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Holt-Oram Syndrome

Synonym: Heart and Hand Syndrome

, MS, CGC, , MS, CGC, and , MD, PhD.

Author Information

Initial Posting: ; Last Update: October 8, 2015.

Estimated reading time: 23 minutes


Clinical characteristics.

Holt-Oram syndrome (HOS) is characterized by:

  • Upper-extremity malformations involving radial, thenar, or carpal bones; and
  • Variably, one or both of the following:
    • Personal and/or family history of congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum
    • Cardiac conduction disease

An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. Seventy-five percent of individuals with HOS have a congenital heart malformation.


The diagnosis of HOS is established in a proband with a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects. More than 70% of individuals who meet strict clinical diagnostic criteria have an identifiable heterozygous pathogenic variant in TBX5.


Treatment of manifestations: Management involves a multidisciplinary team of specialists in medical genetics, cardiology, orthopedics, and hand surgery. Affected individuals and families are also likely to benefit from programs providing social support to those with limb anomalies.

Surveillance: Annual ECG for all affected individuals, annual Holter monitor for individuals with known conduction disease, and echocardiogram every one to five years for those with septal defects.

Evaluation of relatives at risk: Presymptomatic diagnosis and treatment is warranted in relatives at risk to identify those who would benefit from appropriate cardiac management.

Pregnancy management: Affected women who have not undergone cardiac evaluation should do so prior to pregnancy or as soon as the pregnancy is recognized; those with a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a cardiologist during pregnancy.

Genetic counseling.

HOS is inherited in an autosomal dominant manner. Approximately 85% of affected individuals have HOS as the result of a de novo pathogenic variant. Offspring of an affected individual are at a 50% risk of being affected. In pregnancies at 50% risk, detailed high-resolution prenatal ultrasound examination may detect upper-limb malformations and/or congenital heart malformations. Prenatal molecular genetic testing may be used to confirm a diagnosis if the TBX5 pathogenic variant has been identified in an affected relative.


Clinical diagnostic criteria for Holt-Oram syndrome have been established and validated through molecular genetic testing [McDermott et al 2005].

Suggestive Findings

Holt-Oram syndrome (HOS) should be suspected in individuals with the following limb anomalies, cardiac findings, and family history:

  • Upper-limb malformation involving the carpal bone(s) and, variably, the radial and/or thenar bones
    • The upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric.
    • An abnormal carpal bone, present in all affected individuals and identified by performing a posterior-anterior hand x-ray [Poznanski et al 1970, Basson et al 1994], may be the only evidence of disease.
  • Congenital heart malformation, most commonly ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD), especially those occurring in the muscular trabeculated septum
  • Cardiac conduction disease
  • Family history of a first-degree relative with a congenital heart defect or cardiac conduction disease

Note: Congenital malformations involving the following structures or organ systems are not typically within the spectrum of HOS and should prompt the clinician to consider alternate diagnoses: ulnar ray only, kidney, vertebra, craniofacies, auditory system (ear malformations ± hearing loss), lower limb, anus, or eye.

Establishing the Diagnosis

The diagnosis of Holt-Oram syndrome is established in a proband with either a preaxial radial ray anomaly and a personal or family history of cardiac septation and/or conduction defects or, if clinical findings are insufficient, a heterozygous pathogenic variant in TBX5 by molecular genetic testing (see Table 1).

Molecular testing approaches can include single-gene testing and – if the phenotype includes features that are atypical for Holt-Oram syndrome – a multigene panel. Though rare, chromosome rearrangements involving 12q24 have been reported in individuals with Holt-Oram syndrome [Li et al 1997, Basson et al 1999].

  • Single-gene testing. Sequence analysis of TBX5 is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found.
  • A multigene panel that includes TBX5 and other genes of interest (see Differential Diagnosis) may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
    For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Table 1.

Molecular Genetic Testing Used in Holt-Oram syndrome (HOS)

Gene 1Proportion of Pathogenic Variants 2 Detected by Test Method
Sequence analysis 3Gene-targeted deletion/duplication analysis 4
TBX5>70% 5<1% 6

See Molecular Genetics for information on allelic variants detected in this gene.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.


