First Two Cases of Bloom Syndrome in Russia: Lack of Skin Manifestations in a BLM c.1642C&gt;T (p.Q548X) Homozygote as a Likely Cause of Underdiagnosis

Suspitsin, Evgeny N.; Sibgatullina, Farida I.; Lyazina, Lydia V.; Imyanitov, Evgeny N.

doi:10.1159/000454820

Cited by 8 publications

(6 citation statements)

References 13 publications

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“…All three had the same mutation c.1642 C > T (p.Gln548Ter). This mutation in its homozygous state is the cause of Bloom syndrome [15,20].…”

Section: Resultsmentioning

confidence: 99%

“…We identified one recurrent truncating mutation of BLM (c.1642 C>T, p.Gln548Ter). This mutation is a cause of Bloom syndrome, as we and others diagnosed patients with Bloom syndrome homozygous for this protein-truncating variant of BLM [15,20]. However, this specific mutation appears to not be associated with an increased risk of breast cancer among Polish women.…”

Section: Discussionmentioning

confidence: 99%

“…The BLM p.Gln548Ter mutation is the most common cause of Bloom syndrome in Slavic individuals, including Poland and Russia [15]. Among Jews, the predominant mutation, referred to as BLMAsh is a 6-bp deletion and 7-bp insertion at nucleotide position 2207 of the BLM gene [2].…”

Section: Introductionmentioning

confidence: 99%

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Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer

Kluźniak

Wokołorczyk

Rusak

et al. 2019

Cancers

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Bloom Syndrome is a rare recessive disease which includes a susceptibility to various cancers. It is caused by homozygous mutations of the BLM gene. To investigate whether heterozygous carriers of a BLM mutation are predisposed to breast cancer, we sequenced BLM in 617 patients from Polish families with a strong family history of breast cancer. We detected a founder mutation (c.1642C>T, p.Gln548Ter) in 3 of the 617 breast cancer patients (0.49%) who were sequenced. Then, we genotyped 14,804 unselected breast cancer cases and 4698 cancer-free women for the founder mutation. It was identified in 82 of 14,804 (0.55%) unselected cases and in 26 of 4698 (0.55%) controls (OR = 1.0; 95%CI 0.6–1.6). Clinical characteristics of breast cancers in the BLM mutation carriers and non-carriers were similar. Loss of the wild-type BLM allele was not detected in cancers from the BLM mutation carriers. No cancer type was more common in the relatives of mutation carriers compared to relatives of non-carriers. The BLM founder mutation p.Gln548Ter, which in a homozygous state is a cause of Bloom syndrome, does not appear to predispose to breast cancer in a heterozygous state. The finding casts doubt on the designation of BLM as an autosomal dominant breast cancer susceptibility gene.

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“…All three had the same mutation c.1642 C > T (p.Gln548Ter). This mutation in its homozygous state is the cause of Bloom syndrome [15,20].…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer

Kluźniak

Wokołorczyk

Rusak

et al. 2019

Cancers

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“…This holds true for some immune-related diseases, such as ataxia-telangiectasia, Bloom syndrome, and Nijmegen breakage syndrome. [9][10][11] It is possible that systematic genetic analysis of patients with clinical suspicion for IEI will result in identification of novel pathogenic founder alleles, thus enabling genetic screening for some IEIs. This study aimed to analyze known IEI-associated genes in pediatric patients with clinical signs of IEI.…”

Section: Introductionmentioning

confidence: 99%

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

et al. 2020

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Primary immune deficiencies are usually attributed to genetic defects and, therefore, frequently referred to as inborn errors of immunity (IEI). We subjected the genomic DNA of 333 patients with clinical signs of IEI to next generation sequencing (NGS) analysis of 344 immunity‐related genes and, in some instances, additional genetic techniques. Genetic causes of the disease were identified in 69/333 (21%) of subjects, including 11/18 (61%) of children with syndrome‐associated IEIs, 45/202 (22%) of nonsyndromic patients with Jeffrey Modell Foundation (JMF) warning signs, 9/56 (16%) of subjects with periodic fever, 3/30 (10%) of cases of autoimmune cytopenia, 1/21 (5%) of patients with unusually severe infections and 0/6 (0%) of individuals with isolated elevation of IgE level. There were unusual clinical observations: twins with severe immunodeficiency carried a de novo CHARGE syndrome‐associated SEMA3E c.2108C>T (p.S703L) allele; however, they lacked clinical features of CHARGE syndrome. Additionally, there were genetically proven instances of Netherton syndrome, Х‐linked agammaglobulinemia, severe combined immune deficiency (SCID), IPEX and APECED syndromes, among others. Some patients carried recurrent pathogenic alleles, such as AIRE c.769C>T (p.R257*), NBN c.657del5, DCLRE1C c.103C>G (p.H35D), NLRP12 c.1054C>T (p.R352C) and c.910C>T (p.H304Y). NGS is a powerful tool for high‐throughput examination of patients with malfunction of immunity.

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“…The recurrent variant c.1642c>T is enriched in the eastern europe population of the Slavic origin, in which 0.2-0.6% individuals are its carriers. only a few patients with Bloom syndrome carrying homozygous c.1642c>T variant are described in a scientific literature, probably due to the incomplete phenotypic manifestation lacking the presence of a typical uV exposure-induced facial erythema (27,28). it raises the hypothesis of the underdiagnosis of Bloom syndrome at the clinical and molecular level in this population.…”

Section: Discussionmentioning

confidence: 99%

A unique case of Bloom syndrome with a combination of genetic hits: A lesson from trio‑based exome sequencing: A case report

et al. 2023

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Pathogenic variants affecting the BLM gene are responsible for the manifestation of extremely rare cancer-predisposing Bloom syndrome. The present study reports on a case of an infant with a congenital hypotrophy, short stature and abnormal facial appearance. initially she was examined using a routine molecular diagnostic algorithm, including the cytogenetic analysis of her karyotype, microarray analysis and methylation-specific MLPA, however, she remained undiagnosed on a molecular level. Therefore, she and her parents were enrolled in the project of trio-based exome sequencing (eS) using Human core exome kit. She was revealed as a carrier of an extremely rare combination of causative sequence variants altering the BLM gene (nM_000057.4), c.1642c>T and c.2207_2212delinsTaGaTTc in the compound heterozygosity, resulting in a diagnosis of Bloom syndrome. Simultaneously, a mosaic loss of heterozygosity of chromosome 11p was detected and then confirmed as a borderline imprinting center 1 hypermethylation on chromosome 11p15. The diagnosis of Bloom syndrome and mosaic copy-number neutral loss of heterozygosity of chromosome 11p increases a lifetime risk to develop any types of malignancy. This case demonstrates the trio-based eS as a complex approach for the molecular diagnostics of rare pediatric diseases.

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First Two Cases of Bloom Syndrome in Russia: Lack of Skin Manifestations in a BLM c.1642C>T (p.Q548X) Homozygote as a Likely Cause of Underdiagnosis

Cited by 8 publications

References 13 publications

Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer

Inherited Variants in BLM and the Risk and Clinical Characteristics of Breast Cancer

Next generation sequencing analysis of consecutive Russian patients with clinical suspicion of inborn errors of immunity

A unique case of Bloom syndrome with a combination of genetic hits: A lesson from trio‑based exome sequencing: A case report

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