Holt-Oram syndrome

Genetic MONDO:0007732 Pathograph 18 Show in embeddings browser

Holt-Oram syndrome is caused by heterozygous loss-of-function mutations in TBX5, a dosage-sensitive T-box transcription factor. TBX5 haploinsufficiency, compounded by impaired cooperation with cofactors such as GATA4 and chromatin-remodeling partners, disrupts cardiac septation and the conduction system. In the developing forelimb, loss of TBX5 activity disrupts preaxial (radial) ray patterning, yielding the upper-limb skeletal malformations of this heart-hand syndrome.

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Classifications

ISDS Skeletal Nosology

👪

Inheritance

Autosomal Dominant

Holt-Oram syndrome is inherited in an autosomal dominant pattern, with affected individuals typically being heterozygous carriers of TBX5 mutations. Penetrance is high but variable expressivity occurs even within families.

Show evidence (2 references)

PMID:36936432 SUPPORT

"The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father"

Case report demonstrating inheritance of TBX5 variants from heterozygous carrier parents, consistent with autosomal dominant inheritance

PMID:16183809 SUPPORT Human Clinical

"among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%"

Cohort study showing that ~74% of subjects meeting strict clinical criteria for HOS carry an identifiable TBX5 mutation, consistent with autosomal dominant inheritance of TBX5 loss-of-function alleles as the predominant disease cause.

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Pathophysiology

TBX5 Haploinsufficiency and Enhancer Dysfunction

Holt-Oram syndrome is caused by heterozygous loss-of-function mutations in TBX5, a T-box transcription factor that acts as a dosage-sensitive regulator of cardiac and forelimb development. TBX5 haploinsufficiency disrupts enhancer accessibility and 3D chromatin architecture at regulatory regions controlling genes essential for atrial identity, chamber septation, and conduction system development. In the limb, TBX5 is critical for forelimb bud initiation and radial patterning in the lateral plate mesoderm. TBX5 cooperates with cardiac transcription factors GATA4 and NKX2-5 at conserved enhancers and requires chromatin remodeling partners (BAF/SWI-SNF and NuRD/CHD4) to maintain cell-type-specific gene expression programs.

Atrial cardiomyocyte CL:0002129 Cardiac muscle cell CL:0000746

TBX5 hgnc:11604

Heart development GO:0007507 Atrial septum morphogenesis GO:0060413 Cardiac conduction GO:0061337 Limb bud formation GO:0030326 Regulation of gene expression, epigenetic GO:0040029

Chromatin GO:0000785 Nucleosome GO:0000786

Heart atrium UBERON:0002081 Forelimb bud UBERON:0005417 Atrial conduction system UBERON:0002350

Downstream

Cofactor and Chromatin Remodeling Dysfunction TBX5 haploinsufficiency reduces TBX5 occupancy at cardiac enhancers, weakening recruitment of the GATA4/NKX2-5/ZFPM2 cofactor module and the BAF and CHD4/NuRD chromatin remodelers that depend on TBX5 for targeting.

Cardiac Septation and Conduction Defects Reduced TBX5 dosage decreases transcription of downstream conduction and septation effectors (ANF/NPPA, GJA5/Cx40, Atp2a2, Ryr2), driving the structural and electrical cardiac phenotypes of HOS.

Upper Limb Morphogenesis Disruption In the lateral plate mesoderm of the prospective forelimb field, TBX5 haploinsufficiency falls below the dosage threshold required for forelimb bud initiation and preaxial radial patterning, producing the HOS upper-limb spectrum.

Show evidence (3 references)

PMID:38344303 SUPPORT Model Organism

"Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network"

Atrial-myocyte-selective Tbx5 conditional knockout mouse study (snATAC-seq, HiChIP) showing that TBX5 maintains atrial cardiomyocyte identity through a dosage-sensitive chromatin-based mechanism.

PMID:39829922 SUPPORT In Vitro

"Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced TBX5 dosage in a human model of CHD"

TBX5-heterozygous human iPSC-derived cardiomyocyte model demonstrating that TBX5 dosage affects 3D chromatin architecture, directly supporting the haploinsufficiency mechanism in HOS.

PMID:36936432 SUPPORT

"Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS"

Confirms that TBX5 sequence alterations cause HOS with novel pathogenic mechanisms including 3'-UTR variants

Cofactor and Chromatin Remodeling Dysfunction

TBX5 function depends critically on physical interactions with cardiac transcription factor GATA4 and the chromatin modulating protein ZFPM2/FOG2, which together co-occupy atrial-specific enhancers controlling genes required for atrial conduction and calcium handling. Additionally, TBX5 directly interacts with chromatin remodeling complexes including CHD4 (NuRD) and SMARCA4/BRG1 (BAF/SWI-SNF) to maintain accessible chromatin at cardiac enhancers. Reduced TBX5 dosage impairs the formation and maintenance of these enhancer-promoter loops and topologically associating domains (TADs), leading to widespread transcriptional dysregulation of conduction and chamber specification genes.

Atrial cardiomyocyte CL:0002129 Cardiac muscle cell CL:0000746

GATA4 hgnc:4173 ZFPM2 hgnc:16700 CHD4 hgnc:1919 SMARCA4 hgnc:11100 NKX2-5 hgnc:2488

Regulation of gene expression, epigenetic GO:0040029 Cardiac conduction GO:0061337

Downstream

Cardiac Septation and Conduction Defects Loss of GATA4/NKX2-5/ZFPM2 cofactor binding and CHD4/BAF chromatin-remodeler recruitment at TBX5-bound atrial enhancers collapses the gene-regulatory network for conduction (GJA5/Cx40, Atp2a2, Ryr2) and chamber septation, producing structural and electrical cardiac defects.

Show evidence (3 references)

PMID:38189150 SUPPORT Model Organism

"FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus."

ChIP-seq in mouse cardiomyocytes (adult cardiomyocyte-specific FOG2 overexpression model) demonstrates the functional interaction between TBX5, GATA4, and FOG2 at atrial enhancers.

PMID:38189150 SUPPORT Model Organism

"Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency"

Genetic evidence in mice that FOG2/ZFPM2 modulates TBX5-dependent conduction defects, supporting a direct functional interaction

PMID:39677667 SUPPORT Model Organism

"We found that TBX5 recruits CHD4, a chromatin remodeling ATPase, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). As a component of the NuRD complex, CHD4 functions to repress gene transcription. However, combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that..."

Atrial cardiomyocyte-specific Chd4 conditional knockout mouse model with snRNA-seq/snATAC-seq showing that CHD4 is directly recruited by TBX5 and is critical for maintaining atrial cardiomyocyte identity and rhythm homeostasis.

Cardiac Septation and Conduction Defects

The classical molecular mechanism by which TBX5 haploinsufficiency produces structural and electrical heart disease in HOS. TBX5 cooperates with the homeodomain transcription factor NKX2-5 to activate cardiac target genes including atrial natriuretic factor (ANF/NPPA) and connexin 40 (GJA5/Cx40), which are required for chamber septation and atrioventricular conduction. A 50% reduction in TBX5 dosage markedly decreases ANF and Cx40 transcription, impairing endocardial cushion contributions to atrial/ventricular septation and reducing conduction-system gap junction coupling. Missense TBX5 mutations additionally disrupt protein-protein interactions with NKX2-5 and impair nuclear localization of the mutant protein, providing a complementary loss-of-function mechanism alongside truncating haploinsufficiency.

Atrial cardiomyocyte CL:0002129 Cardiac muscle cell CL:0000746

NKX2-5 hgnc:2488

Atrial septum morphogenesis GO:0060413 Cardiac conduction GO:0061337

Cardiac atrium UBERON:0002081 Cardiac conduction system UBERON:0002350

Downstream

Atrial septal defect Reduced TBX5 dosage and impaired TBX5-NKX2-5 cooperative transactivation of atrial chamber/septation genes (e.g., ANF/NPPA) lead to failure of atrial septum morphogenesis and ostium-secundum-type ASD, the most common cardiac phenotype in HOS.

Ventricular septal defect TBX5 dosage reduction also impairs ventricular septation, producing VSDs that may occur in isolation or together with ASD.

Atrioventricular block Loss of TBX5/NKX2-5-dependent transcription of connexin 40 (Cx40) and other conduction-system genes reduces gap-junction coupling in the atrioventricular conduction system, producing progressive AV block independent of structural heart disease.

Atrial fibrillation TBX5/GATA4/FOG2 atrial enhancer-network disruption combined with altered Ca2+ handling and proarrhythmic action-potential remodeling (EADs) increases atrial fibrillation susceptibility.

Proarrhythmic Activity in TBX5-Null Cardiomyocytes The same TBX5-dependent conduction-gene program has an in-vitro readout in TBX5-null cardiomyocytes with proarrhythmic action-potential abnormalities.

Show evidence (3 references)

PMID:11572777 SUPPORT Model Organism

"Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription"

Mouse Tbx5+/- model directly demonstrates that 50% TBX5 dosage reduction reduces transcription of the conduction-system gap junction gene Cx40 and the atrial chamber marker ANF, providing a mechanistic link from haploinsufficiency to septation and conduction phenotypes.

PMID:11572777 SUPPORT Model Organism

"Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated"

Identifies the cooperative TBX5-NKX2-5 transactivation of atrial and conduction-system promoters that is impaired by HOS-causing TBX5 variants.

PMID:15096952 SUPPORT Human Clinical

"missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein"

Human TBX5 missense mutations cause disease through impaired cofactor interaction and protein mislocalization, complementing the truncating-allele haploinsufficiency mechanism.

Upper Limb Morphogenesis Disruption

TBX5 is required cell-autonomously in the lateral plate mesoderm of the prospective forelimb field for forelimb bud initiation and for preaxial (radial) ray patterning. Heterozygous loss-of-function variants reduce TBX5 dosage below the threshold required for normal radial ray morphogenesis, producing the dosage-sensitive HOS limb spectrum that ranges from triphalangeal thumb and thumb hypoplasia to absent thumb, radial hypoplasia and phocomelia. Limb defects in HOS are bilateral but characteristically asymmetric and can occur independently of the severity of the cardiac phenotype.

Embryonic limb morphogenesis GO:0030326

Forelimb bud UBERON:0005417

Downstream

Upper limb abnormality Failed TBX5-driven forelimb-bud initiation and radial patterning produces the cardinal HOS upper-limb phenotype, observed in essentially 100% of clinically diagnosed cases.

Radial ray defect TBX5 is specifically required for preaxial (radial) ray patterning; haploinsufficiency disrupts this program, generating the spectrum of radial ray defects from radial bowing to hypoplasia/aplasia of the radius.

Hypoplasia of the radius TBX5-dependent radial ray patterning failure produces radius hypoplasia at the severe end of the HOS limb spectrum.

Triphalangeal thumb Triphalangeal thumb is a milder manifestation of disrupted preaxial ray patterning in TBX5-haploinsufficient limb mesenchyme.

Show evidence (2 references)

PMID:8988165 SUPPORT Human Clinical

"mutations in the human TBX5 gene underlie this disorder"

Original positional cloning of TBX5 from the 12q24.1 HOS locus, establishing TBX5 as the gene whose disruption causes the characteristic radial ray and cardiac malformations.

PMID:8988165 SUPPORT Human Clinical

"haploinsufficiency of TBX5 causes Holt-Oram syndrome"

Establishes that loss of one functional TBX5 allele (haploinsufficiency) is the primary molecular mechanism producing the limb phenotype, consistent with a dosage-sensitive transcription-factor mechanism.

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Pathograph

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Phenotypes

Cardiovascular 5

Atrial septal defect FREQUENT HP:0001631

Show evidence (2 references)

PMID:39596866 SUPPORT

"Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs"

Establishes that septal defects are cardinal features of congenital heart disease associated with genetic factors including TBX5

PMID:39156428 SUPPORT

"Seventy-five percent of those with Holt-Oram syndrome have a congenital cardiac defect, which most frequently affects the septum"

Clinical epidemiology showing atrial septal defect is the most common cardiac manifestation of HOS

Atrioventricular block FREQUENT HP:0001678

Show evidence (2 references)

PMID:38189150 SUPPORT Human Clinical

"Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network"

Human atrial transcriptomic analysis showing that TBX5-dependent atrial gene networks regulate conduction and rhythm; disruption of this network drives arrhythmia and conduction abnormalities relevant to HOS.

