The Invitae Holt-Oram Syndrome Test analyzes TBX5, which is the gene associated with Holt-Oram syndrome (HOS). HOS involves upper-limb abnormalities and heart problems. It is extremely variable, so genetic testing may provide important insight for individuals who are at risk of having HOS but do not present with obvious symptoms.
Identification of a genetic change related to HOS can impact medical management, provide a predicted outcome for the patient, and indicate the recurrence risk. A diagnosis is important because seemingly asymptomatic individuals may be at risk of developing life-threatening cardiac problems.
The differential diagnosis for individuals with suspected Holt-Oram syndrome may sometimes include Duane-radial ray syndrome (DRRS), Ulnar-mammary syndrome (UMS), and Townes-Brocks syndrome (TBS). Depending on the clinical presentation of the patient, clinicians may wish to broaden analysis by including genes that are associated with DRRS, UMS, and TBS. These tests can be added at no additional charge.
Invitae Invitae Congenital Heart Defects and Heterotaxy Panel has been designed to provide a broad genetic analysis of congenital heart disease. It may be considered as an alternative to testing for specific disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate. It can be ordered at no additional cost.
Holt-Oram syndrome (HOS) is a multisystemic disorder that is characterized by upper-extremity malformations involving the carpal (wrist), radial, or thenar bones, a personal or family history of congenital heart defect (CHD), and cardiac conduction disease. To date, all individuals diagnosed with HOS have an abnormal carpal bone; in some cases, this is the only manifestation of the syndrome.
Approximately 75% of individuals with Holt-Oram syndrome have a congenital heart defect. The most common heart defects in these patients are ostium secundum atrial septal defect (ASD) and ventricular septal defect (VSD). Individuals who do not have a CHD are still at risk for cardiac conduction disease. Upper-limb abnormalities are often more severe on the left side than on the right. The variation in the presentation of HOS is largely dependent on the severity of the congenital heart defect. Cardiac complications can be life-threatening if they are not identified and managed properly.
TBX5 is the only gene currently known to be associated with HOS. More than 70% of individuals who meet clinical diagnostic criteria have an identifiable disease-causing change in TBX5.
HOS is inherited in an autosomal dominant pattern.
Holt-Oram syndrome is considered fully penetrant. Most individuals are identified at birth—especially those with a CHD, but because of the wide range of variable expression, individuals without a CHD at birth may not be diagnosed until later in life, if at all. For example, an individual with mild upper-limb malformations whose cardiac conduction disease does not manifest until middle age may receive a diagnosis of HOS later in life. Some individuals with HOS may only have an abnormal wrist bone and never develop cardiac complications.
The incidence of Holt-Oram syndrome is approximately 1 in 100,000.
Because HOS has a variable clinical presentation, identifying the genetic cause of HOS in an individual enables testing of related asymptomatic adults who could be at risk of having HOS and developing cardiac problems. Individuals with mild upper-limb malformation who do not have a CHD may not be diagnosed without molecular testing and are at risk of cardiac conduction disease.
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|