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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: May 23, 2019.

Estimated reading time: 19 minutes

Summary

Clinical characteristics.

Holt-Oram syndrome (HOS) is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease. Upper-limb malformations may be unilateral, bilateral/symmetric, or bilateral/asymmetric and can range from triphalangeal or absent thumb(s) to phocomelia. 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, sloping shoulders, and restriction of shoulder joint movement. An abnormal carpal bone is present in all affected individuals and may be the only evidence of disease. A congenital heart malformation is present in 75% of individuals with HOS and most commonly involves the septum. Atrial septal defect and ventricular septal defect can vary in number, size, and location. Complex congenital heart malformations can also occur in individuals with HOS. 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.

Diagnosis/testing.

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.

Management.

Treatment of manifestations: Management involves a multidisciplinary team of specialists in medical genetics, cardiology, orthopedics, and hand surgery. Treatment for arrhythmias may require medication, surgery, and/or pacemaker implantation. Pharmacologic treatment for individuals with pulmonary hypertension. Cardiac surgery for congenital heart defects is standard; affected 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.

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 or as directed by a cardiologist.

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.

Diagnosis

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
    • 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, and 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 identified 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 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications.
  • A multigene panel that includes TBX5 and other genes of interest (see Differential Diagnosis) 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. 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. (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 this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
    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

Gene 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
TBX5Sequence analysis 3>70%4
Gene-targeted deletion/duplication analysis 5<1% 6
Unknown 7NA
1.
2.

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

3.

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.

4.

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].

5.

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.

6.

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/variant scanning [Borozdin et al 2006].

7.

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 mild or no 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 involves 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.

Penetrance

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.

Nomenclature

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.

Prevalence

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

Diagnoses summarized in Table 2 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].

Table 2.

Disorders to Consider in the Differential Diagnosis of Holt-Oram Syndrome (HOS)

Disorder/ConditionGene(s) /
Genetic
Mechanism
MOIClinical DescriptionComments
Duane-radial ray syndromeSALL4AD
  • Uni- or bilateral Duane anomaly
  • Radial ray malformation (e.g, thenar hypoplasia, thumb hypoplasia, aplasia, duplication or triphalangeal thumb, radius hypoplasia or aplasia, shortening & radial deviation of forearms)
  • SALL4 pathogenic variants may rarely cause what appears to be clinically typical HOS (i.e., radial ray malformations & cardiac malformations).
  • Further clinical investigations frequently demonstrate features considered exclusionary of HOS (e.g., renal anomalies, Duane anomaly, sensorineural hearing loss).
Acro-renal-ocular syndromeAD
  • Radial ray malformations
  • Renal abnormalities
  • Ocular coloboma
  • Duane anomaly
Ulnar-mammary syndrome
(OMIM 181450)
TBX3AD
  • Primarily involves ulnar ray (e.g., postaxial polydactyly)
  • Breast & nipple hypoplasia & delayed puberty
  • Congenital heart malformations (not commonly observed)
Townes-Brocks syndromeSALL1AD
  • Triad of: imperforate anus; dysplastic ears (overfolded superior helices & preauricular tags) frequently associated w/sensorineural &/or conductive hearing impairment; & thumb malformations (duplication, hypoplasia, or triphalangeal thumbs)
  • Renal impairment incl ESRD w/or w/out structural abnormalities
  • Congenital heart disease
  • Foot malformations (flat feet, overlapping toes)
  • Genitourinary malformations
  • ID in ~10% of affected individuals
Heart-hand syndrome II
(Tabatznik syndrome) 1
Not identifiedAD
  • Type D brachydactyly (shortening of distal phalanx of the thumb ± shortening of 4th & 5th metacarpals)
  • Sloping shoulders
  • Short upper limbs, bowing of distal radii, absence of styloid process of the ulna
  • Cardiac arrhythmias (e.g., supraventricular tachycardia)
  • Mild dysmorphic facial features
  • Mild ID
Heart-hand syndrome III (Spanish type)
(OMIM 140450)
Not identifiedAD
  • Type C brachydactyly (shortening of the middle phalanges) w/accessory wedge-shaped ossicle on proximal phalanx of index fingers
  • Feet typically more mildly affected
  • Intraventricular conduction defects (e.g., sick sinus syndrome)
Long thumb brachydactyly syndrome
(OMIM 112430)
Not identifiedAD
  • Symmetric elongation of thumb distal to proximal interphalangeal joint
  • Index finger brachydactyly
  • Clinodactyly
  • Narrow shoulders
  • Secondary short clavicles
  • Pectus excavatum
  • Cardiac abnormality is often a conduction defect.
Heart-hand syndrome, Slovenian type
(OMIM 610140)
LMNAAD
  • Familial progressive sinoatrial & atrioventricular conduction disease of adult onset w/sudden death
  • Dilated cardiomyopathy
  • Brachydactyly
  • Feet also involved
Fanconi anemia>20 genes 2AR
AD
XL
  • Short stature
  • Abnormal skin pigmentation
  • Malformations of thumbs, forearms, eyes, ears, oral cavity, genitourinary system, heart, gastrointestinal system, central nervous system
  • DD
  • Progressive bone marrow failure w/pancytopenia typically presenting in 1st decade, often initially w/thrombocytopenia or leukopenia
  • Increased risk for malignancy
Thrombocytopenia-absent radius syndrome (TAR)RBM8A 3AR
  • Bilateral absence of radii w/presence of both thumbs
  • Thrombocytopenia (<50 platelets/nL), generally transient
Other findings in TAR, (esp hematologic & neurologic) & frequent involvement of lower limbs differentiate TAR from HOS.
22q11.2 deletion syndrome (del22q11.2)Deletion of 22q11.2 DGCRAD
  • Congenital heart disease
  • ~6% of individuals exhibit upper-extremity anomalies including pre- & postaxial polydactyly, which may result in misdiagnosis of HOS.
Other features in del22q11.2 incl palatal abnormalities (69%), learning difficulties (70%-90), & immune deficiency (77%), distinguish del22q11.2 from HOS.