PMID:38235884 SUPPORT

"HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances"

Clinical evidence that conduction abnormalities are a significant feature requiring therapeutic intervention in HOS

Atrial fibrillation OCCASIONAL HP:0005110

Show evidence (1 reference)

PMID:39677667 SUPPORT Model Organism

"Chd4 AKO mice had increased vulnerability to AF from electrical pacing and a fraction had spontaneous AF"

Atrial-specific Chd4-knockout mouse model shows increased atrial fibrillation susceptibility, supporting that disruption of TBX5's chromatin-remodeling partner CHD4 contributes to HOS-like arrhythmia phenotypes

Ventricular septal defect OCCASIONAL HP:0001629

Show evidence (1 reference)

PMID:39596866 SUPPORT

"Congenital heart diseases (CHDs) are a group of complex diseases characterized by structural and functional malformations during development in the human heart"

Establishes that septal defects are core manifestations of congenital heart disease linked to genetic factors like TBX5

Proarrhythmic Activity in TBX5-Null Cardiomyocytes Arrhythmia HP:0011675

Show evidence (1 reference)

PMID:28246128 SUPPORT In Vitro

"35% of TBX5-KO iPSC-CMs exhibited marked proarrhythmic activity characterized by the development of depolarizing humps during phase 2 and 3 of the action AP that resemble early after-depolarizations (EADs)"

TBX5-knockout iPSC-derived cardiomyocytes display proarrhythmic action-potential abnormalities (EADs), modeling the cardiac conduction abnormalities and arrhythmia susceptibility seen in Holt-Oram syndrome patients.

Limbs 4

Upper limb abnormality OBLIGATE Abnormality of the upper limb HP:0002817

Upper limb abnormalities are a cardinal feature of Holt-Oram syndrome, occurring in nearly 100% of affected individuals.

Show evidence (1 reference)

PMID:36936432 SUPPORT

"Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities"

Case report demonstrating upper limb abnormalities as a cardinal clinical feature of HOS

Radial ray defect FREQUENT Radial bowing HP:0002986

Show evidence (1 reference)

PMID:36936432 SUPPORT

"Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities"

Case report of HOS with upper limb alterations demonstrating the limb phenotype is a cardinal feature

Triphalangeal thumb OCCASIONAL HP:0001199

Triphalangeal thumb is the mildest end of the preaxial radial-ray spectrum produced by TBX5 haploinsufficiency. No HOS-specific PMID in this entry's reference set quotes triphalangeal thumb directly; support comes via the parent radial-ray defect phenotype and the dosage-sensitive limb-patterning mechanism described under "Upper Limb Morphogenesis Disruption".

Show evidence (1 reference)

PMID:30552424 SUPPORT Human Clinical

"the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect"

78-patient TBX5-confirmed HOS series characterizing the bilateral asymmetric radial-ray defect spectrum, of which triphalangeal thumb is the mildest preaxial manifestation; supports triphalangeal thumb as part of the HOS limb spectrum (PARTIAL — the snippet does not name triphalangeal thumb directly).

Hypoplasia of the radius OCCASIONAL HP:0002984

Show evidence (1 reference)

PMID:30552424 SUPPORT Human Clinical

"the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect"

78-patient TBX5-confirmed HOS cohort characterizing bilateral asymmetric radial-ray defects (which include radial hypoplasia) as a hallmark of TBX5-confirmed HOS.

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Genetic Associations

TBX5 (Causative)

Gene: TBX5 hgnc:11604

Show evidence (5 references)

PMID:36936432 SUPPORT

"Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS"

Directly establishes the causal relationship between TBX5 sequence variants and HOS development

PMID:38189150 SUPPORT Model Organism

"Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency"

Mouse Tbx5 haploinsufficiency model demonstrates that reduced TBX5 dosage is sufficient to produce atrial rhythm abnormalities, paralleling HOS cardiac phenotypes

PMID:8988165 SUPPORT Human Clinical

"TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family"

Original positional cloning of TBX5 from the 12q24.1 HOS locus, identifying it as the causative T-box transcription factor.

+ 2 more references

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Medical Actions

Cardiac monitoring and evaluation

Action: cardiac electrophysiologist evaluation Ontology label: Cardiac Electrophysiology Study NCIT:C80414

Regular cardiac evaluation and monitoring is essential to detect and manage arrhythmias, conduction abnormalities, and structural defects. This may include ECG, echocardiography, and long-term monitoring. Severe conduction abnormalities may require pacemaker implantation.

Target Phenotypes: Atrioventricular block HP:0001678 Atrial fibrillation HP:0005110 Arrhythmia HP:0011675

Show evidence (2 references)

PMID:38235884 SUPPORT Human Clinical

"HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances"

Direct clinical evidence that HOS patients commonly require pacemaker implantation for cardiac conduction disturbances, supporting the need for ongoing cardiac electrophysiologic monitoring and evaluation.

PMID:38189150 SUPPORT Human Clinical

"The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF"

Indirect support for cardiac monitoring (PARTIAL — the cited paper is about general HF–AF transition, not HOS-specific monitoring); included because TBX5-haploinsufficient atrial networks confer AF risk that motivates surveillance.

Surgical repair of cardiac defects

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

Surgical intervention may be necessary for significant atrial or ventricular septal defects and other structural abnormalities, depending on severity and hemodynamic significance.

Target Phenotypes: Atrial septal defect HP:0001631 Ventricular septal defect HP:0001629

Show evidence (1 reference)

PMID:39596866 SUPPORT

"Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs."

Establishes that septal defects are cardinal manifestations requiring potential surgical intervention

Orthopedic Surgical Reconstruction

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Reconstructive orthopedic surgery for severe radial-ray defects in HOS, including pollicization (transposition of the index finger to a thumb position) for absent thumb and surgical correction of radial club hand. Performed when the limb deformity meaningfully impairs hand function.

Target Phenotypes: Upper limb abnormality HP:0002817 Hypoplasia of the radius HP:0002984

Physical and Rehabilitation Therapy

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

Physical therapy and rehabilitative care to optimize upper-limb function and mobility in patients with HOS radial-ray defects and associated shoulder/elbow mobility limitations.

Target Phenotypes: Upper limb abnormality HP:0002817 Radial bowing HP:0002986 Hypoplasia of the radius HP:0002984

Show evidence (1 reference)

PMID:36936432 SUPPORT

"Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities"

Case reports of HOS patients with upper limb abnormalities requiring orthopedic and rehabilitative management

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Prevalence

European births

Birth Prevalence 0.7 per 100,000 1–9 per 1,000,000

EUROCAT registry analysis estimated prevalence of cases diagnosed prenatally or in early life at about 1 in 135,615 births.

Show evidence (1 reference)

PMID:25344219 SUPPORT Human Clinical

"The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births."

Population-based European registry study provides the clearest quantitative prevalence estimate for Holt-Oram syndrome.

📊

Related Datasets

MorPhiC Consortium null allele phenotyping of ISL1 in iPSC-derived cardiomyocytes morphic:ISL1

ISL1 is a MorPhiC anchor gene shared across all consortium data production centers. ISL1 cooperates with NKX2-5 in cardiac development, and both interact with TBX5 (the causative gene for Holt-Oram syndrome) in cardiac septation and conduction-system programs. MorPhiC iPSC-to-cardiomyocyte differentiation assays are directly relevant to interrogating the TBX5/NKX2-5/ISL1 cardiac transcription factor network whose dosage perturbation underlies HOS cardiac phenotypes.

human MULTI OMICS PERTURBATION

iPSC-derived cardiomyocyte CL:0000746

PMID:39939790

ISL1, EOMES, GCM1 and NKX2-1 are the MorPhiC anchor genes shared across all data production centers. ISL1 is relevant to Holt-Oram syndrome via its cooperation with NKX2-5 in cardiac development. Data available under CC BY 4.0 at morphic.bio.

