1q41 Deletion Involving the TGFβ Gene

Deletions of 1q41 are not very common, but individuals may present as a well characterized syndrome: Loeys-Dietz Syndrome (LDS). LDS is caused by variants in the gene TGFβ, which is located within the 1q41 segment¹. Although LDS is a well characterized connective tissue disorder with vascular, skeletal, craniofacial, and cutaneous manifestations, individuals who have the condition due to a 1q41 deletion may present with additional clinical features not typical of LDS². Specifically, this includes a neurodevelopmental phenotype².

One of the primary manifestations of LDS are various vascular anomalies. Most commonly, this includes dilations, aneurysms, and dissections of the aorta or other arteries throughout the body. Additionally, tortuosity or the twisting of various blood vessels is commonly seen and can result in complications².

Various skeletal malformations are also common amongst those with LDS. This includes pectus excavatum or carinatum, scoliosis, joint laxity, arachnodactyly, and osteoarthritis². Osteopenia, or low bone density, is also a common finding of those with LDS. Some have estimated that up to 61% of individuals with LDS will have low bone density, putting them at an increased risk for fractures¹. This has been seen in patients as many present with a history of fractures^2,3. Additionally, specific facial features are commonly seen when an individual has LDS due to deletion of 1q41. This includes features like hypertelorism, high arched palate, retrognathia, ptosis, triangular face, low-set ears, thin lips, and anteverted nares⁴.

The last common feature associated with all LDS cases includes various cutaneous or skin findings. Individuals typically present with soft, translucent skin that may feel velvety to the touch. It is also possible for these individuals to experience easy bruising².

Unique to individuals with LDS due to a deletion of 1q41, there appears to be a variable neurodevelopmental phenotype². This includes findings like global developmental delay, gross motor delay, speech delay, self-stimulating or self-injurious behaviors, or sensory integration issues². However, it should be noted that there is a wide spectrum amongst those affected. Some individuals are more severe with one person not being able to walk at age 5, vocalizing no specific words, and having global developmental delay². However, other individuals with 1q41 deletions do not experience any gross motor, fine motor, or speech delays².

References

¹Tsujimoto Y, Yamamoto N, Fukumitsu H, et al. (2025). Diagnosis of skeletal fragility due to Loeys-Dietz syndrome and treatment with romosozumab followed by denosumab. Bone Rep. 25:101849.
²Fry D, Groepper D, MacCarrick G, et al. (2022). Loeys-Dietz syndrome caused by 1q41 deletion including TGFB2 is associated with a neurodevelopmental phenotype. Am J Med Genet A. 188(7):2237–2241.
³Gaspar H, Lutz B, Reicherter K, et al. (2017). 4.7 Mb deletion encompassing TGFB2 associated with features of Loeys-Dietz syndrome and osteoporosis in adulthood. Am J Med Genet A. 173(8): 2289–2292.
⁴Nistri S, De Cario R, Sticchi E, et al. (2021). Differential Diagnosis between Marfan Syndrome and Loeys-Dietz Syndrome Type 4: A Novel Chromosomal Deletion Covering TGFB2. Genes (Basel). 12(10):1462.