Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey

Toksoy, Güven; Alkaya, Dilek Uludağ; Багирова, Г. Г.; Avcı, Şahin; Aghayev, Agharza; Güneş, Nilay; Altunoğlu, Umut; Alanay, Yasemin; Başaran, Seher; Berkay, Ezgi Gizem; Karaman, Birsen; Çelkan, Tiraje; Apak, Hilmi; Kayserili, Hülya; Tüysüz, Beyhan; Uyguner, Zehra Oya

doi:10.1159/000509838

Cited by 15 publications

(14 citation statements)

References 70 publications

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“…2B). Mutations in the various genes of the FA pathway are linked to the autosomal recessively inherited FA disorder (30), and, interestingly, FA shows overlapping clinical features with BS such as primary microcephaly, growth deficiency, and cancer predisposition (31). On the molecular level, FA and FA-associated proteins take part in cellular processes such as DNA replication, DSB repair, and replication fork maintenance (32).…”

Section: Resultsmentioning

confidence: 99%

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Gönenc

Wolff

Schmidt

et al. 2021

Preprint

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Bloom syndrome (BS) is an autosomal recessive disease clinically characterized by primary microcephaly, growth deficiency, immunodeficiency, and predisposition to cancer. It is mainly caused by biallelic loss-of-function mutations in the BLM gene, which encodes the BLM helicase, acting in DNA replication and repair processes. Here, we describe the gene expression profiles of three BS fibroblast cell lines harboring causative, biallelic truncating mutations obtained by single-cell (sc) transcriptome analysis. We compared the scRNA transcription profiles from three BS patient cell lines to two age-matched wild-type controls and observed specific deregulation of gene sets related to the molecular processes characteristically affected in BS, such as mitosis, chromosome segregation, cell cycle regulation, and genomic instability. We also found specific upregulation of genes of the Fanconi anemia pathway, in particular FANCM, FANCD2, and FANCI, which encode known interaction partners of BLM. The significant deregulation of genes associated with inherited forms of primary microcephaly observed in our study might explain in part the molecular pathogenesis of microcephaly in BS, one of the main clinical characteristics in patients. Finally, our data provide first evidence of a novel link between BLM dysfunction and transcriptional changes in condensin complex I and II genes. Overall, our study provides novel insights into gene expression profiles in BS on a single-cell level, linking specific genes and pathways to BLM dysfunction.

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Section: Resultsmentioning

confidence: 99%

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Gönenc

Wolff

Schmidt

et al. 2021

Preprint

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“…If no mutation in FANCA is detected, the screening is extended to other FA genes [ 31 ]. The next most frequently mutated genes that are responsible for ~ 10–15% of cases are FANCC and FANCG [ 8 , 22 , 27 , 28 ]. Causative mutations in other FA genes are rare and account for 0.1–3% of cases per gene [ 8 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…Although a positive chromosome breakage test is highly indicative for FA, it is not 100% specific for FA and can produce false-negative and false-positive results [ 31 , 32 ]. Therefore, a molecular investigation is needed for definitive and accurate diagnosis, prognosis assessment and genetic counseling for FA families [ 28 ]. This, however, can be a daunting, complex, and time-consuming task [ 8 , 20 , 23 , 29 ] due to genetic heterogeneity, large (and constantly growing) number of FA genes, together with a wide spectrum of private mutations [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…Significant proportion of large deletions results from a high content of Alu repeats in this region. Alu repeats can facilitate intrachromosomal recombinations and generate intragenic copy number variants through unequal crossing-over and their presence is directly correlated with deletion breakpoints [ 28 , 29 , 36 – 38 ]. Alu elements can also induce exon skipping with the effect of both upstream and downstream alternative exons [ 23 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

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Next-generation sequencing reveals novel variants and large deletion in FANCA gene in Polish family with Fanconi anemia

Repczyńska

Julga

Skalska‐Sadowska

et al. 2022

Orphanet J Rare Dis

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Background Fanconi anemia (FA) is the most common inherited bone marrow failure syndrome. However, establishing its molecular diagnosis remains challenging. Chromosomal breakage analysis is the gold standard diagnostic test for this disease. Nevertheless, molecular analysis is always required for the identification of pathogenic alterations in the FA genes. Results We report here on a family with FA diagnosis in two siblings. Mitomycin C (MMC) test revealed high level of chromosome breaks and radial figures. In both children, array—Comparative Genomic Hybridization (aCGH) showed maternally inherited 16q24.3 deletion, including FANCA gene, and next generation sequencing (NGS) disclosed paternally inherited novel variants in the FANCA gene—Asn1113Tyr and Ser890Asn. A third sibling was shown to be a carrier of FANCA deletion only. Conclusions Although genetic testing in FA patients often requires a multi-method approach including chromosome breakage test, aCGH, and NGS, every effort should be made to make it available for whole FA families. This is not only to confirm the clinical diagnosis of FA in affected individuals, but also to enable identification of carriers of FA gene(s) alterations, as it has implications for diagnostic and genetic counselling process.

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“…This indicates that at the molecular genetic level, FA is related to disorders of DNA damage response. Finally, the phenotypes of FA show a great deal of functional overlap with Roberts (due to biallelic mutations in the acetyltransferase encoding ESCO2 gene) and Warsaw Breakage syndromes (due to biallelic mutations in the DNA helicase encoding DDX11/ChlR1 gene) [van der Lelij et al, 2010]. Several patients presenting with vertebral anomalies, anal atresia, cardiac abnormalities, tracheoesophageal fistula, renal anomalies, and a radial limb (VACTERL), and also including hydrocephalus (VACTERL-H) were initially diagnosed as cases of VACTERL association with hydrocephalus and Baller-Gerold syndrome [Rossbach et al, 1996].…”

mentioning

confidence: 99%

Fanconi Anemia: A Syndrome of Anemia and Skeletal Malformations Progressing to a Gene Network Involved in Genomic Stability and Malignant Disease

Poot¹

2020

Mol Syndromol

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Clinical and Molecular Characterization of Fanconi Anemia Patients in Turkey

Cited by 15 publications

References 70 publications

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Single-cell transcription profiles in Bloom syndrome patients link BLM deficiency with altered condensin complex expression signatures

Next-generation sequencing reveals novel variants and large deletion in FANCA gene in Polish family with Fanconi anemia

Fanconi Anemia: A Syndrome of Anemia and Skeletal Malformations Progressing to a Gene Network Involved in Genomic Stability and Malignant Disease

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