{ }

Source YAML

click to show

name: Holt-Oram syndrome
creation_date: '2026-01-07T19:35:34Z'
description: >-
  Holt-Oram syndrome is caused by heterozygous loss-of-function mutations in TBX5, a dosage-sensitive T-box transcription factor.
  TBX5 haploinsufficiency, compounded by impaired cooperation with cofactors such as GATA4 and chromatin-remodeling partners, disrupts cardiac septation and the conduction system.
  In the developing forelimb, loss of TBX5 activity disrupts preaxial (radial) ray patterning, yielding the upper-limb skeletal malformations of this heart-hand syndrome.
category: Genetic
disease_term:
  preferred_term: Holt-Oram syndrome
  term:
    id: MONDO:0007732
    label: Holt-Oram syndrome
parents: []
synonyms:
- Heart-Hand Syndrome Type 1
- Cardiac-Limb Syndrome
- Ventriculo-Radial Dysplasia
- Holt-Oram syndrome, TBX5-related
classifications:
  isds_skeletal_category:
  - classification_value: limb_hypoplasia_reduction_defects
    notes: >-
      ISDS Nosology and Classification of Genetic Skeletal Disorders, 2019 revision
      (Mortier et al., PMID:31633310), Table 1 group 39 "Limb hypoplasia-reduction
      defects group"; listed as "Holt-Oram syndrome".
prevalence:
- population: European births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.7
  percentage: 0.7 per 100,000
  notes: >-
    EUROCAT registry analysis estimated prevalence of cases diagnosed prenatally
    or in early life at about 1 in 135,615 births.
  evidence:
  - reference: PMID:25344219
    reference_title: "Holt Oram syndrome: a registry-based study in Europe."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mean prevalence of HOS diagnosed prenatally or in the early years of life in European registries was 0.7 per 100,000 births or 1:135,615 births."
    explanation: Population-based European registry study provides the clearest quantitative prevalence estimate for Holt-Oram syndrome.
pathophysiology:
- name: TBX5 Haploinsufficiency and Enhancer Dysfunction
  description: >
    Holt-Oram syndrome is caused by heterozygous loss-of-function mutations in TBX5,
    a T-box
    transcription factor that acts as a dosage-sensitive regulator of cardiac and
    forelimb development.
    TBX5 haploinsufficiency disrupts enhancer accessibility and 3D chromatin architecture
    at
    regulatory regions controlling genes essential for atrial identity, chamber septation,
    and
    conduction system development. In the limb, TBX5 is critical for forelimb bud
    initiation and
    radial patterning in the lateral plate mesoderm. TBX5 cooperates with cardiac
    transcription
    factors GATA4 and NKX2-5 at conserved enhancers and requires chromatin remodeling
    partners
    (BAF/SWI-SNF and NuRD/CHD4) to maintain cell-type-specific gene expression programs.
  evidence:
  - reference: PMID:38344303
    reference_title: "Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tbx5 maintains atrial identity in post-natal cardiomyocytes by regulating an atrial-specific enhancer network"
    explanation: Atrial-myocyte-selective Tbx5 conditional knockout mouse study (snATAC-seq, HiChIP) showing that TBX5 maintains atrial cardiomyocyte identity through a dosage-sensitive chromatin-based mechanism.
  - reference: PMID:39829922
    reference_title: "Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Genome organization, including compartments, topologically associated domains, and chromatin loops, are sensitive to reduced TBX5 dosage in a human model of CHD"
    explanation: TBX5-heterozygous human iPSC-derived cardiomyocyte model demonstrating that TBX5 dosage affects 3D chromatin architecture, directly supporting the haploinsufficiency mechanism in HOS.
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS"
    explanation: Confirms that TBX5 sequence alterations cause HOS with novel pathogenic mechanisms including 3'-UTR variants
  gene:
    preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  cell_types:
  - preferred_term: Atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  locations:
  - preferred_term: Heart atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  - preferred_term: Forelimb bud
    term:
      id: UBERON:0005417
      label: forelimb bud
  - preferred_term: Atrial conduction system
    term:
      id: UBERON:0002350
      label: conducting system of heart
  biological_processes:
  - preferred_term: Heart development
    term:
      id: GO:0007507
      label: heart development
  - preferred_term: Atrial septum morphogenesis
    term:
      id: GO:0060413
      label: atrial septum morphogenesis
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
  - preferred_term: Limb bud formation
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
  - preferred_term: Regulation of gene expression, epigenetic
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  cellular_components:
  - preferred_term: Chromatin
    term:
      id: GO:0000785
      label: chromatin
  - preferred_term: Nucleosome
    term:
      id: GO:0000786
      label: nucleosome
  downstream:
  - target: Cofactor and Chromatin Remodeling Dysfunction
    causal_link_type: DIRECT
    description: >
      TBX5 haploinsufficiency reduces TBX5 occupancy at cardiac
      enhancers, weakening recruitment of the GATA4/NKX2-5/ZFPM2
      cofactor module and the BAF and CHD4/NuRD chromatin remodelers
      that depend on TBX5 for targeting.
  - target: Cardiac Septation and Conduction Defects
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced enhancer activity at cardiac chamber and conduction-system genes
    - Loss of TBX5-dependent 3D chromatin loops at conduction loci
    description: >
      Reduced TBX5 dosage decreases transcription of downstream
      conduction and septation effectors (ANF/NPPA, GJA5/Cx40, Atp2a2,
      Ryr2), driving the structural and electrical cardiac phenotypes
      of HOS.
  - target: Upper Limb Morphogenesis Disruption
    causal_link_type: DIRECT
    description: >
      In the lateral plate mesoderm of the prospective forelimb field,
      TBX5 haploinsufficiency falls below the dosage threshold
      required for forelimb bud initiation and preaxial radial
      patterning, producing the HOS upper-limb spectrum.
- name: Cofactor and Chromatin Remodeling Dysfunction
  description: >
    TBX5 function depends critically on physical interactions with cardiac transcription
    factor
    GATA4 and the chromatin modulating protein ZFPM2/FOG2, which together co-occupy
    atrial-specific
    enhancers controlling genes required for atrial conduction and calcium handling.
    Additionally,
    TBX5 directly interacts with chromatin remodeling complexes including CHD4 (NuRD)
    and SMARCA4/BRG1
    (BAF/SWI-SNF) to maintain accessible chromatin at cardiac enhancers. Reduced TBX5
    dosage impairs
    the formation and maintenance of these enhancer-promoter loops and topologically
    associating
    domains (TADs), leading to widespread transcriptional dysregulation of conduction
    and chamber
    specification genes.
  evidence:
  - reference: PMID:38189150
    reference_title: "A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: FOG2 bound a subset of GATA4 and TBX5 co-bound genomic locations, defining a shared atrial gene regulatory network. FOG2 repressed TBX5-dependent transcription from a subset of co-bound enhancers, including a conserved enhancer at the Atp2a2 locus.
    explanation: ChIP-seq in mouse cardiomyocytes (adult cardiomyocyte-specific FOG2 overexpression model) demonstrates the functional interaction between TBX5, GATA4, and FOG2 at atrial enhancers.
  - reference: PMID:38189150
    reference_title: "A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency"
    explanation: Genetic evidence in mice that FOG2/ZFPM2 modulates TBX5-dependent conduction defects, supporting a direct functional interaction
  - reference: PMID:39677667
    reference_title: "CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We found that TBX5 recruits CHD4, a chromatin remodeling ATPase, to 33,170 genomic regions (TBX5-enhanced CHD4 sites). As a component of the NuRD complex, CHD4 functions to repress gene transcription. However, combined snRNA-seq and snATAC-seq of CHD4 knockout (KO) and control aCMs revealed that CHD4 has both gene activator and repressor functions.
    explanation: Atrial cardiomyocyte-specific Chd4 conditional knockout mouse model with snRNA-seq/snATAC-seq showing that CHD4 is directly recruited by TBX5 and is critical for maintaining atrial cardiomyocyte identity and rhythm homeostasis.
  genes:
  - preferred_term: GATA4
    term:
      id: hgnc:4173
      label: GATA4
  - preferred_term: ZFPM2
    term:
      id: hgnc:16700
      label: ZFPM2
  - preferred_term: CHD4
    term:
      id: hgnc:1919
      label: CHD4
  - preferred_term: SMARCA4
    term:
      id: hgnc:11100
      label: SMARCA4
  - preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  cell_types:
  - preferred_term: Atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Regulation of gene expression, epigenetic
    term:
      id: GO:0040029
      label: epigenetic regulation of gene expression
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
  downstream:
  - target: Cardiac Septation and Conduction Defects
    causal_link_type: DIRECT
    description: >
      Loss of GATA4/NKX2-5/ZFPM2 cofactor binding and CHD4/BAF
      chromatin-remodeler recruitment at TBX5-bound atrial enhancers
      collapses the gene-regulatory network for conduction
      (GJA5/Cx40, Atp2a2, Ryr2) and chamber septation, producing
      structural and electrical cardiac defects.
- name: Cardiac Septation and Conduction Defects
  description: >
    The classical molecular mechanism by which TBX5 haploinsufficiency
    produces structural and electrical heart disease in HOS. TBX5
    cooperates with the homeodomain transcription factor NKX2-5 to
    activate cardiac target genes including atrial natriuretic factor
    (ANF/NPPA) and connexin 40 (GJA5/Cx40), which are required for
    chamber septation and atrioventricular conduction. A 50% reduction
    in TBX5 dosage markedly decreases ANF and Cx40 transcription,
    impairing endocardial cushion contributions to atrial/ventricular
    septation and reducing conduction-system gap junction coupling.
    Missense TBX5 mutations additionally disrupt protein-protein
    interactions with NKX2-5 and impair nuclear localization of the
    mutant protein, providing a complementary loss-of-function
    mechanism alongside truncating haploinsufficiency.
  cell_types:
  - preferred_term: Atrial cardiomyocyte
    term:
      id: CL:0002129
      label: regular atrial cardiac myocyte
  - preferred_term: Cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  biological_processes:
  - preferred_term: Atrial septum morphogenesis
    term:
      id: GO:0060413
      label: atrial septum morphogenesis
  - preferred_term: Cardiac conduction
    term:
      id: GO:0061337
      label: cardiac conduction
  locations:
  - preferred_term: Cardiac atrium
    term:
      id: UBERON:0002081
      label: cardiac atrium
  - preferred_term: Cardiac conduction system
    term:
      id: UBERON:0002350
      label: conducting system of heart
  genes:
  - preferred_term: NKX2-5
    term:
      id: hgnc:2488
      label: NKX2-5
  evidence:
  - reference: PMID:11572777
    reference_title: "A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Tbx5 haploinsufficiency also markedly decreased atrial natriuretic factor (ANF) and connexin 40 (cx40) transcription"
    explanation: >-
      Mouse Tbx5+/- model directly demonstrates that 50% TBX5 dosage
      reduction reduces transcription of the conduction-system gap
      junction gene Cx40 and the atrial chamber marker ANF, providing a
      mechanistic link from haploinsufficiency to septation and
      conduction phenotypes.
  - reference: PMID:11572777
    reference_title: "A murine model of Holt-Oram syndrome defines roles of the T-box transcription factor Tbx5 in cardiogenesis and disease."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Direct and cooperative transactivation of the ANF and cx40 promoters by Tbx5 and the homeodomain transcription factor Nkx2-5 was also demonstrated"
    explanation: >-
      Identifies the cooperative TBX5-NKX2-5 transactivation of atrial
      and conduction-system promoters that is impaired by HOS-causing
      TBX5 variants.
  - reference: PMID:15096952
    reference_title: "TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein"
    explanation: >-
      Human TBX5 missense mutations cause disease through impaired
      cofactor interaction and protein mislocalization, complementing
      the truncating-allele haploinsufficiency mechanism.
  downstream:
  - target: Atrial septal defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced TBX5/NKX2-5-driven expression of atrial septation genes
    - Failed primary atrial septum / endocardial cushion remodeling
    description: >
      Reduced TBX5 dosage and impaired TBX5-NKX2-5 cooperative
      transactivation of atrial chamber/septation genes (e.g.,
      ANF/NPPA) lead to failure of atrial septum morphogenesis and
      ostium-secundum-type ASD, the most common cardiac phenotype in
      HOS.
  - target: Ventricular septal defect
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced TBX5-dependent ventricular chamber program
    description: >
      TBX5 dosage reduction also impairs ventricular septation,
      producing VSDs that may occur in isolation or together with ASD.
  - target: Atrioventricular block
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Decreased GJA5 (connexin 40) transcription
    - Impaired conduction-system gap-junction coupling
    description: >
      Loss of TBX5/NKX2-5-dependent transcription of connexin 40
      (Cx40) and other conduction-system genes reduces gap-junction
      coupling in the atrioventricular conduction system, producing
      progressive AV block independent of structural heart disease.
  - target: Atrial fibrillation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Loss of atrial-cardiomyocyte identity
    - Dysregulation of Ca2+-handling genes (Atp2a2, Ryr2)
    description: >
      TBX5/GATA4/FOG2 atrial enhancer-network disruption combined with
      altered Ca2+ handling and proarrhythmic action-potential
      remodeling (EADs) increases atrial fibrillation susceptibility.
  - target: Proarrhythmic Activity in TBX5-Null Cardiomyocytes
    causal_link_type: DIRECT
    description: >
      The same TBX5-dependent conduction-gene program has an in-vitro
      readout in TBX5-null cardiomyocytes with proarrhythmic
      action-potential abnormalities.
- name: Upper Limb Morphogenesis Disruption
  description: >
    TBX5 is required cell-autonomously in the lateral plate mesoderm of
    the prospective forelimb field for forelimb bud initiation and for
    preaxial (radial) ray patterning. Heterozygous loss-of-function
    variants reduce TBX5 dosage below the threshold required for normal
    radial ray morphogenesis, producing the dosage-sensitive HOS limb
    spectrum that ranges from triphalangeal thumb and thumb hypoplasia
    to absent thumb, radial hypoplasia and phocomelia. Limb defects in
    HOS are bilateral but characteristically asymmetric and can occur
    independently of the severity of the cardiac phenotype.
  biological_processes:
  - preferred_term: Embryonic limb morphogenesis
    term:
      id: GO:0030326
      label: embryonic limb morphogenesis
  locations:
  - preferred_term: Forelimb bud
    term:
      id: UBERON:0005417
      label: forelimb bud
  evidence:
  - reference: PMID:8988165
    reference_title: "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "mutations in the human TBX5 gene underlie this disorder"
    explanation: >-
      Original positional cloning of TBX5 from the 12q24.1 HOS locus,
      establishing TBX5 as the gene whose disruption causes the
      characteristic radial ray and cardiac malformations.
  - reference: PMID:8988165
    reference_title: "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "haploinsufficiency of TBX5 causes Holt-Oram syndrome"
    explanation: >-
      Establishes that loss of one functional TBX5 allele
      (haploinsufficiency) is the primary molecular mechanism producing
      the limb phenotype, consistent with a dosage-sensitive
      transcription-factor mechanism.
  downstream:
  - target: Upper limb abnormality
    causal_link_type: DIRECT
    description: >
      Failed TBX5-driven forelimb-bud initiation and radial patterning
      produces the cardinal HOS upper-limb phenotype, observed in
      essentially 100% of clinically diagnosed cases.
  - target: Radial ray defect
    causal_link_type: DIRECT
    description: >
      TBX5 is specifically required for preaxial (radial) ray
      patterning; haploinsufficiency disrupts this program, generating
      the spectrum of radial ray defects from radial bowing to
      hypoplasia/aplasia of the radius.
  - target: Hypoplasia of the radius
    causal_link_type: DIRECT
    description: >
      TBX5-dependent radial ray patterning failure produces radius
      hypoplasia at the severe end of the HOS limb spectrum.
  - target: Triphalangeal thumb
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Dosage-sensitive radial ray patterning failure
    description: >
      Triphalangeal thumb is a milder manifestation of disrupted
      preaxial ray patterning in TBX5-haploinsufficient limb
      mesenchyme.
phenotypes:
- category: Skeletal
  name: Upper limb abnormality
  phenotype_term:
    preferred_term: Upper limb abnormality
    term:
      id: HP:0002817
      label: Abnormality of the upper limb
  description: >
    Characteristic skeletal abnormalities of the upper limbs, ranging from thumb anomalies
    (thumb hypoplasia or aplasia) to severe bilateral upper limb malformations including
    radial ray defects, carpal abnormalities, and forearm hypoplasia.
  frequency: OBLIGATE
  diagnostic: true
  notes: Upper limb abnormalities are a cardinal feature of Holt-Oram syndrome, occurring in nearly 100% of affected individuals.
  evidence:
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities"
    explanation: Case report demonstrating upper limb abnormalities as a cardinal clinical feature of HOS
- category: Skeletal
  name: Radial ray defect
  phenotype_term:
    preferred_term: Radial bowing
    term:
      id: HP:0002986
      label: Radial bowing
  description: >
    Abnormalities of the radial rays (digits 1-5 and their skeletal components on
    the radial side of the upper limb).
    Common manifestations include thumb hypoplasia, aplasia, radial bowing, and radial
    ray defects.
  frequency: FREQUENT
  evidence:
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities, congenital heart defects, and/or conduction abnormalities"
    explanation: Case report of HOS with upper limb alterations demonstrating the limb phenotype is a cardinal feature
- category: Skeletal
  name: Triphalangeal thumb
  phenotype_term:
    preferred_term: Triphalangeal thumb
    term:
      id: HP:0001199
      label: Triphalangeal thumb
  description: >
    A thumb with three phalanges rather than the normal two, presenting as an elongated
    thumb with
    an additional bone segment.
  frequency: OCCASIONAL
  notes: >-
    Triphalangeal thumb is the mildest end of the preaxial radial-ray
    spectrum produced by TBX5 haploinsufficiency. No HOS-specific PMID
    in this entry's reference set quotes triphalangeal thumb directly;
    support comes via the parent radial-ray defect phenotype and the
    dosage-sensitive limb-patterning mechanism described under
    "Upper Limb Morphogenesis Disruption".
  evidence:
  - reference: PMID:30552424
    reference_title: "Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect"
    explanation: >-
      78-patient TBX5-confirmed HOS series characterizing the bilateral
      asymmetric radial-ray defect spectrum, of which triphalangeal
      thumb is the mildest preaxial manifestation; supports
      triphalangeal thumb as part of the HOS limb spectrum (PARTIAL —
      the snippet does not name triphalangeal thumb directly).
- category: Skeletal
  name: Hypoplasia of the radius
