Holt-Oram syndrome
General Information (adopted from Orphanet):
Synonyms, Signs: |
HOS HOS1 Atriodigital dysplasia Heart-hand syndrome Heart-hand syndrome type 1 Atriodigital dysplasia type 1 |
Number of Symptoms | 45 |
OrphanetNr: | 392 |
OMIM Id: |
142900
|
ICD-10: |
Q87.2 |
UMLs: |
C0265264 |
MeSH: |
C535326 |
MedDRA: |
10050469 |
Snomed: |
19092004 |
Prevalence, inheritance and age of onset:
Prevalence: | < 1 - PMID: 25344219 [IBIS] |
Inheritance: |
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Age of onset: |
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Disease classification (adopted from Orphanet):
Parent Diseases: |
AARSKOG SYNDROME, AUTOSOMAL DOMINANT
-AARSKOG SYNDROME, AUTOSOMAL DOMINANT Genetic cardiac rhythm disease -Rare cardiac disease -Rare genetic disease Genetic multiple congenital anomalies/dysmorphic syndrome without intellectual deficit -Rare genetic disease Heart-hand syndrome -Rare bone disease -Rare developmental defect during embryogenesis Multiple congenital anomalies/dysmorphic syndrome without intellectual deficit -Rare developmental defect during embryogenesis Rare syndrome with cardiac malformations -Rare developmental defect during embryogenesis -Rare genetic disease |
Symptom Information:
|
(HPO:0030680) | Abnormality of cardiovascular system morphology | 25216260 | IBIS | 355 / 7739 | ||
|
(HPO:0006101) | Finger syndactyly | Occasional [Orphanet] | 26243320 | IBIS | 198 / 7739 | |
|
(HPO:0002650) | Scoliosis | Occasional [Orphanet] | 17502954 | IBIS | 705 / 7739 | |
|
(HPO:0003468) | Abnormality of the vertebrae | 25344219 | IBIS | 77 / 7739 | ||
|
(HPO:0000912) | Sprengel anomaly | Occasional [Orphanet] | 1870097 | IBIS | 51 / 7739 | |
|
(HPO:0000766) | Abnormality of the sternum | 7.5000 % [HPO] | 25468972 | IBIS | 31 / 7739 | |
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(HPO:0003063) | Abnormality of the humerus | Occasional [Orphanet] | 25344219 | IBIS | 36 / 7739 | |
|
(HPO:0009829) | Phocomelia | Occasional [Orphanet] 10.9756 % [HPO] | 25344219 | IBIS | 20 / 7739 | |
|
(HPO:0002984) | Hypoplasia of the radius | 37.8049 % [HPO] | 25344219 | IBIS | 44 / 7739 | |
|
(HPO:0001227) | Abnormality of the thenar eminence | 18351627 | IBIS | 1 / 7739 | ||
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(HPO:0002818) | Abnormality of the radius | Frequent [Orphanet] | 26243320 | IBIS | 96 / 7739 | |
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(HPO:0001191) | Abnormality of the carpal bones | 24826304 | IBIS | 6 / 7739 | ||
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(HPO:0003019) | Abnormality of the wrist | Very frequent [Orphanet] | 24826304 | IBIS | 52 / 7739 | |
|
(HPO:0002943) | Thoracic scoliosis | 7.5000 % [HPO] | 6519847 | IBIS | 12 / 7739 | |
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(HPO:0009944) | Partial duplication of thumb phalanx | 26243320 | IBIS | 7 / 7739 | ||
|
(HPO:0002973) | Abnormality of the forearm | 14402857 | IBIS | 3 / 7739 | ||
|
(HPO:0000774) | Narrow chest | Occasional [Orphanet] | 22190901 | IBIS | 167 / 7739 | |
|
(HPO:0002817) | Abnormality of the upper limb | 26243320 | IBIS | 25 / 7739 | ||
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(HPO:0009777) | Absent thumb | 1870097 | IBIS | 31 / 7739 | ||
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(HPO:0009751) | Aplasia of the pectoralis major muscle | 7.5000 % [HPO] | 8730285 | IBIS | 8 / 7739 | |
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(HPO:0001163) | Abnormality of the metacarpal bones | Frequent [Orphanet] | 25344219 | IBIS | 149 / 7739 | |
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(HPO:0001172) | Abnormality of the thumb | Occasional [Orphanet] | 26243320 | IBIS | 103 / 7739 | |
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(HPO:0009601) | Aplasia/Hypoplasia of the thumb | Frequent [Orphanet] | 26243320 | IBIS | 80 / 7739 | |
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(HPO:0002974) | Radioulnar synostosis | Occasional [Orphanet] | 21637475 | IBIS | 52 / 7739 | |
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(HPO:0000767) | Pectus excavatum | Occasional [Orphanet] | 24879328 | IBIS | 244 / 7739 | |
