predominance.
- category: Skeletal
  name: Hypoplastic Triangular Tibia
  phenotype_term:
    preferred_term: Short tibia
    term:
      id: HP:0005736
      label: Short tibia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data indicate that the distinct deletion 6p22.3 is associated with
      mesomelic dysplasia Savarirayan type featuring hypoplastic,
      triangular-shaped tibiae and abnormally shaped or hypoplastic fibulae.
    explanation: >-
      Names the triangular hypoplastic tibia as a defining radiographic feature.
- category: Skeletal
  name: Fibular Hypoplasia
  phenotype_term:
    preferred_term: Fibular hypoplasia
    term:
      id: HP:0003038
      label: Fibular hypoplasia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients showed mesomelia of the lower limbs with hypoplastic tibiae
      and fibulae.
    explanation: >-
      Records fibular hypoplasia in all patients of the defining series.
genetic:
- name: ID4 (6p22.3 regulatory landscape)
  gene_term:
    preferred_term: ID4
    term:
      id: hgnc:5363
      label: ID4
  relationship_type: CAUSATIVE
  notes: >-
    The causal unit is a genomic region rather than a gene, and ID4 is named as
    the effector on positional grounds only — its coding sequence is intact and
    it lies outside the smallest deleted interval. Diagnostically this means ID4
    sequencing is uninformative; copy-number analysis finds the deletion alleles
    and whole-genome sequencing can identify inversion alleles. The
    deleted interval itself contains MBOAT1, E2F3, CDKAL1 and SOX4. The proposed
    regulatory effect on ID4 is distinct from the loss of these coding genes.
  evidence:
  - reference: PMID:26032025
    reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4.
    explanation: >-
      Names the genes actually removed, which are not the gene the disorder is
      attributed to.
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, this case broadens the genetic spectrum in MDST and provides further
      support to the role of ID4 dysregulation as the main underlying molecular
      mechanism of this ultra-rare skeletal disorder.
    explanation: >-
      States the ID4-dysregulation attribution, at the strength the source gives
      it ("further support", not proof).
  variants:
  - name: 6p22.3 deletion spanning hg19 chr6:19974194-22013061
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    - intron
    - intergenic region
    regulatory_target_gene:
      preferred_term: ID4
      term:
        id: hgnc:5363
        label: ID4
    description: >-
      Heterozygous deletion reported as arr[hg19] 6p22.3
      (19974194-22013061)x1 in the 2015 series. These coordinates are the
      outermost deleted probes, not nucleotide-resolved breakpoints; Table 2
      gives flanking normal probes at chr6:19965294 and chr6:22016585.
      The interval removes MBOAT1, E2F3, CDKAL1 and SOX4, including coding,
      intronic and intervening intergenic sequence, while retaining ID4.
      ID4 is the proposed regulatory target, not a deleted coding gene.
      Parental samples were unavailable, so origin is unconfirmed for this
      allele despite the abstract's collective de novo wording.
    functional_effects:
    - function: Spatial regulation of ID4 expression during limb development
      type: predicted enhancer adoption
      regulatory_element_type: TAD_BOUNDARY
      affected_developmental_stage: embryonic limb development
      regulatory_mechanism: >-
        Deletion of regulatory boundaries is predicted to expose intact ID4
        to normally insulated limb enhancers.
      description: >-
        The proposed outcome is gain of ectopic ID4 expression in limb buds.
        This remains a positional hypothesis; expression was not measured.
    evidence:
    - reference: PMID:26032025
      reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The deletions encompass four known genes: MBOAT1, E2F3, CDKAL1 and SOX4.
      explanation: >-
        Establishes the coding-gene content of the disease-associated
        deletions. The Results and Table 2 identify this allele as patient 2
        and give the hg19 probe limits and unavailable parental testing.
    - reference: PMID:26032025
      reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Analysis of the genomic region showed that the deletion removes two
        regulatory boundaries and brings several potential limb enhancers into
        close proximity of ID4.
      explanation: >-
        Genomic-position analysis supports the enhancer-adoption hypothesis,
        not a directly observed ID4 expression change.
  - name: 6p22.3 deletion spanning hg19 chr6:19849280-21604600
    variant_type: deletion
    genomic_contexts:
    - coding sequence