  phenotype_term:
    preferred_term: Hypoplasia of the radius
    term:
      id: HP:0002984
      label: Hypoplasia of the radius
  description: >
    Hypoplasia or aplasia of the radius represents the more severe end
    of the radial-ray spectrum in HOS, resulting from failed
    TBX5-driven preaxial limb patterning. May be unilateral or
    bilateral and is often associated with thumb hypoplasia/aplasia
    and forearm shortening.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30552424
    reference_title: "Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect"
    explanation: >-
      78-patient TBX5-confirmed HOS cohort characterizing bilateral
      asymmetric radial-ray defects (which include radial hypoplasia)
      as a hallmark of TBX5-confirmed HOS.
- category: Cardiac
  name: Atrial septal defect
  phenotype_term:
    preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  description: >
    Defects in the interatrial septum are the most common cardiac manifestation, typically
    ostium secundum type but can include other types of ASDs.
  frequency: FREQUENT
  evidence:
  - reference: PMID:39596866
    reference_title: "Genetic Insights into Congenital Cardiac Septal Defects-A Narrative Review."
    supports: SUPPORT
    snippet: "Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs"
    explanation: Establishes that septal defects are cardinal features of congenital heart disease associated with genetic factors including TBX5
  - reference: PMID:39156428
    reference_title: "Holt-Oram Syndrome With Atrial Septal Defect."
    supports: SUPPORT
    snippet: "Seventy-five percent of those with Holt-Oram syndrome have a congenital cardiac defect, which most frequently affects the septum"
    explanation: Clinical epidemiology showing atrial septal defect is the most common cardiac manifestation of HOS
- category: Cardiac
  name: Atrioventricular block
  phenotype_term:
    preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  description: >
    Electrical conduction defects in the heart, including first-degree atrioventricular
    block,
    progressive conduction abnormalities, and other forms of heart block.
  frequency: FREQUENT
  evidence:
  - reference: PMID:38189150
    reference_title: "A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transcriptional changes in the atria observed in human HF directly antagonize the atrial rhythm gene regulatory network"
    explanation: Human atrial transcriptomic analysis showing that TBX5-dependent atrial gene networks regulate conduction and rhythm; disruption of this network drives arrhythmia and conduction abnormalities relevant to HOS.
  - reference: PMID:38235884
    reference_title: "Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances"
    explanation: Clinical evidence that conduction abnormalities are a significant feature requiring therapeutic intervention in HOS
- category: Cardiac
  name: Atrial fibrillation
  phenotype_term:
    preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  description: >
    Irregular atrial electrical activity and ineffective atrial contractions, contributing
    to
    arrhythmia risk in HOS patients, particularly later in life.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39677667
    reference_title: "CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Chd4 AKO mice had increased vulnerability to AF from electrical pacing and a fraction had spontaneous AF"
    explanation: Atrial-specific Chd4-knockout mouse model shows increased atrial fibrillation susceptibility, supporting that disruption of TBX5's chromatin-remodeling partner CHD4 contributes to HOS-like arrhythmia phenotypes
- category: Cardiac
  name: Ventricular septal defect
  phenotype_term:
    preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  description: >
    Defects in the interventricular septum occurring with lesser frequency than ASDs
    but still common in HOS patients.
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:39596866
    reference_title: "Genetic Insights into Congenital Cardiac Septal Defects-A Narrative Review."
    supports: SUPPORT
    snippet: "Congenital heart diseases (CHDs) are a group of complex diseases characterized by structural and functional malformations during development in the human heart"
    explanation: Establishes that septal defects are core manifestations of congenital heart disease linked to genetic factors like TBX5
- category: Cellular
  name: Proarrhythmic Activity in TBX5-Null Cardiomyocytes
  description: >
    TBX5-knockout iPSC-derived cardiomyocytes exhibit proarrhythmic
    activity characterized by early after-depolarizations (EADs),
    profoundly altered gene expression, and dysregulated extracellular
    matrix and ion-handling pathways. This in-vitro cellular phenotype
    recapitulates the conduction-disease and arrhythmia susceptibility
    seen in HOS patients and provides a tractable model of the
    TBX5-haploinsufficient cardiomyocyte state.
  phenotype_term:
    preferred_term: Proarrhythmic activity in iPSC-derived cardiomyocytes
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:28246128
    reference_title: "A Comprehensive TALEN-Based Knockout Library for Generating Human-Induced Pluripotent Stem Cell-Based Models for Cardiovascular Diseases."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "35% of TBX5-KO iPSC-CMs exhibited marked proarrhythmic activity characterized by the development of depolarizing humps during phase 2 and 3 of the action AP that resemble early after-depolarizations (EADs)"
    explanation: >-
      TBX5-knockout iPSC-derived cardiomyocytes display proarrhythmic
      action-potential abnormalities (EADs), modeling the cardiac
      conduction abnormalities and arrhythmia susceptibility seen in
      Holt-Oram syndrome patients.
genetic:
- name: TBX5
  gene_term:
    preferred_term: TBX5
    term:
      id: hgnc:11604
      label: TBX5
  presence: Positive
  association: Causative
  notes: >
    Loss-of-function mutations in TBX5 cause Holt-Oram syndrome with autosomal dominant
    inheritance. Heterozygous loss-of-function variants account for approximately
    90% of
    familial cases. The T-box transcription factor TBX5 is essential for cardiac and
    upper limb development. Gene dosage sensitivity is critical, as even partial loss
    of
    TBX5 function due to haploinsufficiency disrupts regulatory networks.
  evidence:
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "Sequence alteration of T-box transcription factor 5 (TBX5) is correlated with the incidence of HOS"
    explanation: Directly establishes the causal relationship between TBX5 sequence variants and HOS development
  - reference: PMID:38189150
    reference_title: "A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Atrial rhythm abnormalities in mice caused by Tbx5 haploinsufficiency were rescued by Zfpm2 haploinsufficiency"
    explanation: Mouse Tbx5 haploinsufficiency model demonstrates that reduced TBX5 dosage is sufficient to produce atrial rhythm abnormalities, paralleling HOS cardiac phenotypes
  - reference: PMID:8988165
    reference_title: "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TBX5 was cloned from the disease locus on human chromosome 12q24.1 and identified as a member of the T-box transcription factor family"
    explanation: >-
      Original positional cloning of TBX5 from the 12q24.1 HOS locus,
      identifying it as the causative T-box transcription factor.
  - reference: PMID:30552424
    reference_title: "Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%)"
    explanation: >-
      Largest molecular series of TBX5-confirmed HOS (78 patients)
      showing 91% rate of congenital heart disease with ASD as the
      most common (61.5%), supporting TBX5 as the causative gene and
      ASD as the most frequent cardiac phenotype.
  - reference: CGGV:assertion_24e6c85a-33cf-4248-be1f-6431c7c6b1e5-2025-03-25T160000.000Z
    reference_title: "TBX5 / Holt-Oram syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "TBX5 | HGNC:11604 | Holt-Oram syndrome | MONDO:0007732 | AD | Definitive"
    explanation: ClinGen classifies the TBX5-Holt-Oram syndrome gene-disease relationship as definitive with autosomal dominant inheritance.
inheritance:
- name: Autosomal Dominant
  description: >
    Holt-Oram syndrome is inherited in an autosomal dominant pattern, with affected
    individuals
    typically being heterozygous carriers of TBX5 mutations. Penetrance is high but
    variable expressivity
    occurs even within families.
  evidence:
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "The patient inherited a base T (reference C) at rs883079 from her mother and base C (reference T) at rs10850326 from her father"
    explanation: Case report demonstrating inheritance of TBX5 variants from heterozygous carrier parents, consistent with autosomal dominant inheritance
  - reference: PMID:16183809
    reference_title: "TBX5 genetic testing validates strict clinical criteria for Holt-Oram syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%"
    explanation: >-
      Cohort study showing that ~74% of subjects meeting strict
      clinical criteria for HOS carry an identifiable TBX5 mutation,
      consistent with autosomal dominant inheritance of TBX5
      loss-of-function alleles as the predominant disease cause.
treatments:
- name: Cardiac monitoring and evaluation
  description: >
    Regular cardiac evaluation and monitoring is essential to detect and manage arrhythmias,
    conduction abnormalities, and structural defects. This may include ECG, echocardiography,
    and long-term monitoring. Severe conduction abnormalities may require pacemaker
    implantation.
  treatment_term:
    preferred_term: cardiac electrophysiologist evaluation
    term:
      id: NCIT:C80414
      label: Cardiac Electrophysiology Study
  target_phenotypes:
  - preferred_term: Atrioventricular block
    term:
      id: HP:0001678
      label: Atrioventricular block
  - preferred_term: Atrial fibrillation
    term:
      id: HP:0005110
      label: Atrial fibrillation
  - preferred_term: Arrhythmia
    term:
      id: HP:0011675
      label: Arrhythmia
  evidence:
  - reference: PMID:38235884
    reference_title: "Holt-Oram syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HOS usually requires the implantation of a pacemaker, because of cardiac conduction disturbances"
    explanation: >-
      Direct clinical evidence that HOS patients commonly require
      pacemaker implantation for cardiac conduction disturbances,
      supporting the need for ongoing cardiac electrophysiologic
      monitoring and evaluation.
  - reference: PMID:38189150
    reference_title: "A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relationship between heart failure (HF) and atrial fibrillation (AF) is clear, with up to half of patients with HF progressing to AF"
    explanation: >-
      Indirect support for cardiac monitoring (PARTIAL — the cited
      paper is about general HF–AF transition, not HOS-specific
      monitoring); included because TBX5-haploinsufficient atrial
      networks confer AF risk that motivates surveillance.
- name: Surgical repair of cardiac defects
  description: >
    Surgical intervention may be necessary for significant atrial or ventricular septal
    defects
    and other structural abnormalities, depending on severity and hemodynamic significance.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_phenotypes:
  - preferred_term: Atrial septal defect
    term:
      id: HP:0001631
      label: Atrial septal defect
  - preferred_term: Ventricular septal defect
    term:
      id: HP:0001629
      label: Ventricular septal defect
  evidence:
  - reference: PMID:39596866
    reference_title: "Genetic Insights into Congenital Cardiac Septal Defects-A Narrative Review."
    supports: SUPPORT
    snippet: Within these malformations, septal defects such as ventricular (VSD) and atrial septal defects (ASD) are the most common forms of CHDs.
    explanation: Establishes that septal defects are cardinal manifestations requiring potential surgical intervention
- name: Orthopedic Surgical Reconstruction
  description: >
    Reconstructive orthopedic surgery for severe radial-ray defects in
    HOS, including pollicization (transposition of the index finger to
    a thumb position) for absent thumb and surgical correction of
    radial club hand. Performed when the limb deformity meaningfully
    impairs hand function.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Upper limb abnormality
    term:
      id: HP:0002817
      label: Abnormality of the upper limb
  - preferred_term: Hypoplasia of the radius
    term:
      id: HP:0002984
      label: Hypoplasia of the radius
- name: Physical and Rehabilitation Therapy
  description: >
    Physical therapy and rehabilitative care to optimize upper-limb
    function and mobility in patients with HOS radial-ray defects and
    associated shoulder/elbow mobility limitations.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Upper limb abnormality
    term:
      id: HP:0002817
      label: Abnormality of the upper limb
  - preferred_term: Radial bowing
    term:
      id: HP:0002986
      label: Radial bowing
  - preferred_term: Hypoplasia of the radius
    term:
      id: HP:0002984
      label: Hypoplasia of the radius
  evidence:
  - reference: PMID:36936432
    reference_title: "Case report: Novel TBX5-related pathogenic mechanism of Holt-Oram syndrome."
    supports: SUPPORT
    snippet: "Holt-Oram syndrome (HOS) is a rare genetic disorder characterized by upper limb abnormalities"
    explanation: Case reports of HOS patients with upper limb abnormalities requiring orthopedic and rehabilitative management
datasets:
- accession: morphic:ISL1
  title: >-
    MorPhiC Consortium null allele phenotyping of ISL1 in iPSC-derived
    cardiomyocytes
  description: >-
    ISL1 is a MorPhiC anchor gene shared across all consortium data
    production centers. ISL1 cooperates with NKX2-5 in cardiac
    development, and both interact with TBX5 (the causative gene for
    Holt-Oram syndrome) in cardiac septation and conduction-system
    programs. MorPhiC iPSC-to-cardiomyocyte differentiation assays are
    directly relevant to interrogating the TBX5/NKX2-5/ISL1 cardiac
    transcription factor network whose dosage perturbation underlies
    HOS cardiac phenotypes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: MULTI_OMICS_PERTURBATION
  sample_types:
  - preferred_term: iPSC-derived cardiomyocyte
    tissue_term:
      preferred_term: heart
      term:
        id: UBERON:0000948
        label: heart
    cell_type_term:
      preferred_term: cardiomyocyte
      term:
        id: CL:0000746
        label: cardiac muscle cell
  genes:
  - preferred_term: ISL1
  notes: >-
    ISL1, EOMES, GCM1 and NKX2-1 are the MorPhiC anchor genes shared
    across all data production centers. ISL1 is relevant to Holt-Oram
    syndrome via its cooperation with NKX2-5 in cardiac development.
    Data available under CC BY 4.0 at morphic.bio.
  publication: PMID:39939790
notes: >
  Holt-Oram syndrome is a rare autosomal dominant genetic disorder with an estimated
  incidence of
  1 in 100,000 live births, characterized by the combination of cardiac and upper
  limb abnormalities
  caused by mutations in the TBX5 gene located on chromosome 12q24.1. The disorder
  exhibits near
  complete penetrance with variable expressivity, with approximately 60% of cases
  being familial and
  40% sporadic. Clinical manifestations are highly variable, ranging from subtle cardiac
  conduction
  abnormalities with minimal or no limb involvement to severe cardiac defects (septal
  defects in 75%
  of cases) and bilateral upper limb malformations. The recent discovery of TBX5-dependent
  enhancer
  networks and chromatin remodeling mechanisms provides molecular insight into the
  pathophysiology
  underlying both cardiac and limb phenotypes. Advanced cardiac interventions including
  pacemaker
  implantation may be required for managing conduction abnormalities. Genetic counseling
  is strongly
  recommended for affected families due to the high penetrance and inheritance pattern.
references:
- reference: DOI:10.1038/s44161-023-00334-7
  title: Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network
  findings:
  - statement: Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network
    supporting_text: Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
- reference: DOI:10.1101/2024.12.04.626894
  title: CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes
  findings: []
- reference: DOI:10.1101/2025.01.09.632202
  title: Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor
  findings: []
- reference: DOI:10.1161/circulationaha.123.066804
  title: 'A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network'
  findings: []
- reference: DOI:10.3389/fgene.2023.1063202
  title: 'Case report: Novel TBX5-related pathogenic mechanism of Holt–Oram syndrome'
  findings: []
- reference: DOI:10.3390/biology13110911
  title: Genetic Insights into Congenital Cardiac Septal Defects—A Narrative Review
  findings: []
- reference: DOI:10.1055/s-0043-1761827
  title: Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line
    supporting_text: Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line
- reference: DOI:10.1161/circulationaha.121.054347
  title: Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation.
    supporting_text: The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation.
- reference: DOI:10.1186/s13019-026-03913-4
  title: 'Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study'
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: 'Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study'
    supporting_text: 'Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study'
- reference: DOI:10.1186/s43044-024-00549-4
  title: 'When the heart and hands tell a story: an intriguing case of Holt–Oram syndrome'
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations.
    supporting_text: Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations.
    evidence:
    - reference: DOI:10.1186/s43044-024-00549-4
      reference_title: 'When the heart and hands tell a story: an intriguing case of Holt–Oram syndrome'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations.
      explanation: Deep research cited this publication as relevant literature for Holt-Oram Syndrome.
- reference: DOI:10.12775/qs.2025.45.66549
  title: 'Holt-Oram Syndrome: When hand deformity leads to diagnosis of congenital heart disease'
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome.
    supporting_text: The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome.
    evidence:
    - reference: DOI:10.12775/qs.2025.45.66549
      reference_title: 'Holt-Oram Syndrome: When hand deformity leads to diagnosis of congenital heart disease'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome.
      explanation: Deep research cited this publication as relevant literature for Holt-Oram Syndrome.
- reference: DOI:10.33574/hjog.0584
  title: First live birth in Greece after blastocyst trophectoderm biopsy and preimplantation genetic testing for Holt-Oram Syndrome
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction.
    supporting_text: Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction.
    evidence:
    - reference: DOI:10.33574/hjog.0584
      reference_title: First live birth in Greece after blastocyst trophectoderm biopsy and preimplantation genetic testing for Holt-Oram Syndrome
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction.
      explanation: Deep research cited this publication as relevant literature for Holt-Oram Syndrome.
- reference: DOI:10.7554/elife.80317
  title: An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings:
  - statement: Heart development and rhythm control are highly Tbx5 dosage-sensitive.
    supporting_text: Heart development and rhythm control are highly Tbx5 dosage-sensitive.
- reference: DOI:10.1038/s41431-018-0303-3
  title: 'Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants'
  found_in:
  - Holt-Oram_Syndrome-deep-research-falcon.md
  findings: []