Individuals meeting the strict diagnostic criteria of upper-limb defect and personal and/or family history of structural or conductive heart disease have a heterozygous TBX5 pathogenic variant predicted to cause disease [McDermott et al 2005, Debeer et al 2007]. Lower pathogenic variant detection rates (30%-40%) reported in some studies likely result from the inclusion of individuals who would not meet the strict diagnostic criteria outlined above [Cross et al 2000, Brassington et al 2003].


Deletion of one or more exons or the entire gene was detected in about 2% of individuals with HOS who did not have a pathogenic variant identified by sequence analysis/mutation scanning [Borozdin et al 2006].


That current molecular analysis fails to identify a heterozygous pathogenic variant in TBX5 in up to 30% of individuals with HOS suggests the presence of pathogenic variants in noncoding regions or regulatory regions around TBX5 [McDermott et al 2005, Debeer et al 2007].

Clinical Characteristics

Clinical Description

Holt-Oram syndrome is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease [Holt & Oram 1960].

Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia, a malformation in which the hands are attached close to the body; intermediate presentations resulting from abnormal development of the bones involved may also be observed. Other upper-limb malformations can include unequal arm length caused by aplasia or hypoplasia of the radius, fusion or anomalous development of the carpal and thenar bones, abnormal forearm pronation and supination, abnormal opposition of the thumb, and sloping shoulders and restriction of shoulder joint movement.

While all individuals have an upper-limb defect, the broad range of severity of these findings is such that some individuals with the mildest upper-limb malformations and no or mild congenital heart malformation may escape diagnosis. These individuals may only be diagnosed when a more severely affected relative is born or when symptoms develop in middle age as a result of cardiac abnormalities such as pulmonary hypertension, high-grade atrioventricular block, and/or atrial fibrillation. Cardiac conduction disease can be progressive.

A congenital heart malformation is present in 75% of individuals with HOS and most commonly involve the septum. Atrial septal defect (ASD) and ventricular septal defect (VSD) can vary in number, size, and location. ASDs can present as a common atrium and are often associated with cardiac chamber isomerism; that is, the defining features of the cardiac chambers, based on their anatomic location, are altered (e.g., what may be considered right atrium based on its anatomic location may not have the atrial appendage morphology typical of the right atrium).

Some individuals with severe congenital heart malformation may require surgery early in life to repair significant septal defects [Sletten & Pierpont 1996].

Other individuals may have complex congenital heart malformations [Faria et al 2008, Baban et al 2014, Barisic et al 2014]; conotruncal malformations, though observed in HOS, are not common and may be caused by other genetic defects.

Cardiac conduction disease. Individuals with HOS with or without a congenital heart malformation are at risk for cardiac conduction disease. While individuals may present at birth with sinus bradycardia and first-degree atrioventricular (AV) block, AV block can progress unpredictably to a higher grade including complete heart block with and without atrial fibrillation.

The natural history of HOS varies by individual and largely depends on the severity of the congenital heart malformation. Potential complications (which can be life threatening if not recognized and appropriately managed) include: congestive heart failure, pulmonary hypertension, arrhythmias, heart block, atrial fibrillation, and infective endocarditis.

Genotype-Phenotype Correlations

It has been reported that pathogenic missense variants at the 5' end of the T-box (which binds the major groove of the target DNA sequence) are associated with more serious cardiac defects.

Pathogenic missense variants at the 3' end of the T-box (which binds the minor groove of the target DNA) result in more pronounced limb defects. Caution is warranted, however, in applying these population-based associations to individuals in whom pathogenic variants may not predict specific phenotypes [Basson et al 1999, Brassington et al 2003].

In addition, genotypes do not appear to predict the progressive hemodynamic course associated with any particular cardiac septal defect.


The upper-limb malformations in HOS are fully penetrant.

Congenital heart malformations occur in approximately 75% of affected individuals [Basson et al 1999]. Conduction defects may occur in the presence or absence of structural heart defects.


Statistically significant anticipation is not observed in HOS. Because of the variable expressivity of HOS, what appears to be anticipation may reflect ascertainment bias. In small kindreds, the diagnosis of a more severely affected young person can lead to evaluation and subsequent diagnosis of older, more mildly affected individuals [Newbury-Ecob et al 1996]. However, examination of large, multigenerational kindreds with HOS does not support anticipation.


HOS has been referred to as heart-hand syndrome, a nonspecific designation that could apply to any number of conditions with involvement of these structures.