    - intron
    - intergenic region
    regulatory_target_gene:
      preferred_term: ID4
      term:
        id: hgnc:5363
        label: ID4
    description: >-
      De novo heterozygous deletion reported as arr[hg19] 6p22.3
      (19849280-21604600)x1 in the 2015 series. These are the outermost
      deleted probes; Table 2 gives flanking normal probes at chr6:19840492
      and chr6:21630684. The approximately 1.76 Mb minimum interval removes
      MBOAT1, E2F3, CDKAL1 and SOX4, including coding, intronic and intervening
      intergenic sequence, but leaves the proposed target ID4 intact.
      The deletion and its de novo origin were confirmed by qPCR.
    functional_effects:
    - function: Spatial regulation of ID4 expression during limb development
      type: predicted enhancer adoption
      regulatory_element_type: TAD_BOUNDARY
      affected_developmental_stage: embryonic limb development
      regulatory_mechanism: >-
        Removal of regulatory boundaries is predicted to place limb enhancers
        in the regulatory domain of ID4 without deleting its coding sequence.
      description: >-
        Ectopic ID4 expression is proposed to explain the limb phenotype;
        neither the expression change nor the causal enhancer contacts were
        measured in this allele.
    evidence:
    - reference: PMID:26032025
      reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We performed array comparative genomic hybridisation in three unrelated
        patients with mesomelic dysplasia Savarirayan type and identified 2 Mb
        overlapping de novo microdeletions on chromosome 6p22.3.
      explanation: >-
        The abstract summarizes the overlapping deletions. The Results and
        Table 2 identify this smaller allele as patient 3, give its hg19 probe
        limits and document parental qPCR confirmation of de novo origin.
    - reference: PMID:26032025
      reference_title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: >-
        Analysis of the genomic region showed that the deletion removes two
        regulatory boundaries and brings several potential limb enhancers into
        close proximity of ID4.
      explanation: >-
        The preserved ID4 coding sequence and altered regulatory boundaries
        support a predicted expression effect rather than ID4 haploinsufficiency.
  - name: 6p22.3 inversion with a breakpoint insertion
    variant_type: inversion
    regulatory_target_gene:
      preferred_term: ID4
      term:
        id: hgnc:5363
        label: ID4
    description: >-
      De novo inversion identified by whole-genome sequencing after a negative
      array in the 2026 report. The author-deposited LOVD record gives the hg38
      genomic description on chromosome 6 as
      g.19066060_21763046delins[CGAATTAACTGT;19066051_21763045inv].
      Supplementary Figure 2 documents a templated insertion at the telomeric
      breakpoint, so this is not represented as a completely balanced simple
      inversion. ID4 is a predicted regulatory target whose coding sequence is
      retained. Genomic contexts are omitted because the accessed abstract and
      supplement do not establish transcript-specific breakpoint overlaps.
    external_assertions:
    - name: LOVD 6p22.3 inversion record 0001070241
      source: Global Variome shared LOVD
      external_id: '0001070241'
      assertion_type: author-deposited variant record
      url: https://databases.lovd.nl/shared/individuals/00474045
      description: >-
        Variant linked from individual 00474045 in the publication's data
        availability statement. The record includes hg19 and hg38 descriptions
        and resolves the associated inversion junction insertion.
    functional_effects:
    - function: Spatial regulation of ID4 expression during limb development
      type: predicted enhancer adoption
      regulatory_element_type: TAD_BOUNDARY
      affected_developmental_stage: embryonic limb development
      regulatory_mechanism: >-
        The inversion is predicted to alter TAD organization and reposition
        intact ID4 relative to telomeric limb enhancers.
      description: >-
        The proposed gain of ectopic expression is supported by genomic
        position and POSTRE prediction, not by direct measurement of ID4 RNA
        or protein in developing limb tissue.
    evidence:
    - reference: PMID:42069959
      reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        No deletion was identified by array. However, whole genome sequencing
        (WGS) revealed a de novo inversion at 6p22.3.
      explanation: >-
        Establishes the observed SV class and de novo origin. Supplementary
        Figure 2 and the linked LOVD deposition provide junction detail.