📚

References & Deep Research

References

DOI:10.1038/s44161-023-00334-7

Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network

1 finding

Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network

"Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network"

DOI:10.1101/2024.12.04.626894

CHD4 Interacts With TBX5 to Maintain the Gene Regulatory Network of Postnatal Atrial Cardiomyocytes

No top-level findings curated for this source.

DOI:10.1101/2025.01.09.632202

Dose-dependent sensitivity of human 3D chromatin to a heart disease-linked transcription factor

No top-level findings curated for this source.

DOI:10.1161/circulationaha.123.066804

A Genomic Link From Heart Failure to Atrial Fibrillation Risk: FOG2 Modulates a TBX5/GATA4-Dependent Atrial Gene Regulatory Network

No top-level findings curated for this source.

DOI:10.3389/fgene.2023.1063202

Case report: Novel TBX5-related pathogenic mechanism of Holt–Oram syndrome

No top-level findings curated for this source.

DOI:10.3390/biology13110911

Genetic Insights into Congenital Cardiac Septal Defects—A Narrative Review

No top-level findings curated for this source.

DOI:10.1055/s-0043-1761827

Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line

1 finding

Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line

"Comparative Single-Cell RNAseq Analysis of Cardiac Progenitor Cells from a Holt-Oram Syndrome Patient iPS Line and the CRISPR/Cas9 Corrected Isogenic iPS Line"

DOI:10.1161/circulationaha.121.054347

Patient-Specific TBX5-G125R Variant Induces Profound Transcriptional Deregulation and Atrial Dysfunction

1 finding

The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation.

"The pathogenic missense variant p.G125R in TBX5 (T-box transcription factor 5) causes Holt–Oram syndrome (also known as hand–heart syndrome) and early onset of atrial fibrillation."

DOI:10.1186/s13019-026-03913-4

Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study

1 finding

Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study

"Experience with patients presenting with the clinical features of Holt-Oram syndrome: a single center retrospective study"

DOI:10.1186/s43044-024-00549-4

When the heart and hands tell a story: an intriguing case of Holt–Oram syndrome

1 finding

Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations.

"Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations."

Show evidence (1 reference)

DOI:10.1186/s43044-024-00549-4 SUPPORT Human Clinical

"Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations."

Deep research cited this publication as relevant literature for Holt-Oram Syndrome.

DOI:10.12775/qs.2025.45.66549

Holt-Oram Syndrome: When hand deformity leads to diagnosis of congenital heart disease

1 finding

The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome.

"The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome."

Show evidence (1 reference)

DOI:10.12775/qs.2025.45.66549 SUPPORT Human Clinical

"The following review paper is an in-depth analysis of a rare condition called Holt-Oram syndrome."

Deep research cited this publication as relevant literature for Holt-Oram Syndrome.

DOI:10.33574/hjog.0584

First live birth in Greece after blastocyst trophectoderm biopsy and preimplantation genetic testing for Holt-Oram Syndrome

1 finding

Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction.

"Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction."

Show evidence (1 reference)

DOI:10.33574/hjog.0584 SUPPORT Human Clinical

"Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction."

Deep research cited this publication as relevant literature for Holt-Oram Syndrome.

DOI:10.7554/elife.80317

An atrial fibrillation-associated regulatory region modulates cardiac Tbx5 levels and arrhythmia susceptibility

1 finding

Heart development and rhythm control are highly Tbx5 dosage-sensitive.

"Heart development and rhythm control are highly Tbx5 dosage-sensitive."

DOI:10.1038/s41431-018-0303-3

Holt-Oram syndrome: clinical and molecular description of 78 patients with TBX5 variants

No top-level findings curated for this source.

Deep Research

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 32 citations 2026-05-09T22:46:37.066173

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: Holt-Oram syndrome
MONDO ID: (if available)
Category: Genetic

Research Objectives

Please provide a comprehensive research report on Holt-Oram syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Holt–Oram syndrome (HOS) — Disease Characteristics Research Report (Genetic)

Executive summary

Holt–Oram syndrome (HOS) is an autosomal dominant “heart–hand” syndrome defined by congenital upper-limb (classically preaxial/radial-ray) malformations together with congenital heart disease (especially septal defects) and/or cardiac conduction/rhythm abnormalities, most often caused by pathogenic variants in TBX5 (12q24) (vanlerberghe2019holtoramsyndromeclinical pages 1-2, atlas2024whentheheart pages 1-3). Disease burden and mortality risk are primarily driven by the cardiac phenotype, while skeletal anomalies dominate functional impairment (atlas2024whentheheart pages 1-3, dmowski2025holtoramsyndromewhen pages 8-12).

1. Disease information

1.1 What is the disease?

HOS is a congenital malformation syndrome in which upper-limb radial/preaxial anomalies co-occur with congenital heart defects (CHD) (most commonly ASD/VSD) and conduction/rhythm disturbances (vanlerberghe2019holtoramsyndromeclinical pages 1-2, vanlerberghe2019holtoramsyndromeclinical pages 4-5). A 2024 case report summarizes: “Holt–Oram syndrome is a rare genetic disorder caused by a mutation in the TBX5 gene, combining skeletal and cardiac malformations” (published 2024-09-xx; URL: https://doi.org/10.1186/s43044-024-00549-4) (atlas2024whentheheart pages 1-3).

1.2 Key identifiers (and gaps)

OMIM disease: Holt–Oram syndrome (MIM/OMIM #142900) (vanlerberghe2019holtoramsyndromeclinical pages 1-2, economou2025firstlivebirth pages 1-3, ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2).
TBX5 gene: cited with OMIM ID 601620 in TBX5/HOS literature ().
Orphanet / ICD-10 / ICD-11 / MeSH / MONDO: not directly retrievable from the currently available full-text evidence set used here; therefore not reported with primary citations.

1.3 Synonyms and alternative names

Heart–hand syndrome / hand–heart syndrome (ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2).
Atrio-digital syndrome (used in clinical literature) (liu2026experiencewithpatients pages 1-2).

1.4 Evidence source type

This report integrates: * Aggregated disease-level evidence from cohort studies and mechanistic model studies (e.g., Vanlerberghe 2019; Bosada 2023; van Ouwerkerk 2022) (vanlerberghe2019holtoramsyndromeclinical pages 1-2, bosada2023anatrialfibrillationassociated pages 1-2, ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2). * Individual patient evidence from case reports and implementation reports (Atlas 2024; Economou 2025) (atlas2024whentheheart pages 1-3, economou2025firstlivebirth pages 1-3).

2. Etiology

2.1 Disease causal factors

Primary cause: germline pathogenic variants affecting TBX5, a T-box transcription factor required for cardiac septation, conduction system development, and forelimb initiation/patterning (vanlerberghe2019holtoramsyndromeclinical pages 1-2, dmowski2025holtoramsyndromewhen pages 5-8).

Inheritance: autosomal dominant (vanlerberghe2019holtoramsyndromeclinical pages 1-2, atlas2024whentheheart pages 1-3).

De novo occurrence: many cases are sporadic; a recent retrospective series states “roughly 85% are reported as de novo mutations” (liu2026experiencewithpatients pages 4-6).

2.2 Risk factors

Genetic risk factor (causal): heterozygous pathogenic TBX5 variants (loss-of-function predominates) (vanlerberghe2019holtoramsyndromeclinical pages 2-4, vanlerberghe2019holtoramsyndromeclinical pages 1-2).

Variant classes (2019 largest molecular series of TBX5-positive patients): among TBX5-positive probands, point variants were ~87% with many truncating (nonsense 37%, frameshift 26%, splice-site 10%); intragenic deletions 8% and duplications 4% detected by MLPA (vanlerberghe2019holtoramsyndromeclinical pages 2-4).

Reduced penetrance/mosaicism: asymptomatic carrier parents were documented, and one father showed somatic mosaicism (~10% in blood), complicating family-history-based risk inference (vanlerberghe2019holtoramsyndromeclinical pages 2-4).

Environmental/lifestyle risk factors are not established for this primarily monogenic developmental disorder in the evidence set.

