12q24.31 duplication

12q24.31 duplication

The segment q24.31 on the long arm of chromosome 12 contains two well-known morbid genes: TBX5 and TBX3. Each of these genes is important in development of several systems of human body.

chromosome 12

TBX5 plays a crucial role in the formation of upper limbs, cardiac septum, and the electrical system that coordinates the heartbeat. Mutations of TBX5 cause the so-called Holt-Oram syndrome, typically including preaxial limb anomalies, congenital heart defects, and progressive conduction abnormalities (disruption of electrical impulses in the heart)¹.

TBX3 plays an essential role in limb development as well, but also has roles in the development of mammary and apocrine glands and teeth¹. Individuals with mutations of TBX3 present with Ulnar-Mammary syndrome, which manifests as a combination of ulnar or postaxial limb anomalies, hypoplastic mammary glands, abnormal dentition, and genital anomalies¹.

Because TBX5 and TBX3 are close neighbors, most patients with duplications of 12q24.31 have combined effect of duplication of both these genes. Generally, individuals with 12q24.31 duplications present with various cardiac defects, hand malformations, and abnormal mammary glands¹.

The most common clinical finding of those with 12q24.31 duplications are cardiac malformations (88%)¹. This includes atrial ventricular septal defects, pulmonary stenosis, hypoplastic left heart syndrome, hypoplastic left ventricle, mitral valve stenosis, bicuspid aortic valve, septal defects, conduction abnormalities (commonly atrial fibrillation), and aortic stenosis^1,2.

Duplications of 12q24.31 also frequently result in hand malformations for most patients (71%)¹. This has included short fifth fingers, fifth finger clinodactyly, short thumbs, thenar hypoplasia, ulnar deviation of fingers, and difficulty with supination and/or pronation of the forearm².

Lastly, some mammary gland abnormalities may also be present. Additional mammary glands and widely spaced, hypoplastic nipples have been previously seen^1,3.

It is important to note that there can be clinical variability amongst individuals who have 12q24.31 duplications, even within the same family. It is possible for some individuals with this duplication to not present with any features at all¹.

REFERENCES

¹Cenni C, Andres S, Hempel M, et al. (2021). TBX3 and TBX5 duplication: A family with an atypical overlapping Holt-Oram/ulnar-mammary syndrome phenotype. Eur J Med Genet. 64(7):104213.

²Patel C, Silcock L, McMullan D, et al. (2012). TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype. Eur J Hum Genet. 20(8):863–869.

³Brugués N (2012). Identification and characterization of disease-related copy number variations (CNVs) by high-dense SNP oligonucleotide microarrays [Doctoral dissertation, Universitat de Barcelona].