    - reference: PMID:42069959
      reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: COMPUTATIONAL
      snippet: >-
        we predict that the structural variant disrupts several topologically
        associated domains (TADs) in the region and is likely to place ID4 in
        closer proximity to more telomerically located limb enhancers, which could
        result in enhancer adoption and potentially lead to ID4 limb misexpression
      explanation: >-
        The authors predict altered enhancer access. This is mechanistic
        support by inference, not confirmation of an ectopic-expression phenotype.
diagnosis:
- name: Radiographic Recognition
  description: >-
    Suspected from severe lower-limb mesomelia with hypoplastic triangular
    tibiae and hypoplastic or abnormally shaped fibulae. Upper-limb involvement
    is variable. The radiographic picture is characteristic enough that the 2026
    inversion case was recognized clinically before any variant was found.
  diagnosis_term:
    preferred_term: diagnostic radiography
    term:
      id: NCIT:C17369
      label: Imaging Procedure
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 9 year-old female with severe mesomelic lower limb shortening and
      characteristic radiographic findings, highly resembling those identified
      in previous MDST patients
    explanation: >-
      Supports radiographic recognizability: the diagnosis was made on imaging
      resemblance to prior cases.
- name: Structural-Variant Analysis of 6p22.3
  description: >-
    Array CGH identifies the microdeletion alleles. A negative array does not
    exclude the diagnosis: the fifth reported patient had a normal array and a
    de novo inversion found only on whole-genome sequencing. In a
    radiographically typical case with a negative array, WGS is the next step.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:42069959
    reference_title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No deletion was identified by array. However, whole genome sequencing
      (WGS) revealed a de novo inversion at 6p22.3.
    explanation: >-
      Directly supports the recommendation to proceed to WGS after a negative
      array.
differential_diagnoses:
- name: Mesomelic dysplasia, Kantaputra type
  description: >-
    The same class of lesion — enhancer adoption after a structural rearrangement
    — at a different locus (HOXD, 2q31), with all four limbs affected and carpal
    and tarsal synostoses. The mechanistic parallel is close enough that the two
    disorders are best read together.
- name: KINSSHIP syndrome
  description: >-
    Named in the KINSSHIP acronym for its Savarirayan-like limb radiographs, but
    a different condition per the nosology's own comment: AFF3-related, and with
    horseshoe kidney, seizures, and intellectual disability that this disorder
    does not produce.
- name: Langer mesomelic dysplasia
  description: >-
    Biallelic SHOX deficiency, which affects the forearms as well as the lower
    legs and has no 6p22.3 lesion.
discussions:
- discussion_id: mdst_id4_misexpression_unmeasured
  kind: KNOWLEDGE_GAP
  prompt: >-
    Has ID4 actually been shown to be misexpressed in the limb bud in this
    disorder, or is the attribution still entirely positional?
  attaches_to:
  - pathophysiology#Enhancer Adoption by ID4 in the Limb Bud
  rationale: >-
    Both papers state the model as a prediction from breakpoint position — "could
    result", "we predict", "likely to place" — and neither reports an expression
    measurement. The comparison case is instructive: at the HOXD locus the
    equivalent hypothesis was settled by an engineered mouse inversion plus an
    in-cis null rescue. Nothing equivalent exists here, and with five patients
    worldwide the route to it is a mouse model of the rearrangement rather than
    more human genetics.
references:
- reference: PMID:26032025
  title: "Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type."
- reference: PMID:36779427
  title: "Nosology of genetic skeletal disorders: 2023 revision."
- reference: PMID:42069959
  title: "Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type."

📚

References & Deep Research

References

3

PMID:26032025

Microdeletions on 6p22.3 are associated with mesomelic dysplasia Savarirayan type.

No top-level findings curated for this source.

PMID:36779427

Nosology of genetic skeletal disorders: 2023 revision.

No top-level findings curated for this source.

PMID:42069959

Genomic inversion at 6p22.3 supports ID4 dysregulation as the pathogenic mechanism of Mesomelic dysplasia Savarirayan-type.

No top-level findings curated for this source.

Mesomelic Dysplasia, Savarirayan Type

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