2.3 Protective factors

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

2.4 Gene–environment interactions

No direct gene–environment interaction evidence specific to HOS was identified in the retrieved evidence.

3. Phenotypes

3.1 Core phenotype domains

HOS is characterized by: 1) Upper limb radial/preaxial malformations (thumb/thenar/radius/forearm), 2) Congenital heart defects (especially septal defects), and 3) Conduction/rhythm abnormalities, sometimes independent of structural CHD (dmowski2025holtoramsyndromewhen pages 5-8, vanlerberghe2019holtoramsyndromeclinical pages 4-5).

3.2 Quantitative phenotype frequencies (key recent data)

The largest molecular cohort in this evidence set (Vanlerberghe et al., Eur J Hum Genet, accepted 2018-10-25; URL: https://doi.org/10.1038/s41431-018-0303-3; published 2019) reports (probands with TBX5 variants): * Any CHD: 91% (vanlerberghe2019holtoramsyndromeclinical pages 1-2). * ASD: 61.5%; VSD: 34.6% (vanlerberghe2019holtoramsyndromeclinical pages 4-5). * Conduction disturbances: isolated 4.2%, and with CHD 25.3% (including sinus bradycardia 8.5%, AV block 2.8%, RBBB 7%) (vanlerberghe2019holtoramsyndromeclinical pages 4-5). * Common limb findings include thenar hypoplasia (~26–28%), thumb hypoplasia (~30–33%), thumb agenesis (~22–32%), and I–II syndactyly (~14–15%) (vanlerberghe2019holtoramsyndromeclinical pages 4-5).

A structured comparison table is provided below.

Domain	Finding	Frequency/Statistic	Study/Cohort	Notes
Clinical features	Congenital heart disease (CHD) overall	91% (71/78)	Vanlerberghe 2019; 78 TBX5-variant probands	Molecularly confirmed TBX5 cohort; septal defects dominated the cardiac spectrum (vanlerberghe2019holtoramsyndromeclinical pages 1-2, vanlerberghe2019holtoramsyndromeclinical pages 4-5)
Clinical features	Atrial septal defect (ASD)	61.5% (48/78)	Vanlerberghe 2019; 78 TBX5-variant probands	Most common structural lesion; includes ostium secundum ASD predominance in HOS literature (vanlerberghe2019holtoramsyndromeclinical pages 4-5, vanlerberghe2019holtoramsyndromeclinical pages 1-2)
Clinical features	Ventricular septal defect (VSD)	34.6% (27/78)	Vanlerberghe 2019; 78 TBX5-variant probands	Other CHD such as PDA, coarctation, and pulmonary stenosis were less common (vanlerberghe2019holtoramsyndromeclinical pages 4-5)
Clinical features	Rhythm or conduction disturbance overall	~29.6% (21/71 total evaluable)	Vanlerberghe 2019; 71 evaluable for rhythm data	Composed of 25.3% with CHD (18/71) plus 4.2% isolated (3/71); included sinus bradycardia, AV block, RBBB, junctional tachycardia, and rare long QT (vanlerberghe2019holtoramsyndromeclinical pages 4-5)
Clinical features	Thumb hypoplasia	Right 29.5% (23/78); Left 33.3% (26/78)	Vanlerberghe 2019; 78 TBX5-variant probands	Representative preaxial/radial-ray anomaly; bilateral involvement common in cohort (vanlerberghe2019holtoramsyndromeclinical pages 4-5, vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Clinical features	Thumb agenesis	Right 21.8% (17/78); Left 32.1% (25/78)	Vanlerberghe 2019; 78 TBX5-variant probands	Left side often more severely affected (vanlerberghe2019holtoramsyndromeclinical pages 4-5, vanlerberghe2019holtoramsyndromeclinical pages 1-2)
Clinical features	Triphalangeal thumb	~21% to 27%	Vanlerberghe 2019; 78 TBX5-variant probands	Frequency reported as a range across sides and summary text (vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Clinical features	Thenar hypoplasia	~25% to 28%	Vanlerberghe 2019; 78 TBX5-variant probands	Common subtle hand finding relevant to diagnosis (vanlerberghe2019holtoramsyndromeclinical pages 4-5, vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Clinical features	I to II syndactyly	~13% to 15%	Vanlerberghe 2019; 78 TBX5-variant probands	Less frequent but recurrent upper-limb feature (vanlerberghe2019holtoramsyndromeclinical pages 4-5, vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Clinical features	Radial hypoplasia or agenesis	~20% hypoplasia; ~4% to 10% agenesis	Vanlerberghe 2019; 78 TBX5-variant probands	Supports radial-ray disease pattern in HOS (vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Clinical features	CHD overall	10/11 (90.9%)	Liu 2026; 11 clinically suspected or diagnosed patients	Single-center retrospective series; 1/11 had isolated arrhythmia without structural CHD (liu2026experiencewithpatients pages 2-4)
Clinical features	Atrial septal defect (ASD)	8/10 CHD cases (~80% of CHD cases)	Liu 2026; 11 patients	Secundum ASD was most frequent subtype; article text also describes ASD as 80% in series summaries (liu2026experiencewithpatients pages 2-4, liu2026experiencewithpatients pages 1-2)
Clinical features	Ventricular septal defect (VSD)	2/11 (18.2%)	Liu 2026; 11 patients	PDA in 4/11 also reported; complex CHD such as TOF, pulmonary atresia, and Ebstein anomaly occurred (liu2026experiencewithpatients pages 2-4)
Clinical features	ECG abnormality or conduction-arrhythmia overall	10/11 (90.9%)	Liu 2026; 11 patients	Very high ECG abnormality burden in this referral cohort; included SVT, sinus tachycardia, AV block, bundle branch block, and atrial fibrillation (liu2026experiencewithpatients pages 4-6)
Clinical features	Supraventricular tachycardia (SVT)	4/11 (36.4%)	Liu 2026; 11 patients	Atrial fibrillation and first-degree AV block also documented; median follow-up was 7.2 years (liu2026experiencewithpatients pages 4-6)
Clinical features	Triphalangeal thumb	8/10 with limb-detail available (80%)	Liu 2026; 11 patients	Most frequent specific limb anomaly highlighted by authors (liu2026experiencewithpatients pages 1-2)
Clinical features	Upper-limb malformations overall	11/11 (100%)	Liu 2026; 11 patients	Mostly hand-limited; examples included absent or floating thumb, syndactyly, polydactyly, and radial defects (liu2026experiencewithpatients pages 2-4, liu2026experiencewithpatients pages 1-2)
Genetics or testing	TBX5 testing yield in referred suspected HOS cohort	58% (78/212)	Vanlerberghe 2019; 212 referred for TBX5 screening	Yield increased to 70% in subgroup with bilateral anterior upper-limb defect plus CHD (vanlerberghe2019holtoramsyndromeclinical pages 2-4, vanlerberghe2019holtoramsyndromeclinical pages 1-2)
Genetics or testing	Variant class: point variants overall	87% of TBX5-positive probands	Vanlerberghe 2019; 78 TBX5-variant probands	Majority of pathogenic findings were sequence-level variants (vanlerberghe2019holtoramsyndromeclinical pages 2-4)
Genetics or testing	Variant class: nonsense	37%	Vanlerberghe 2019; 78 TBX5-variant probands	Truncating variants predominated (vanlerberghe2019holtoramsyndromeclinical pages 2-4, vanlerberghe2019holtoramsyndromeclinical pages 5-7)
Genetics or testing	Variant class: frameshift	26%	Vanlerberghe 2019; 78 TBX5-variant probands	Supports haploinsufficiency as major mechanism (vanlerberghe2019holtoramsyndromeclinical pages 2-4)
Genetics or testing	Variant class: splice-site	10%	Vanlerberghe 2019; 78 TBX5-variant probands	Includes functionally important noncanonical splice effects in broader literature (vanlerberghe2019holtoramsyndromeclinical pages 2-4)
Genetics or testing	Variant class: missense	~14%	Vanlerberghe 2019; 78 TBX5-variant probands	Some missense variants were de novo and functionally validated (vanlerberghe2019holtoramsyndromeclinical pages 2-4)
Genetics or testing	Copy-number variants: intragenic deletions	8%	Vanlerberghe 2019; 78 TBX5-variant probands	Detected by MLPA; supports CNV analysis in diagnostics (vanlerberghe2019holtoramsyndromeclinical pages 2-4)
Genetics or testing	Copy-number variants: intragenic duplications	4%	Vanlerberghe 2019; 78 TBX5-variant probands	Important atypical mechanism; argues for dosage-sensitive disease biology (vanlerberghe2019holtoramsyndromeclinical pages 2-4, bosada2023anatrialfibrillationassociated pages 23-24)
Genetics or testing	Reduced penetrance or mosaicism	4 asymptomatic carrier parents; 1 father with ~10% somatic mosaicism in blood	Vanlerberghe 2019; familial cases within cohort	Important for counseling and interpretation of negative or atypical family histories (vanlerberghe2019holtoramsyndromeclinical pages 2-4)

Table: This table compiles core clinical frequencies and genetic testing findings for Holt-Oram syndrome from the largest 2019 TBX5-positive cohort and a recent single-center clinical series. It is useful for quickly comparing phenotype prevalence, arrhythmia burden, and the distribution of TBX5 variant classes relevant to diagnosis and counseling.

3.3 Age of onset, severity, progression

Onset is congenital (structural limb/cardiac malformations); however, arrhythmias and conduction disease may appear “over the course of life” (vanlerberghe2019holtoramsyndromeclinical pages 1-2).
Adult presentation can occur; a 49-year-old presented with de novo congestive heart failure and atrial flutter plus ASD (Atlas 2024; URL: https://doi.org/10.1186/s43044-024-00549-4) (atlas2024whentheheart pages 1-3).
Conduction abnormalities may be evident at birth and can progress unpredictably toward advanced block; arrhythmias (including AF, WPW) are described (dmowski2025holtoramsyndromewhen pages 5-8).

3.4 Quality-of-life impact

Direct QoL instrument data (e.g., SF-36/EQ-5D) were not found in the retrieved evidence. Functional impact is inferred from the frequency of mobility limitation and need for orthopedic surgery (e.g., orthopaedic surgery reported in ~25% in one cohort) (vanlerberghe2019holtoramsyndromeclinical pages 4-5).

3.5 Suggested HPO terms (examples)

Skeletal/limb: * Abnormality of the thumb (HP:0009601) * Triphalangeal thumb (HP:0001199) * Thenar hypoplasia (HP:0001182) * Radial ray defect (HP:0002980) * Abnormal forearm pronation/supination (HP:0004046) * Upper limb reduction defect (HP:0009828)

Cardiac structural: * Atrial septal defect (HP:0001631) * Ventricular septal defect (HP:0001629)

Conduction/rhythm: * Atrial fibrillation (HP:0005110) * Atrial flutter (HP:0001658) * Atrioventricular block (HP:0001678) * Sinus bradycardia (HP:0001688)

(These suggestions are consistent with phenotypes described in cohorts/cases) (vanlerberghe2019holtoramsyndromeclinical pages 4-5, dmowski2025holtoramsyndromewhen pages 5-8, atlas2024whentheheart pages 1-3).

4. Genetic / molecular information

4.1 Causal gene

TBX5 is the principal causal gene (chromosome 12q24) encoding a T-box transcription factor essential for heart and forelimb development (vanlerberghe2019holtoramsyndromeclinical pages 1-2, dmowski2025holtoramsyndromewhen pages 5-8).

4.2 Pathogenic variant spectrum and interpretation

Testing yield and heterogeneity: among patients referred for suspected HOS and screened for TBX5, detection yields vary; one large referral series reported 58% overall yield (and higher in clinically “classic” subgroups) (vanlerberghe2019holtoramsyndromeclinical pages 2-4).

Variant types: truncating variants are common; CNVs (intragenic deletions/duplications) occur and should be explicitly assayed (vanlerberghe2019holtoramsyndromeclinical pages 2-4).

Functional consequence: haploinsufficiency is widely supported as a dominant mechanism; reviews and cohorts explicitly refer to TBX5 haploinsufficiency (dmowski2025holtoramsyndromewhen pages 5-8).

4.3 Modifier genes

No validated modifier genes specific to HOS severity were identified in the retrieved evidence; however, TBX5 interacts functionally with other cardiac regulators (see Mechanism).

4.4 Epigenetic/regulatory mechanisms relevant to disease expression

Noncoding regulatory changes can modulate TBX5 dosage and phenotype risk. In a 2023 eLife paper (published 2023-01-30; URL: https://doi.org/10.7554/eLife.80317), the authors note TBX5 is dosage-sensitive and show that deletion of AF-associated regulatory regions near Tbx5 causes a modest ~30% atrial increase in Tbx5 and increases arrhythmia susceptibility (bosada2023anatrialfibrillationassociated pages 1-2).