HOS is the most common of the heart-hand syndromes. The estimated prevalence of HOS is between 0.7 and 1 per 100,000 births [Elek et al 1991, Barisic et al 2014].

HOS has been reported from a number of countries worldwide and in individuals of different racial and ethnic backgrounds [Boehme & Shotar 1989, Yang et al 2000, Barisic et al 2014, Kimura et al 2015].

Differential Diagnosis

The following diagnoses can be considered when anomalies involving the ulna, lower limbs, kidneys, genitourinary system, vertebrae, craniofaces, and auditory or ocular systems are present [Newbury-Ecob et al 1996, Allanson & Newbury-Ecob 2003, Bressan et al 2003].

Autosomal dominant disorders

  • SALL4-related disorders include Duane-radial ray syndrome (DRRS) and acro-renal-ocular syndrome (AROS). DRRS is characterized by uni- or bilateral Duane anomaly and radial ray malformation that can include thenar hypoplasia and/or hypoplasia or aplasia of the thumbs; hypoplasia or aplasia of the radii; shortening and radial deviation of the forearms; triphalangeal thumbs; and duplication of the thumb (preaxial polydactyly). Acro-renal-ocular syndrome is characterized by radial ray malformations, renal abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, vesicoureteral reflux, bladder diverticula), ocular coloboma, and Duane anomaly. SALL4 pathogenic variants may rarely cause what appears to be clinically typical Holt-Oram syndrome (i.e., radial ray malformations and cardiac malformations), but further clinical investigations frequently demonstrate features that are considered exclusionary for a diagnosis of HOS (e.g., renal anomalies, Duane anomaly, sensorineural hearing loss) [Kohlhase et al 2003].
  • Ulnar-mammary syndrome (UMS) (OMIM 181450) is caused by pathogenic variants in another T-box gene, TBX3, which, like TBX5, is localized to 12q24.1. These two genes arose via gene duplication. UMS, an autosomal dominant condition, involves primarily the ulnar ray; postaxial polydactyly may be seen. Breast and nipple hypoplasia and delayed puberty are also observed. Although not commonly observed in UMS, congenital heart malformations have been reported. UMS can be diagnosed clinically or by using molecular genetic testing [Bamshad et al 1997, Bamshad et al 1999].
  • Townes-Brocks syndrome (TBS) is characterized by the triad of imperforate anus (82%), dysplastic ears (88%) (overfolded superior helices and preauricular tags) frequently associated with sensorineural and/or conductive hearing impairment (65%), and thumb malformations (89%) (triphalangeal thumbs, duplication of the thumb [preaxial polydactyly], and rarely hypoplasia of the thumbs). Renal impairment (27%), including end-stage renal disease (ESRD) (42%), may occur with or without structural abnormalities (mild malrotation, ectopia, horseshoe kidney, renal hypoplasia, polycystic kidneys, vesicoutereral reflux). Congenital heart disease occurs in 25%. Foot malformations (52%) (flat feet, overlapping toes) and genitourinary malformations (36%) are common. Intellectual disability occurs in approximately 10% of cases. Rare features include iris coloboma, Duane anomaly, Arnold-Chiari malformation type 1, and growth retardation.
  • Heart-hand syndrome II (Tabatznik syndrome) is characterized by type D brachydactyly (shortening of the distal phalanx of the thumb ± shortening of the 4th and 5th metacarpals), sloping shoulders, short upper limbs, bowing of the distal radii, and absence of the styloid process of the ulna with supraventricular tachycardia. Affected individuals may also have mild dysmorphic facial features, mild intellectual disability, and cardiac arrhythmias [Silengo et al 1990]. To date, no related gene has been identified.
  • Heart-hand syndrome III (Spanish type) (OMIM 140450) is characterized by type C brachydactyly (shortening of the middle phalanges) with an accessory wedge-shaped ossicle on the proximal phalanx of the index fingers. Feet are typically more mildly affected. Intraventricular conduction defects and sick sinus syndrome may also occur [Ruiz de la Fuente & Prieto 1980]. To date, no related gene has been identified.
  • Long thumb brachydactyly syndrome (OMIM 112430) is characterized by symmetric elongation of the thumb distal to the proximal interphalangeal (PIP) joint, often associated with index finger brachydactyly, clinodactyly, narrow shoulders, secondary short clavicles, and pectus excavatum. Occasionally, rhizomelic limb shortening occurs. The cardiac abnormality is often a conductive defect [Hollister & Hollister 1981]. To date, no related gene has been identified.
  • Familial progressive sinoatrial and atrioventricular conduction disease of adult onset with sudden death, dilated cardiomyopathy, and brachydactyly. This disorder, possibly a new heart-hand syndrome with involvement of the feet as well, was reported by Sinkovec et al [2005]. Heart-hand syndrome, Slovenian type (OMIM 610140) is caused by heterozygous pathogenic variants in LMNA.