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DGCR = DiGeorge chromosome region; ESRD = end-stage renal disease; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked

1.
2.

Genes known to be associated with Fanconi anemia: BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, MAD2L2, PALB2, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2

3.

The diagnosis of TAR syndrome is established in a proband with bilateral absent radii, present thumbs, and thrombocytopenia. Identification of a heterozygous null allele (most often a minimally deleted 200-kb region at chromosome band 1q21.1) in trans with a heterozygous RBM8A hypomorphic allele on molecular genetic testing confirms the diagnosis.

Other Diagnoses to Consider in the Differential Diagnosis of HOS

Disorders of unknown cause

  • VACTERL (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].

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with Holt-Oram syndrome (HOS), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Holt-Oram Syndrome

System/ConcernEvaluationComment
MusculoskeletalPhysical examination for limb involvementHand & upper-limb radiographs may be recommended by orthopedist to aid in management of radial ray malformations.
CardiacChest radiographyTo identify enlarged pulmonary arteries caused by pulmonary hypertension or cardiomegaly &/or evidence of congestive heart failure
EchocardiographyTo identify septal defects or other structural cardiac anomalies
ECGTo identify cardiac conduction disease
OtherConsultation w/clinical geneticist &/or genetic counselor

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 individuals with 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).

Surveillance

Table 4.

Recommended Surveillance for Individuals with Holt-Oram Syndrome

System/ConcernEvaluationFrequency
CardiacECGAnnually in individuals at risk of developing a conduction defect
ECG combined w/Holter monitorAnnually in individuals w/known conduction disease to assess progression
EchocardiogramEvery 1-5 yrs – may be recommended by the managing cardiologist depending on nature & significance of potential septal defects.

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.

See MotherToBaby for further information on medication use during pregnancy.

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for 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.
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Presumed parental germline mosaicism has been reported [Braulke et al 1991].
  • 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 the TBX5 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Significant intrafamilial clinical variability is observed.
  • If the parents are clinically unaffected and the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to the sibs of a proband appears to be low but slightly greater than the general population risk of approximately 1/100,000 because of the possibility of parental germline mosaicism.

Offspring of a proband

Other family members. The risk to other family members depends on the status of the proband's parents; if a parent is affected/has the pathogenic variant, 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 the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

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 and Preimplantation Genetic Diagnosis

For pregnancies known to be at increased risk for HOS

For pregnancies not known to be at increased risk for HOS. If a routine US examination has identified limb and cardiac manifestations characteristic of HOS, consider prenatal molecular genetic testing from a clinical laboratory that offers testing for TBX5 or custom prenatal testing for other disorders in the differential diagnosis (see Differential Diagnosis).

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. While most centers would consider decisions regarding 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.

Resources

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)
    Email: review.personal.info@heart.org
  • 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
    Email: reach@reach.org.uk

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)

142900HOLT-ORAM SYNDROME; HOS
601620T-BOX TRANSCRIPTION FACTOR 5; TBX5

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

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].

Mechanism of disease causation. Loss of function or dominant-negative interference with function

References

Literature Cited

  • Allanson JE, Newbury-Ecob RA. Holt-Oram syndrome: is there a "face"? Am J Med Genet. 2003;118A:314–8. [PubMed: 12687661]
  • Baban A, Pitto L, Pulignani S, Cresci M, Mariani L, Gambacciani C, Digilio MC, Pongiglione G, Albanese S. Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. Am J Med Genet A. 2014;164A:1419–24. [PubMed: 24664498]
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Chapter Notes

Revision History

  • 23 May 2019 (sw) Comprehensive update posted live
  • 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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