02
Apr

6q25.1 Deletion

6q25.1 Deletion

Deletions of the 6q25.1 region of the long arm of chromosome 6 constitute a specific syndrome. The main findings of this condition are defects of cardiac valves caused by the loss of the TAB2 gene, which is located in this segment. The protein encoded by the TAB2 gene stimulates a cascade of other genes that are active in the development of endocardial cushion and cardiac valves during embryonic development1. Due to the important role TAB2 plays in cardiac development, deletions of this gene or region are associated with non-syndromic congenital heart defects and cardiomyopathy2.

There are a variety of congenital heart anomalies found in individuals with 6q25.1 deletions. This includes congenital valve defects in one or multiple cardiac valves such as myxomatous mitral and/or tricuspid valves (this is distinctive mark of this condition; such defects are highly unusual for other chromosomal disorders), bicuspid aortic valve, aortic stenosis, or pulmonic stenosis1. Atrial septal defect, ventricular septal defect, cardiomyopathy, and aortic dilation may also be seen2. Some individuals may present with multiple cardiac features that combine to create hypoplastic left heart syndrome. This syndrome is characterized by hypoplasia of the left ventricle and ascending aorta, an atrial septal defect, and a patent ductus arteriosus. Depending on the cardiac anomaly that is present, surgical intervention may be necessary as some of these conditions are fatal in infancy3. It should be noted that heart defects are an obligate finding of this deletion (all reported patients so far have been reported having these defects).

While congenital heart anomalies are the most prominent feature of 6q25.1 deletions, other features may be identified in individuals. There are several facial features such as a broad forehead, hypertelorism, ptosis, low set ears, frontal bossing, short and/or narrow palpebral fissures, and retrognathia that can be seen1,2,4.

Other features such as short stature, intrauterine growth restriction, and hypotonia may also be seen2. Connective tissue abnormalities like joint laxity or hypermobility, skeletal and skin abnormalities, and pectus excavatum have also been reported1. Some individuals may also present with varying levels of intellectual and developmental abilities. However, the delays generally fall within the mild to severe categories2. Some authors suggest that patients with deletions of 6q25.1 have many manifestations in common with Noonan syndrome (a non-chromosomal genetically heterogeneous condition) such as association of heart defects, short stature and mild intellectual disability.

There is a group of patients that have mutations in TAB2 rather than deletions. Clinical manifestations in these individuals are the same as for patients with 6q25.1 deletion. This confirms the role of the TAB2 gene in the origin of these abnormalities2.

References

1Cheng A, Dinulos MBP, Neufeld-Kaiser W, et al. (2017). 6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy. Am J Med Genet A, v. 173(7), 1848–1857.
2Engwerda A, Leenders EKSM, Frentz B, et al. (2021). TAB2 deletions and variants cause a highly recognisable syndrome with mitral valve disease, cardiomyopathy, short stature and hypermobility. Eur J Hum Genet., v. 29 (11), 1669–1676.
3Cheng A, Neufeld-Kaiser W, Byers PH, et al. (2020). 6q25.1 (TAB2) microdeletion is a risk factor for hypoplastic left heart: a case report that expands the phenotype. BMC Cardiovasc Disord, v. 20:137.
4Karmegaraj B. (2024). Myxomatous degeneration of cardiac valves in a fetus with 6q25.1 (TAB2) deletion. Cardiol Young, v. 34 (2), 459–461.

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