Autosomal recessive disorders

  • Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in 60%-75% of affected individuals, include short stature; abnormal skin pigmentation; malformations of the thumbs, forearms, skeletal system, eyes, kidneys and urinary tract, ear, heart, gastrointestinal system, oral cavity, and central nervous system; hearing loss; hypogonadism; and developmental delay. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. FA is caused by pathogenic variants in one of at least 15 genes; the diagnosis of FA rests on the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC).
  • Thrombocytopenia-absent radius syndrome (TAR) is characterized by bilateral absence of the radii with the presence of both thumbs and thrombocytopenia (<50 platelets/nL) that is generally transient. Individuals with TAR syndrome almost always have a minimally deleted 200-kb region at chromosome band 1q21.1. Other findings (particularly hematologic and neurologic) and frequent involvement of the lower limbs differentiate TAR from HOS [Greenhalgh et al 2002].

Chromosomal etiology

  • 22q11.2 deletion syndrome (del22q11.2) is characterized by a range of findings including congenital heart disease (74% of affected individuals) (particularly conotruncal malformations) and other features not seen in HOS such as palatal abnormalities (69%), learning difficulties (70%-90%), and immune deficiency (77%). About 6% of individuals exhibit upper-extremity anomalies including pre- and postaxial polydactyly, which may result in misdiagnosis of HOS. Del 22q11.2 can be diagnosed using fluorescence in situ hybridization (FISH) or other genomic technologies, such as chromosomal microarray.

Disorders of unknown cause

  • VACTERL is an acronym for vertebral defects, anal atresia, cardiac malformation, tracheo-esophageal fistula with esophageal atresia, renal anomalies, and limb anomalies.

Teratogen exposure

  • Thalidomide. Exposure to thalidomide in pregnancy places the fetus at risk for severe upper- and lower-limb defects (e.g., phocomelia, amelia), cardiac defects, and malformations in other systems not observed in HOS (renal, ocular, auditory, gastrointestinal, and craniofacial) [Matthews & McCoy 2003, McDermott et al 2005, Vianna et al 2013].
  • Valproate. Exposure to valproate, particularly in the first trimester, places the fetus at risk for major congenital defects including congenital heart defects that can overlap those seen in HOS; however, the other malformations seen (e.g., polydactyly, spina bifida) are not features of HOS [McDermott et al 2005, Wyszynski et al 2005].


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Holt-Oram syndrome, the following evaluations are recommended:

  • Genetic. Consultation with a clinical geneticist and/or genetic counselor
  • Limb
    • Limb involvement is determined by physical examination.
    • If limb involvement is not grossly obvious, upper-limb and hand radiographs can be performed to determine if subtle anomalies of the carpal bones are present.
  • Cardiac
    • Chest radiography may demonstrate enlarged pulmonary arteries caused by pulmonary hypertension or cardiomegaly and/or evidence of congestive heart failure.
    • Echocardiography is the procedure of choice to define the presence of septal defects or other structural cardiac anomalies.
    • ECG is recommended for the detection of cardiac conduction disease.

Treatment of Manifestations

The management of individuals with HOS optimally involves a multidisciplinary team approach with specialists in medical genetics, cardiology, and orthopedics, including a specialist in hand surgery.

A cardiologist can assist in determining the need for antiarrhythmic medications and surgery. Individuals with severe heart block may require pacemaker implantation. Pharmacologic treatment for affected individuals with pulmonary hypertension may be appropriate. Individuals with pulmonary hypertension and/or structural heart malformation may require tertiary care center cardiology follow up. Cardiac surgery, if required for congenital heart defect, is standard.

The orthopedic team may be able to guide individuals in decisions regarding surgery for improved upper-limb and hand function as well as physical and occupational therapy options. Those individuals born with severe upper-limb malformations may be candidates for surgery to improve function, such as pollicization (creation of a thumb-like digit by moving another digit into the thenar position) in the case of thumb aplasia/hypoplasia [Vaienti et al 2009]. Children with severe limb shortening may benefit from prostheses as well as from physical and occupational therapy.