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(HPO:0000772) | Abnormality of the ribs | Occasional [Orphanet] | 21637475 | IBIS | 146 / 7739 | |
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(HPO:0001643) | Patent ductus arteriosus | Occasional [Orphanet] 7.5000 % [HPO] | 24879328 | IBIS | 228 / 7739 | |
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(HPO:0012303) | Abnormality of the aortic arch | Occasional [Orphanet] | 18685167 | IBIS | 57 / 7739 | |
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(HPO:0001631) | Atria septal defect | Frequent [Orphanet] 41.4634 % [HPO] | 25344219 | IBIS | 274 / 7739 | |
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(HPO:0001629) | Ventricular septal defect | Frequent [Orphanet] 14.6341 % [HPO] | 25344219 | IBIS | 316 / 7739 | |
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(HPO:0011025) | Abnormality of cardiovascular system physiology | Frequent [Orphanet] | 25344219 | IBIS | 41 / 7739 | |
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(HPO:0001671) | Abnormality of the cardiac septa | 25344219 | IBIS | 55 / 7739 | ||
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(HPO:0006695) | Atrioventricular canal defect | Occasional [Orphanet] | 24664498 | IBIS | 27 / 7739 | |
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(HPO:0001678) | Atrioventricular block | 25216260 | IBIS | 59 / 7739 | ||
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(HPO:0004383) | Hypoplastic left heart | Occasional [Orphanet] | 2766565 | IBIS | 29 / 7739 | |
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(HPO:0011675) | Arrhythmia | 25216260 | IBIS | 226 / 7739 | ||
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(HPO:0010772) | Anomalous pulmonary venous return | Occasional [Orphanet] | 24879328 | IBIS | 11 / 7739 | |
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(HPO:0001688) | Sinus bradycardia | 15292570 | IBIS | 18 / 7739 | ||
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(HPO:0001961) | Hypoplastic heart | 2766565 | IBIS | 9 / 7739 | ||
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(OMIM) | Asymmetric involvement | 8730285 | IBIS | 1 / 7739 | ||
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(HPO:0001199) | Triphalangeal thumb | Frequent [Orphanet] | 26243320 | IBIS | 56 / 7739 | |
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(OMIM) | Limited forearm pronation and supination | 14402857 | IBIS | 3 / 7739 | ||
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(MedDRA:10000032) | Cardiac conduction disorders | 25216260 | IBIS | 5 / 7739 | ||
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(OMIM) | Congenital heart malformation | 25216260 | IBIS | 3 / 7739 | ||
|
(OMIM) | Radial-ulnar anomalies | 12789647 | IBIS | 1 / 7739 |
Associated genes:
TBX5; |
ClinVar (via SNiPA)
Gene symbol | Variation | Clinical significance | Reference |
---|---|---|---|
TBX5 | rs104894377 | pathogenic | RCV000008456.3 |
TBX5 | rs104894379 | pathogenic | RCV000008463.2 |
TBX5 | rs104894381 | pathogenic | RCV000008458.2 |
TBX5 | rs104894382 | pathogenic | RCV000008459.2 |
TBX5 | rs104894383 | pathogenic | RCV000008461.2 |
TBX5 | rs104894384 | pathogenic | RCV000008462.2 |
Additional Information:
Molecular genetics OMIM |
Li et al. (1997) and Basson et al. (1997) demonstrated mutations in the TBX5 (601620) gene as the basis of this disorder. The dominant phenotype of HOS appears to result from haploinsufficiency of TBX5. The glu69-to-ter mutation (601620.0002) identified ... |
