Trait Document

Holt-Oram syndrome is a genetic condition characterized by heart and upper limb birth defects. The heart defects seen in this syndrome include atrial septal defects (i.e., a hole between the upper two heart chambers), ventricular septal defects (i.e., a hole between the bottom two heart chambers), and cardiac arrhythmias (i.e., abnormal heart rhythms). The upper limb defects seen in this syndrome range from severe abnormalities such as phocomelia (i.e. a birth defect where the upper part of the arm is absent or poorly developed so that the hands are attached close to the body) to mild abnormalities such as slight defects involving the wrist bones. Other common upper limb abnormalities include absent or finger-like thumbs. These limb abnormalities may involve one or both arms and/or hands. Intelligence is usually normal in Holt-Oram syndrome.

Holt-Oram syndrome can be diagnosed either by meeting certain clinical criteria or by genetic testing for a change or mutation in a gene called TBX5. This gene encodes the T-box 5 transcription factor protein that plays an important role in both heart and limb development. Mutations in the TBX5 gene disrupt the development of the heart and upper limbs, causing the classic features seen in this syndrome.

Management of Holt-Oram syndrome often involves regular heart ultrasounds and EKGs (i.e., tests that check for problems with the electrical activity of the heart). Hand x-rays are useful in identifying subtle upper limb defects. Some individuals with Holt-Oram syndrome require surgical repair of their heart defect and/or limb abnormality.

Holt-Oram syndrome is inherited in an autosomal dominant pattern. This means inheriting one mutation is enough for an individual to be affected and show signs of Holt-Oram syndrome. The mutation can be inherited from an affected parent or it can occur brand new (de novo) in an affected child. Most individuals with Holt-Oram syndrome do not have an affected parent.

The risk to family members depends on whether or not an individual with Holt-Oram syndrome has a parent affected with Holt-Oram syndrome. If a parent also has Holt-Oram syndrome, the risk of having a child with Holt-Oram syndrome is 50% with each pregnancy. If a parent does not have Holt-Oram syndrome, the risk of future pregnancies being affected is very low.

There are other genetic conditions that have overlapping features with Holt-Oram syndrome. Mutations in the TBX5 gene are thought to explain the cause of Holt-Oram syndrome in approximately 70% of individuals with classic features of the condition. While the heart and upper limb defects seen in Holt-Oram syndrome are extremely variable (even within families), all individuals with this syndrome have abnormalities involving the wrist or thumb bones.