4.5 Chromosomal abnormalities

Intragenic deletions/duplications in TBX5 are documented by MLPA in HOS cohorts (vanlerberghe2019holtoramsyndromeclinical pages 2-4). A microdeletion spanning TBX5/TBX3 is also described in a Spanish-language series (cruz2026síndromedeholtoram pages 50-54).

5. Environmental information

No infectious, lifestyle, or toxic environmental causes of HOS were identified in the retrieved evidence; HOS is best supported as a genetic developmental disorder.

6. Mechanism / pathophysiology

6.1 Causal chain (developmental biology to clinical disease)

1) Primary trigger: germline TBX5 dosage/function change (often loss-of-function; sometimes dosage increase or missense with altered binding/cooperativity) (vanlerberghe2019holtoramsyndromeclinical pages 2-4, bosada2023anatrialfibrillationassociated pages 1-2). 2) Upstream developmental disruption: impaired transcriptional control of cardiogenesis and forelimb initiation/patterning; TBX5 is required for septation and conduction system development and is forelimb-specific during limb development (vanlerberghe2019holtoramsyndromeclinical pages 1-2). 3) Downstream tissue outcomes: septal CHD (ASD/VSD), conduction system dysfunction/arrhythmias, and radial-ray limb malformations (vanlerberghe2019holtoramsyndromeclinical pages 4-5, dmowski2025holtoramsyndromewhen pages 5-8).

6.2 Recent mechanistic developments (prioritizing 2023–2024)

(i) Small TBX5 dosage increases from noncoding variation can be arrhythmogenic (2023). Bosada et al. (eLife, published 2023-01-30; https://doi.org/10.7554/eLife.80317) state: “Heart development and rhythm control are highly Tbx5 dosage-sensitive. TBX5 haploinsufficiency causes congenital conduction disorders…” and show that deleting two AF-associated regulatory regions causes a “modest (30%) increase of Tbx5 in the postnatal atria” with “increased susceptibility to atrial arrhythmias” and “increased action potential duration” (bosada2023anatrialfibrillationassociated pages 1-2).

(ii) TBX5 enhancer-network regulation maintains atrial identity (2023). A 2023 study in Nature Cardiovascular Research (Sweat et al., Oct 2023; https://doi.org/10.1038/s44161-023-00334-7) investigated TBX5 function with multi-omic profiling (scRNA/ATAC and chromatin interaction mapping) and provides direct support that atrial TBX5 regulates atrial-specific enhancer networks in postnatal cardiomyocytes (sweat2023tbx5maintainsatrial pages 1-2).

6.3 Expert/authoritative interpretation (high-quality sources)

A mechanistically detailed example of how a specific TBX5 missense variant can rewire the atrial regulatory network is provided by van Ouwerkerk et al. (Circulation, published 2022-02-22; https://doi.org/10.1161/circulationaha.121.054347). In their abstract they report: “We discovered high incidence of atrial extra systoles and atrioventricular conduction disturbances in Holt–Oram syndrome patients” and that atrial transcriptional profiling identified “over a thousand coding and noncoding transcripts” differentially expressed, with “thousands” of variant-sensitive regulatory elements gaining accessibility (ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2).

6.4 Pathways, cellular processes, and suggested ontology terms

Representative GO Biological Process terms (suggested): * heart development; cardiac septum development; regulation of transcription by RNA polymerase II; cardiac conduction; limb development.

Representative cell types (Cell Ontology; suggested): * cardiomyocyte; cardiac conduction system cell; cardiac fibroblast (relevant in multi-cell-type profiling, though effects were strongest in cardiomyocytes in the TBX5-G125R model) (ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2).

7. Anatomical structures affected

Primary organ systems: * Heart (septum; conduction system; atria) (vanlerberghe2019holtoramsyndromeclinical pages 4-5, bosada2023anatrialfibrillationassociated pages 1-2). * Upper limbs (thumb/thenar/carpal/radius/forearm) (vanlerberghe2019holtoramsyndromeclinical pages 4-5, dmowski2025holtoramsyndromewhen pages 5-8).

Suggested UBERON (examples): heart (UBERON:0000948), atrial septum, ventricular septum; forelimb/upper limb (UBERON:0001460), radius (UBERON:0001423), thumb (UBERON:0002398).

8. Temporal development

Onset pattern: congenital structural anomalies; arrhythmias/conduction disease may be detected at birth or emerge later (dmowski2025holtoramsyndromewhen pages 5-8, vanlerberghe2019holtoramsyndromeclinical pages 1-2).

Course: lifelong condition requiring continued cardiac surveillance; progression to heart failure/pulmonary hypertension/arrhythmia complications is described in clinical reviews (dmowski2025holtoramsyndromewhen pages 8-12).

9. Inheritance and population

9.1 Epidemiology

Prevalence/incidence: estimated around 1 in 100,000 births (Vanlerberghe 2019) (vanlerberghe2019holtoramsyndromeclinical pages 1-2). A review cites ~0.95 per 100,000 births from a single population study in Hungary (dmowski2025holtoramsyndromewhen pages 1-5).
Sex/ancestry distribution: one review states equal frequency between males and females and across racial/ethnic groups, while noting limited population-based data (dmowski2025holtoramsyndromewhen pages 1-5).

9.2 Inheritance pattern, penetrance, expressivity

Autosomal dominant inheritance (vanlerberghe2019holtoramsyndromeclinical pages 1-2).
High penetrance with variable expressivity is emphasized in GeneReviews-like summaries and cohorts; reduced penetrance is documented by asymptomatic carriers and mosaicism (vanlerberghe2019holtoramsyndromeclinical pages 2-4, vanlerberghe2019holtoramsyndromeclinical pages 1-2).

10. Diagnostics

10.1 Clinical criteria and diagnostic approach

A practical criteria set used in cohort work requires preaxial/radial upper-limb defect (uni/bilateral) plus personal/family history of CHD and/or rhythm disturbance, and the diagnosis can be challenging due to overlap with Okihiro, TAR, and Fanconi anemia (vanlerberghe2019holtoramsyndromeclinical pages 1-2).

10.2 Testing modalities (real-world)

Cardiac: ECG and echocardiography are central; ECG is required because conduction disease can occur without structural heart disease (dmowski2025holtoramsyndromewhen pages 5-8). Echo identifies septal defects and other CHD (vanlerberghe2019holtoramsyndromeclinical pages 4-5).

Skeletal: clinical limb exam plus radiography; subtle cases may show only delayed carpal maturation, motivating wrist radiographs (dmowski2025holtoramsyndromewhen pages 8-12).

Genetic testing: * TBX5 sequencing of coding exons and splice junctions plus copy-number analysis (e.g., MLPA) is supported by the documented CNV fraction (vanlerberghe2019holtoramsyndromeclinical pages 2-4).

10.3 Differential diagnosis

Key differentials include Okihiro (SALL4), TAR syndrome, Fanconi anemia, teratogen exposure (thalidomide, valproate), and other heart–hand / radial ray syndromes (dmowski2025holtoramsyndromewhen pages 5-8, atlas2024whentheheart pages 5-6).

10.4 Screening (prenatal)

Prenatal imaging windows cited include visibility of radius/ulna by ~13–16 weeks and many cardiac defects by ~18–20 weeks (dmowski2025holtoramsyndromewhen pages 8-12). Molecular confirmation can inform pregnancy decision-making and neonatal delivery planning (dmowski2025holtoramsyndromewhen pages 8-12).

11. Outcome / prognosis

Prognosis is largely determined by cardiac involvement. Atlas 2024 states “Vital prognosis depends essentially on cardiac involvement, while skeletal malformations determine functional prognosis” (atlas2024whentheheart pages 1-3). Heart failure and arrhythmias can occur, and clinical reviews cite risks including sudden cardiac death, supporting lifelong surveillance (dmowski2025holtoramsyndromewhen pages 8-12).

12. Treatment

12.1 Standard of care (symptom-directed)

There is no disease-specific curative therapy; management is individualized and multidisciplinary (genetics, cardiology, orthopedics/hand surgery, rehabilitation) (dmowski2025holtoramsyndromewhen pages 8-12).

Cardiac structural defects: many patients require ASD/VSD repair in childhood (dmowski2025holtoramsyndromewhen pages 8-12).

Arrhythmia/conduction disease: may require medications, electrophysiology procedures, or pacemaker implantation; a review notes absence of specific pacing guidelines and reports individualized physiological His-bundle pacing in a symptomatic bradycardia case (dmowski2025holtoramsyndromewhen pages 8-12).

Heart failure therapy (real-world example, 2024): in an adult case, guideline-based pharmacologic therapy (diuretics, ACE inhibitor, beta-blocker, MRA, SGLT2 inhibitor) was used with short-term clinical improvement (atlas2024whentheheart pages 3-5).

Supportive/rehab: physiotherapy and occupational therapy are frequently used for functional impairment (dmowski2025holtoramsyndromewhen pages 8-12).

Suggested MAXO terms (examples): surgical repair of atrial septal defect; cardiac electrophysiological ablation; pacemaker implantation; physical therapy; genetic counseling.

12.2 Experimental / clinical trials

No interventional HOS-specific therapeutic trials were identified in the retrieved ClinicalTrials.gov set; retrieved studies were observational and not clearly HOS-targeted.

13. Prevention

13.1 Genetic counseling and reproductive prevention

A concrete real-world implementation is PGT-M for a familial TBX5 pathogenic variant. Economou et al. (Hellenic J Obstet Gynecol, published 2025-01; https://doi.org/10.33574/hjog.0584) report: “Preimplantation genetic testing for monogenic/single-gene defects (PGT-M) is a well established tool in assisted reproduction” and screened 10 embryos, identifying 4 unaffected embryos, leading to a live birth after transfer of an unaffected blastocyst (economou2025firstlivebirth pages 1-3).

13.2 Secondary/tertiary prevention

Lifelong rhythm and structural surveillance (ECG/echo-based monitoring) is emphasized in clinical reviews to prevent or mitigate arrhythmia and heart failure complications (dmowski2025holtoramsyndromewhen pages 8-12).

14. Other species / natural disease

No naturally occurring veterinary HOS analogs were identified in the retrieved evidence.

15. Model organisms

15.1 Mouse models (key recent examples)

Noncoding regulatory element deletion models (2023): deletion of AF-associated regulatory regions near Tbx5 modestly increased atrial Tbx5 expression (~30%) and increased atrial arrhythmia susceptibility, linking cis-regulatory variation to electrophysiology phenotypes (Bosada et al., eLife 2023-01-30; https://doi.org/10.7554/eLife.80317) (bosada2023anatrialfibrillationassociated pages 1-2).
Patient-specific missense knock-in model (2022): Tbx5G125R/+ mice recapitulate atrial ectopy and AF susceptibility and show large-scale transcriptional/epigenetic perturbations (van Ouwerkerk et al., Circulation 2022-02-22; https://doi.org/10.1161/circulationaha.121.054347) (ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2).

15.2 Patient-derived iPSC models

A 2023 report describes single-cell RNA-seq comparison of cardiac progenitor cells from an HOS patient iPSC line and an isogenic CRISPR-corrected line, indicating an emerging platform for mechanism and therapeutic exploration; however, detailed results were not available in the excerpted text (dressen2023comparativesinglecellrnaseq pages 1-2).

Key data points (quick list)

Prevalence ~1/100,000 births (vanlerberghe2019holtoramsyndromeclinical pages 1-2).
In TBX5-confirmed cohort (n=78 probands): ASD 61.5%, VSD 34.6%, conduction disturbances ~29.6% among evaluable patients (vanlerberghe2019holtoramsyndromeclinical pages 4-5).
Variant spectrum in TBX5-positive probands: truncating variants predominate (nonsense 37%, frameshift 26%, splice-site 10%); CNVs (deletions 8%, duplications 4%) support including CNV testing (vanlerberghe2019holtoramsyndromeclinical pages 2-4).
2023 mechanistic advance: modest (~30%) atrial TBX5 increase from noncoding regulatory perturbation increases arrhythmia susceptibility (bosada2023anatrialfibrillationassociated pages 1-2).

Notes on missing identifiers (knowledge base population)

The evidence retrieved here did not include Orphanet, ICD-10/11, MeSH, or MONDO identifiers in citable text; these should be added by querying the corresponding databases directly.