Diagnosis GeneReviews | The diagnosis of Holt-Oram syndrome (HOS) can be established clinically. The diagnostic criteria have been validated with molecular testing [McDermott et al 2005]. Clinical findings in HOS:... Gene SymbolTest MethodsMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityTBX5Sequence analysis | Sequence variants 2>70% 3Clinical Mutation scanning 4, 5Deletion / duplication analysis 6Exonic or whole-gene deletions/duplications71. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. 3. Individuals meeting the strict diagnostic criteria of upper-limb defect and personal and/or family history of structural or conductive heart disease have a TBX5 mutation predicted to cause disease [McDermott et al 2005]. Lower mutation 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]. 4. Mutation detection frequency in individuals who meet strict diagnostic criteria (i.e., presence of an upper-limb defect and personal and/or family history of structural or conductive heart disease)5. McDermott et al [2005]6. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.7. Deletion of one or more exons or of the entire TBX5 gene was detected in about 2% of individuals with HOS who did not have a mutation identified by sequence analysis/mutation scanning [Borozdin et al 2006]. Therefore, the detection rate of deletion analysis among all individuals with HOS is less than 1%. Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants). Testing Strategy for a ProbandTo confirm/establish the diagnosis in a probandThorough clinical examination and complete family history Hand x-rays (posterior-anterior view) Echocardiography and electrocardiography If a clinical diagnosis of HOS is made, confirmatory diagnostic molecular genetic testing of TBX5 (Note: Presence or absence of a TBX5 mutation does not alter management.) Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersNo phenotypes other than those discussed in this GeneReview are known to be associated with germline mutations in TBX5 [Reamon-Buettner & Borlak 2004].
Clinical Description GeneReviews | Holt-Oram syndrome is characterized by upper-limb defects, congenital heart malformation, and cardiac conduction disease [Holt & Oram 1960].... |
Genotype-Phenotype Correlations GeneReviews | It has been reported that missense mutations 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. ... |
Differential Diagnosis GeneReviews | 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]: ... |
Management GeneReviews | To establish the extent of disease and needs in an individual diagnosed with Holt-Oram syndrome, the following evaluations are recommended:... |
Molecular genetics GeneReviews |
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.... Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTBX512q24 | T-box transcription factor TBX5TBX5 homepage - Mendelian genesTBX5Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Holt-Oram Syndrome (View All in OMIM) View in own window 142900HOLT-ORAM SYNDROME; HOS 601620T-BOX 5; TBX5Normal allelic variants. TBX5 is a member of the T-box family of transcription factors [Basson et al 1997, Li et al 1997]. The T-box domain, which is the DNA binding region, is highly conserved across species and among members of the T-box family of transcription factors. TBX5 consists of nine coding exons. At least two alternatively spliced isoforms 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]. Pathologic allelic variants. Most HOS results from small intragenic mutations that alter TBX5 gene dosage. Nearly 70 mutations have been described in TBX5. While most are private mutations, at least two recurrent mutations have been reported, suggesting that these may be "hot spots." Disease-causing mutations may be missense or nonsense mutations; 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]. 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 mutations have not been shown to be directly related to specific ocular abnormalities in humans. Deleterious mutations 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 mutations 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]. Genome-wide association studies have identified several loci including one which encompasses TBX5 and TBX3 as well as other genomic elements that may participate in regulating cardiac conduction velocities [Holm et al 2010, Pfeufer et al 2010].Abnormal gene product. It is hypothesized that most nonsense and frameshift mutations lead to mutant TBX5 mRNAs that are degraded with resulting impaired nuclear localization and haploinsufficiency. Some missense mutations result in transcripts that have diminished DNA binding activity. Both result in a reduced TBX5 dose, which leads to disease [Hatcher & Basson 2001]. 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].