Individuals and families are also likely to benefit from programs providing social support to those with limb anomalies.

Prevention of Secondary Complications

A cardiologist can assist in determining the need for anticoagulants and antibiotic prophylaxis for bacterial endocarditis (SBE).


ECG is indicated annually or more often in individuals diagnosed with a conduction defect, as well as in individuals at risk for developing a conduction defect.

ECG should be combined with annual Holter monitor in individuals with known conduction disease to assess progression.

Depending on the nature and significance of potential septal defects, echocardiogram surveillance may be requested every one to five years by the managing cardiologist.

Agents/Circumstances to Avoid

Certain medications may be contraindicated in individuals with arrhythmias, cardiomyopathy, and/or pulmonary hypertension. People with such disorders require individual assessment by a cardiologist.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from appropriate cardiac management. Evaluations can include:

  • Molecular genetic testing if the TBX5 pathogenic variant in the family is known;
  • Echocardiography, ECG, and hand x-rays (anterior/posterior view) if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnant women with HOS who have a known history of a structural cardiac defect or cardiac conduction abnormality should be followed by a multidisciplinary team (including a cardiologist) during pregnancy. Affected women who have not undergone cardiac evaluation should do so prior to pregnancy if possible, or as soon as the pregnancy is recognized.

Therapies Under Investigation

Search in the US and in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Holt-Oram syndrome (HOS) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Some individuals diagnosed with HOS have an affected parent.
  • A proband with HOS often has the disorder as the result of a heterozygous de novo TBX5 pathogenic variant. Up to 85% of cases are caused by a de novo pathogenic variant [Elek et al 1991], while approximately 15% of cases are familial [Barisic et al 2014].
  • Recommendations for the evaluation of parents of a proband with an apparent heterozygous de novo pathogenic variant include echocardiography, ECG, and hand x-rays (anterior/posterior view) to determine their affected status. Alternatively, molecular genetic testing can be performed on the parents if the TBX5 pathogenic variant in the proband has been identified.
  • The family history of some individuals diagnosed with HOS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disorder in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the pathogenic variant first occurred, s/he may be mildly/minimally affected.

Sibs of a proband

  • The risk to sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected or has a TBX5 pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%.
  • When the parents are clinically unaffected and the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to the sibs of a proband appears to be low (similar to the general population risk, on the order of 1/100,000).
  • When the TBX5 pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the two possible explanations are germline mosaicism in a parent or de novo mutation in the proband. Although no instances of germline mosaicism have been confirmed, it remains a possibility [Braulke et al 1991].

Offspring of a proband

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her family members are at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Specific risk issues. Specific clinical risks of concern for at-risk family members are those related to life-threatening cardiac issues including congestive heart failure, arrhythmias, heart block, atrial fibrillation, pulmonary hypertension, and infective endocarditis.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the TBX5 pathogenic variant in the family.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has a pathogenic variant or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, other possible non-medical explanations that could be explored include alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

For pregnancies known to be at increased risk for HOS

  • If the TBX5 pathogenic variant in the family is known, molecular genetic testing first followed by detailed ultrasound (US) evaluation if the fetus has the pathogenic variant
  • If the pathogenic variant in the family is not known, US examination evaluating for characteristic limb and cardiac manifestations (including fetal echocardiogram). Note: A normal ultrasound examination does not eliminate the possibility of HOS in the fetus.

For pregnancies not known to be at increased risk for HOS

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Because of the significant variable expressivity observed in individuals with HOS both among and within families with the same pathogenic variant, the severity of upper-limb defects and congenital heart malformations cannot be accurately predicted by molecular genetic testing alone.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the TBX5 pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • American Heart Association (AHA)
    7272 Greenville Avenue
    Dallas TX 75231
    Phone: 800-242-8721 (toll-free)
  • Reach: The Association for Children with Hand or Arm Deficiency
    PO Box 54
    Helston Cornwall TR13 8WD
    United Kingdom
    Phone: +44 0845 1306 225
    Fax: +44 0845 1300 262

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Holt-Oram Syndrome: Genes and Databases

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TBX512q24​.21T-box transcription factor TBX5TBX5 databaseTBX5TBX5

