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Molecular diagnosis of very rare Proteus syndrome expands phenotype

In a young patient referred to the Institute of Human Genetics at the University Medical Center Göttingen, the clinical suspicion of Proteus syndrome was made and confirmed by molecular genetic diagnostics. The patient presented with a progressively protruding frontal bone due to an intraosseus lipoma (a benign tumor of fat tissue) and, additionally, mild developmental delay, unilateral hearing impairment, strabism and a dermoid of the eye. DNA analysis performed on a tissue sample yielded from the lipoma showed that the patient carries a specific heterozygous variant of the AKT1 gene that is known to cause Proteus syndrome. This variant is present in a mosaic state, i.e. it occurred spontaneously as a de novo mutation after fertilization at some point in embryonic development. Therefore, it is not present in every cell of the body. Mosaic genetic variants are more difficult to detect in molecular diagnostics. In such cases, a clinical suspicion of an underlying mosaic disorder and selection of an appropriate sample for genetic testing are crucially important, because analysis of standard blood samples will usually not reveal the causative variant.

Proteus syndrome is a very rare disorder and only occurs in a mosaic form. Its clinical manifestations vary considerably, depending on which cells and tissues are affected by the genetic defect. The syndrome is characterized by disproportionate and asymmetric overgrowth affecting some parts of the patient’s body and by specific skin anomalies. As the researchers report in Clinical Genetics, their patient is the first case of a molecularly confirmed Proteus syndrome with a progressive intraosseous lipoma of the frontal bone but without other, characteristic features – in particular without any suggestive skin anomalies. For the patient, the correct molecular diagnosis may also have implications for novel treatment options, because AKT1-inhibiting substances are available and are already applied in clinical studies.

Schmidt J, Bremmer F, Brockmann K, Kaulfuß S, Wollnik B. Progressive frontal intraosseous lipoma: Detection of the mosaic AKT1 variant discloses Proteus syndrome. Clin Genet. 2022 Jun 7. doi: 10.1111/cge.14174. Epub ahead of print.

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First evidence of a link between BLM deficiency and overexpression of condensin complex genes

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Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures
Gönenc II, Wolff A, Schmidt J, Zibat A, Müller C, Cyganek L, Argyriou L, Räschle M, Yigit G, Wollnik B
Hum Mol Genet. 2022 Jan 31:ddab373. doi: 10.1093/hmg/ddab373. Epub ahead of print.

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Cellular models and therapeutic perspectives in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is one of the most common hereditary disorders of the heart. It causes thickening of the heart muscle, which may impair the heart’s function. Several hundreds of variants in more than 20 genes are known to cause HCM. Modern molecular genetic diagnostics using high-throughput sequencing increasingly detect additional, previously unknown variants as potential genetic factors underlying HCM. To assess these variants in terms of their pathogenic effect is often challenging. A review article published in Medizinische Genetik describes the importance of novel cell and tissue models for identifying HCM-causing genetic variants and for gaining further insights into the function of heart muscle cells. It also highlights how these models, combined with genome editing, might contribute to novel therapeutic perspectives in hypertrophic cardiomyopathy.

Cellular models and therapeutic perspectives in hypertrophic cardiomyopathy
Yigit G, Wollnik B.
Medizinische Genetik. 2021;33(3): 235-243.

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Identifying germline variants in susceptibility genes for colorectal cancer

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Survey of germline variants in cancer-associated genes in young adults with colorectal cancer
Mikaeel RR, Young JP, Li Y, Smith E, Horsnell M, Uylaki W, Tapia Rico G, Poplawski NK, Hardingham JE, Tomita Y, Townsend AR, Feng J, Zibat A, Kaulfuß S, Müller C, Yigit G, Wollnik B, Price TJ.
Genes Chromosomes Cancer. 2021 Nov 11. doi: 10.1002/gcc.23011. Epub ahead of print.

RNF43 pathogenic Germline variant in a family with colorectal cancer
Mikaeel RR, Young JP, Li Y, Poplawski NK, Smith E, Horsnell M, Uylaki W, Tomita Y, Townsend AR, Feng J, Zibat A, Kaulfuß S, Müller C, Yigit G, Wollnik B, Scott H, Rawlings L, Henry D, Vakulin C, Dubowsky A, Price TJ.
Clin Genet. 2021 Sep 19. doi: 10.1111/cge.14064. Epub ahead of print.

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