Invitae Holt-Oram Syndrome Test


Test description

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.

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Primary panel (1 gene)


Alternative tests to consider

The Invitae Isolated and Syndromic Congenital Heart Disease 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 charge.

Holt-Oram syndrome (HOS)

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.

Assay and technical information

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
TBX5 NM_000192.3