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Holt-Oram Syndrome (View All in OMIM)

601620T-BOX 5; TBX5

Gene structure. TBX5 is a member of the T-box family of transcription factors [Basson et al 1997, Li et al 1997]. TBX5 consists of nine coding exons. At least two alternatively spliced transcript variants modify the coding region to add or remove the terminal exon, whose presence modifies TBX5 activity but is not necessarily required [Basson et al 1999, Ghosh et al 2001]. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. Most HOS is caused by small intragenic pathogenic variants that result in a null allele and haploinsufficinecy. Nearly 70 pathogenic variants have been described in TBX5. While most are private pathogenic variants, at least two recurrent pathogenic variants have been reported, suggesting that these may be "hot spots." Pathogenic variants may be missense or nonsense; large deletions of multiple exons or the entire gene have also been reported [Basson et al 1997, Basson et al 1999, Cross et al 2000, Akrami et al 2001, Brassington et al 2003, Heinritz et al 2005, McDermott et al 2005]. Frameshift pathogenic variants leading to elongated TBX5 have been reported, although associated phenotypes have features that fail to meet strict diagnostic criteria of HOS [Böhm et al 2008, Muru et al 2011]. Intragenic TBX5 duplications involving exons 2-9 [Patel et al 2012] and exons 1-6 [Kimura et al 2015] have also been reported.

Normal gene product. T-box transcription factor TBX5 functions as a transcription factor that has an important role in both cardiogenesis and limb development.

In vitro and in vivo animal models support a role for TBX5 in cellular arrest signaling pathways during cardiac growth and development, particularly in cardiac septation, as well as in the development of a cardiac conduction system, independent of its role in cardiac morphogenesis [Basson et al 1994, Moskowitz et al 2004, Moskowitz et al 2007, Puskaric et al 2010]. In vivo studies also support a role for TBX5 in forelimb specification and outgrowth. Moreover, in vivo studies suggest that TBX5 is an early marker of dorsoventral patterning of the eye [Veien et al 2008, Zhang et al 2009], though specific TBX5 pathogenic variants have not been shown to be directly related to specific ocular abnormalities in humans. Pathogenic variants are not known to result in ocular abnormalities in humans.

TBX5 can interact with other transcription factors including NKX2.5 and GATA4, and these interactions may participate in regulating cardiogenesis. Appropriate balance between expression of TBX5 and other T-box transcription factors may be required for specification of cardiac and limb structures during embryogenesis [Hatcher et al 2001, Rallis et al 2003, Ghosh et al 2009, Maitra et al 2009, Rothschild et al 2009, Camarata et al 2010a, Camarata et al 2010b, Nadeau et al 2010].

Recent functional analyses of TBX5 pathogenic variants have supported the role of TBX5 protein levels and interaction with other transcription factors in the clinical findings of HOS in animal models [Boogerd et al 2010]. A recent study suggests that Tbx5 specifically affects muscle and tendon patterning without disrupting bone development in an animal model [Hasson et al 2010].

Abnormal gene product. It is hypothesized that most nonsense and frameshift pathogenic variants lead to mutated TBX5 mRNAs that are degraded, resulting in haploinsufficiency. Some missense pathogenic variants result in transcripts that have diminished DNA binding activity. Both result in reduced functional TBX5, which leads to disease [Hatcher & Basson 2001]. By contrast, studies reporting pathogenic variants predicting either an elongated TBX5 or an intragenic TBX5 duplication suggest the possibility of a dominant-negative effect on downstream targets [Böhm et al 2008, Patel et al 2012]. Researchers who recently elucidated the crystal structure of the TBX5 T-box domain in its DNA-unbound and DNA-bound forms have identified an inducible C-terminal element within the T-box domain that may be required for the interaction of TBX5 with DNA [Stirnimann et al 2010].


Literature Cited

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Chapter Notes

Revision History

  • 8 October 2015 (me) Comprehensive update posted live
  • 4 April 2013 (me) Comprehensive update posted live
  • 4 January 2011 (me) Comprehensive update posted live
  • 22 November 2006 (cd) Revision: array genomic hybridization and deletion/duplication testing clinically available
  • 21 September 2006 (me) Comprehensive update posted live
  • 20 July 2004 (me) Review posted live
  • 23 December 2003 (cb) Original submission
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