References

(vanlerberghe2019holtoramsyndromeclinical pages 1-2): Clémence Vanlerberghe, Anne-Sophie Jourdain, Jamal Ghoumid, Frédéric Frenois, Aurélie Mezel, Guy Vaksmann, Bruno Lenne, Bruno Delobel, Nicole Porchet, Valérie Cormier-Daire, Thomas Smol, Fabienne Escande, Sylvie Manouvrier-Hanu, and Florence Petit. Holt-oram syndrome: clinical and molecular description of 78 patients with tbx5 variants. European Journal of Human Genetics, 27:360-368, Dec 2019. URL: https://doi.org/10.1038/s41431-018-0303-3, doi:10.1038/s41431-018-0303-3. This article has 67 citations and is from a domain leading peer-reviewed journal.
(atlas2024whentheheart pages 1-3): Ilyas Atlas, Soukaina Zagdan, Mohamed Megzari, Salim Arous, and Abdenasser Drighil. When the heart and hands tell a story: an intriguing case of holt–oram syndrome. The Egyptian Heart Journal, Sep 2024. URL: https://doi.org/10.1186/s43044-024-00549-4, doi:10.1186/s43044-024-00549-4. This article has 2 citations.
(dmowski2025holtoramsyndromewhen pages 8-12): Daniel Dmowski, Michał Świda, Jakub Bazarewicz, Cezary Kubuj, Grzegorz Adaśko, Urszula Mazur, Marcin Siwik, Anna Michalska, Paulina Ogonowska, and Julia Waszak. Holt-oram syndrome: when hand deformity leads to diagnosis of congenital heart disease. Quality in Sport, 45:66549, Nov 2025. URL: https://doi.org/10.12775/qs.2025.45.66549, doi:10.12775/qs.2025.45.66549. This article has 0 citations.
(vanlerberghe2019holtoramsyndromeclinical pages 4-5): Clémence Vanlerberghe, Anne-Sophie Jourdain, Jamal Ghoumid, Frédéric Frenois, Aurélie Mezel, Guy Vaksmann, Bruno Lenne, Bruno Delobel, Nicole Porchet, Valérie Cormier-Daire, Thomas Smol, Fabienne Escande, Sylvie Manouvrier-Hanu, and Florence Petit. Holt-oram syndrome: clinical and molecular description of 78 patients with tbx5 variants. European Journal of Human Genetics, 27:360-368, Dec 2019. URL: https://doi.org/10.1038/s41431-018-0303-3, doi:10.1038/s41431-018-0303-3. This article has 67 citations and is from a domain leading peer-reviewed journal.
(economou2025firstlivebirth pages 1-3): Konstantinos A. Economou, Chrysanthi Bili, Lina Florentin, Fotios Thymis, and Dimitrios Papanicolaou. First live birth in greece after blastocyst trophectoderm biopsy and preimplantation genetic testing for holt-oram syndrome. Hellenic Journal of Obstetrics and Gynecology, 24:55-61, Jan 2025. URL: https://doi.org/10.33574/hjog.0584, doi:10.33574/hjog.0584. This article has 0 citations.
(ouwerkerk2022patientspecifictbx5g125rvariant pages 1-2): Antoinette F. van Ouwerkerk, Fernanda M. Bosada, Karel van Duijvenboden, Arjan C. Houweling, Koen T. Scholman, Vincent Wakker, Cornelis P. Allaart, Jae-Sun Uhm, Inge B. Mathijssen, Ton Baartscheer, Alex V. Postma, Phil Barnett, Arie O. Verkerk, Bastiaan J. Boukens, and Vincent M. Christoffels. Patient-specific tbx5-g125r variant induces profound transcriptional deregulation and atrial dysfunction. Circulation, 145:606-619, Feb 2022. URL: https://doi.org/10.1161/circulationaha.121.054347, doi:10.1161/circulationaha.121.054347. This article has 40 citations and is from a highest quality peer-reviewed journal.
(liu2026experiencewithpatients pages 1-2): Xuechen Liu, Lei Yang, Jian Cui, Mengqian Liao, Zonghui Hou, Mengqi Zhao, and Lianyi Wang. Experience with patients presenting with the clinical features of holt-oram syndrome: a single center retrospective study. Journal of Cardiothoracic Surgery, Mar 2026. URL: https://doi.org/10.1186/s13019-026-03913-4, doi:10.1186/s13019-026-03913-4. This article has 0 citations and is from a peer-reviewed journal.
(bosada2023anatrialfibrillationassociated pages 1-2): Fernanda M Bosada, Karel van Duijvenboden, Alexandra E Giovou, Mathilde R Rivaud, Jae-Sun Uhm, Arie O Verkerk, Bastiaan J Boukens, and Vincent M Christoffels. An atrial fibrillation-associated regulatory region modulates cardiac tbx5 levels and arrhythmia susceptibility. eLife, Jan 2023. URL: https://doi.org/10.7554/elife.80317, doi:10.7554/elife.80317. This article has 14 citations and is from a domain leading peer-reviewed journal.
(dmowski2025holtoramsyndromewhen pages 5-8): Daniel Dmowski, Michał Świda, Jakub Bazarewicz, Cezary Kubuj, Grzegorz Adaśko, Urszula Mazur, Marcin Siwik, Anna Michalska, Paulina Ogonowska, and Julia Waszak. Holt-oram syndrome: when hand deformity leads to diagnosis of congenital heart disease. Quality in Sport, 45:66549, Nov 2025. URL: https://doi.org/10.12775/qs.2025.45.66549, doi:10.12775/qs.2025.45.66549. This article has 0 citations.
(liu2026experiencewithpatients pages 4-6): Xuechen Liu, Lei Yang, Jian Cui, Mengqian Liao, Zonghui Hou, Mengqi Zhao, and Lianyi Wang. Experience with patients presenting with the clinical features of holt-oram syndrome: a single center retrospective study. Journal of Cardiothoracic Surgery, Mar 2026. URL: https://doi.org/10.1186/s13019-026-03913-4, doi:10.1186/s13019-026-03913-4. This article has 0 citations and is from a peer-reviewed journal.
(vanlerberghe2019holtoramsyndromeclinical pages 2-4): Clémence Vanlerberghe, Anne-Sophie Jourdain, Jamal Ghoumid, Frédéric Frenois, Aurélie Mezel, Guy Vaksmann, Bruno Lenne, Bruno Delobel, Nicole Porchet, Valérie Cormier-Daire, Thomas Smol, Fabienne Escande, Sylvie Manouvrier-Hanu, and Florence Petit. Holt-oram syndrome: clinical and molecular description of 78 patients with tbx5 variants. European Journal of Human Genetics, 27:360-368, Dec 2019. URL: https://doi.org/10.1038/s41431-018-0303-3, doi:10.1038/s41431-018-0303-3. This article has 67 citations and is from a domain leading peer-reviewed journal.
(vanlerberghe2019holtoramsyndromeclinical pages 5-7): Clémence Vanlerberghe, Anne-Sophie Jourdain, Jamal Ghoumid, Frédéric Frenois, Aurélie Mezel, Guy Vaksmann, Bruno Lenne, Bruno Delobel, Nicole Porchet, Valérie Cormier-Daire, Thomas Smol, Fabienne Escande, Sylvie Manouvrier-Hanu, and Florence Petit. Holt-oram syndrome: clinical and molecular description of 78 patients with tbx5 variants. European Journal of Human Genetics, 27:360-368, Dec 2019. URL: https://doi.org/10.1038/s41431-018-0303-3, doi:10.1038/s41431-018-0303-3. This article has 67 citations and is from a domain leading peer-reviewed journal.
(liu2026experiencewithpatients pages 2-4): Xuechen Liu, Lei Yang, Jian Cui, Mengqian Liao, Zonghui Hou, Mengqi Zhao, and Lianyi Wang. Experience with patients presenting with the clinical features of holt-oram syndrome: a single center retrospective study. Journal of Cardiothoracic Surgery, Mar 2026. URL: https://doi.org/10.1186/s13019-026-03913-4, doi:10.1186/s13019-026-03913-4. This article has 0 citations and is from a peer-reviewed journal.
(bosada2023anatrialfibrillationassociated pages 23-24): Fernanda M Bosada, Karel van Duijvenboden, Alexandra E Giovou, Mathilde R Rivaud, Jae-Sun Uhm, Arie O Verkerk, Bastiaan J Boukens, and Vincent M Christoffels. An atrial fibrillation-associated regulatory region modulates cardiac tbx5 levels and arrhythmia susceptibility. eLife, Jan 2023. URL: https://doi.org/10.7554/elife.80317, doi:10.7554/elife.80317. This article has 14 citations and is from a domain leading peer-reviewed journal.
(cruz2026síndromedeholtoram pages 50-54): MC CRUZ. Síndrome de holt-oram: descripción clínica y molecular en un grupo de pacientes con defectos en miembros superiores asociados a cardiopatía congénita. Unknown journal, 2026.
(sweat2023tbx5maintainsatrial pages 1-2): Mason E. Sweat, Yangpo Cao, Xiaoran Zhang, Ozanna Burnicka-Turek, Carlos Perez-Cervantes, Arulsamy Kulandaisamy, Fujian Lu, Erin M. Keating, Brynn N. Akerberg, Qing Ma, Hiroko Wakimoto, Joshua M. Gorham, Lauren D. Hill, Mi Kyoung Song, Michael A. Trembley, Peizhe Wang, Matteo Gianeselli, Maksymilian Prondzynski, Raul H. Bortolin, Vassilios J. Bezzerides, Kaifu Chen, Jonathan G. Seidman, Christine E. Seidman, Ivan P. Moskowitz, and William T. Pu. Tbx5 maintains atrial identity in postnatal cardiomyocytes by regulating an atrial-specific enhancer network. Nature Cardiovascular Research, 2:881-898, Oct 2023. URL: https://doi.org/10.1038/s44161-023-00334-7, doi:10.1038/s44161-023-00334-7. This article has 33 citations and is from a peer-reviewed journal.
(dmowski2025holtoramsyndromewhen pages 1-5): Daniel Dmowski, Michał Świda, Jakub Bazarewicz, Cezary Kubuj, Grzegorz Adaśko, Urszula Mazur, Marcin Siwik, Anna Michalska, Paulina Ogonowska, and Julia Waszak. Holt-oram syndrome: when hand deformity leads to diagnosis of congenital heart disease. Quality in Sport, 45:66549, Nov 2025. URL: https://doi.org/10.12775/qs.2025.45.66549, doi:10.12775/qs.2025.45.66549. This article has 0 citations.
(atlas2024whentheheart pages 5-6): Ilyas Atlas, Soukaina Zagdan, Mohamed Megzari, Salim Arous, and Abdenasser Drighil. When the heart and hands tell a story: an intriguing case of holt–oram syndrome. The Egyptian Heart Journal, Sep 2024. URL: https://doi.org/10.1186/s43044-024-00549-4, doi:10.1186/s43044-024-00549-4. This article has 2 citations.
(atlas2024whentheheart pages 3-5): Ilyas Atlas, Soukaina Zagdan, Mohamed Megzari, Salim Arous, and Abdenasser Drighil. When the heart and hands tell a story: an intriguing case of holt–oram syndrome. The Egyptian Heart Journal, Sep 2024. URL: https://doi.org/10.1186/s43044-024-00549-4, doi:10.1186/s43044-024-00549-4. This article has 2 citations.
(dressen2023comparativesinglecellrnaseq pages 1-2): M. Dreßen, H. Lahm, F. Wirth, I. Neb, C. Abou-Ajram, E. Dzilic, S. Doppler, and R. Lange. Comparative single-cell rnaseq analysis of cardiac progenitor cells from a holt-oram syndrome patient ips line and the crispr/cas9 corrected isogenic ips line. The Thoracic and Cardiovascular Surgeon, Jan 2023. URL: https://doi.org/10.1055/s-0043-1761827, doi:10.1055/s-0043-1761827. This article has 0 citations.

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Medical Actions

Prevalence

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Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

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Output Format

Holt–Oram syndrome (HOS) — Disease Characteristics Research Report (Genetic)

Executive summary

1. Disease information

1.1 What is the disease?

1.2 Key identifiers (and gaps)

1.3 Synonyms and alternative names

1.4 Evidence source type

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes

3.1 Core phenotype domains

3.2 Quantitative phenotype frequencies (key recent data)

3.3 Age of onset, severity, progression

3.4 Quality-of-life impact

3.5 Suggested HPO terms (examples)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variant spectrum and interpretation

4.3 Modifier genes

4.4 Epigenetic/regulatory mechanisms relevant to disease expression

4.5 Chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Causal chain (developmental biology to clinical disease)

6.2 Recent mechanistic developments (prioritizing 2023–2024)

6.3 Expert/authoritative interpretation (high-quality sources)

6.4 Pathways, cellular processes, and suggested ontology terms

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

9.1 Epidemiology

9.2 Inheritance pattern, penetrance, expressivity

10. Diagnostics

10.1 Clinical criteria and diagnostic approach

10.2 Testing modalities (real-world)

10.3 Differential diagnosis

10.4 Screening (prenatal)

11. Outcome / prognosis

12. Treatment

12.1 Standard of care (symptom-directed)

12.2 Experimental / clinical trials

13. Prevention