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First pathogenic mosaic variant in STAG2 identified: New insights into an associated rare disorder

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Somatic mosaicism in STAG2-associated cohesinopathies: Expansion of the genotypic and phenotypic spectrum
Schmidt J, Dreha-Kulaczewski S, Zafeiriou M-P, Schreiber M-K, Wilken B, Funke R, Neuhofer CM, Altmüller J, Thiele H, Nürnberg P, Biskup S, Li Y, Zimmermann WH, Kaulfuß S, Yigit G and Wollnik B.
Front. Cell Dev. Biol.. 2022 10:1025332. doi: 10.3389/fcell.2022.1025332.

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Biallelic WARS1 variants identified as genetic cause of neurodevelopmental syndrome

WARS1 is one of many key enzymes required for protein synthesis. Genetic variants in WARS1 are rare, with extremely limited evidence implicating it in a clinically heterogeneous autosomal recessive disorder. A study led by PD Dr Barbara Vona, researcher at the Institute of Human Genetics and the Institute of Auditory Neuroscience at the University Medical Center Göttingen, identified two families with different homozygous variants in WARS1 that show varying severities of intellectual disability and developmental delay. The researchers also observed several variable clinical features including hearing impairment. In further studies in a knockout zebrafish model, they investigated the functional effects of WARS1 variants and found that one part of the gene may be especially important in the auditory system. While this study, published in Human Mutation, only scratches the surface of the biology and function of WARS1, it provided further genetic evidence to implicate it in an autosomal recessive neurodevelopmental syndrome.

Biallelic variants in WARS1 cause a highly variable neurodevelopmental syndrome and implicate a critical exon for normal auditory function
Lin SJ, Vona B, Porter HM, Izadi M, Huang K, Lacassie Y, Rosenfeld JA, Khan S, Petree C, Ali TA, Muhammad N, Khan SA, Muhammad N, Liu P, Haymon ML, Rüschendorf F, Kong IK, Schnapp L, Shur N, Chorich L, Layman L, Haaf T, Pourkarimi E, Kim HG, Varshney GK.
Hum Mutat. 2022 Jul 11. doi: 10.1002/humu.24435. Epub ahead of print.

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Identified biallelic variants in tRNA synthetases reveal an emerging associated disease spectrum

Visual Bögershausen et al, Human Mutat 2022

WARS1 and SARS1: two tRNA synthetases implicated in autosomal recessive microcephaly.
Bögershausen N, Krawczyk HE, Jamra RA, Lin SJ, Yigit G, Hüning I, Polo AM, Vona B, Huang K, Schmidt J, Altmüller J, Luppe J, Platzer K, Dörgeloh BB, Busche A, Biskup S, Mendes MI, Smith DEC, Salomons GS, Zibat A, Bültmann E, Nürnberg P, Spielmann M, Lemke JR, Li Y, Zenker M, Varshney GK, Hillen HS, Kratz CP, Wollnik B.
Hum Mutat. 2022 Jul 5. doi: 10.1002/humu.24430. Epub ahead of print.

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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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