Genotype-phenotype associations in Fanconi anemia: A literature review

Fiesco-Roa, Moisés Ó; Giri, Neelam; McReynolds, Lisa J.; Best, Ana F.; Alter, Blanche P.

doi:10.1016/j.blre.2019.100589

Cited by 132 publications

(178 citation statements)

References 34 publications

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“…FA-A is the most common complementation group and covers 65% of patients. 15 Consistent with this report FA-A is the most common complementation group (78.2%) in our study. Frequency of other groups were consistent with previous studies.…”

Section: Discussionsupporting

confidence: 93%

Fanconi anemia: a single center experience of a large cohort

et al. 2019

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Kesici S, Ünal Ş, Kuşkonmaz B, Aytaç S, Çetin M, Gümrük F. Fanconi anemia: a single center experience of a large cohort. Turk J Pediatr 2019; 61: 477-484.Fanconi anemia (FA) is an inherited disease, characterized by congenital malformations, short stature, progressive bone marrow failure and predisposition to leukemia and solid tumors. The aim of this study was to evaluate the clinical and prognostic features of FA patients followed in a single center.The charts of FA patients were reviewed 35 years retrospectively and a total of 175 patients were included in the study in which 51.4% of patients were male. The mean age at diagnosis was 6.3±4.1 years. The incidence of microcephaly was 92.6%, skin findings were 88.0%, eye abnormality was 74.3%, thumb and radius abnormality was 53.1%, urinary system abnormality was 30.9%, skeletal system abnormality other than thumb and radius was 18.9%, genital system abnormality was 11.4%, cardiovascular system abnormality was 11.4%, ear and hearing abnormalities were 9.7% and gastrointestinal system abnormality was 5.7%. Short stature was present in 75.4% of the patients. Of the 175 patients 167 (95.4%) developed bone marrow failure during follow-up and the mean age of bone marrow failure was 7. 1 ±3.7 years (1 month-old-19.8 years). The first clinical symptom was thrombocytopenia in 83.4% of patients. Malignancy developed in a total of 23 (13.1 %) patients (20 leukemia, 3 solid tumors) during follow-up. Of 175 patients, 35 (20%) underwent hematopoietic stem cell transplantation. Fatality rate among patients who underwent hematopoietic stem cell transplantation was 31.4% (11/35) and fatality rate among other patients was 63.4% (83/131; p<0.05). Of 94 patients who deceased, death was due to bleeding in 44.7%, infection in 34%, leukemia progression in 16.0% and graft versus host disease in 5.3%.In terms of the number of patients included, this study is one of the largest cohorts with a remarkable duration of follow-up time. Hematopoietic stem cell transplantation was found to have a good impact on survival of patients.

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Section: Discussionsupporting

confidence: 93%

Fanconi anemia: a single center experience of a large cohort

et al. 2019

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“…FA usually manifests early in life with congenital anomalies involving many organ systems, progressive BMF and a very high risk for the development of MDS, AML, head and neck carcinomas, as well as multiple other cancer types. A number of comprehensive studies and reviews on FA and FA-associated cancers have been published elsewhere (82)(83)(84)(85).…”

Section: Syndromes Caused By Faulty Double-stranded Break Repairmentioning

confidence: 99%

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

2020

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DNA damage response is essential to human physiology. A broad spectrum of pathologies are displayed by individuals carrying monoallelic or biallelic loss-of-function mutations in DNA damage repair genes. DNA repair syndromes with biallelic disturbance of essential DNA damage response pathways manifest early in life with multi-systemic involvement and a high propensity for hematologic and solid cancers, as well as bone marrow failure. In this review, we describe classic biallelic DNA repair cancer syndromes arising from faulty single-and double-strand DNA break repair, as well as dysfunctional DNA helicases. These clinical entities include xeroderma pigmentosum, constitutional mismatch repair deficiency, ataxia telangiectasia, Nijmegen breakage syndrome, deficiencies of DNA ligase IV, NHEJ/Cernunnos, and ERCC6L2, as well as Bloom, Werner, and Rothmund-Thompson syndromes. To give an in-depth understanding of these disorders, we provide historical overview and discuss the interplay between complex biology and heterogeneous clinical manifestations.

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“…4,5 These syndromes include inherited causes of trilineage bone marrow aplasia such as Fanconi anemia (FA) and telomere biology disorders, as well as diseases associated with single lineage failure such as Diamond-Blackfan anemia (DBA), congenital neutropenias, and inherited thrombocytopenias. [6][7][8][9][10][11][12] They also include recently described disorders such as GATA2 haploinsufficiency and SAMD9/SAMD9L syndromes, which have variable impacts on hematopoietic function but carry a high risk of MDS transformation. [13][14][15] IBMF and hematologic malignancy predisposition syndromes have widely variable phenotypes and penetrance, even within families, making prognostic counseling of patients and families difficult.…”

Section: Introductionmentioning

confidence: 99%

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes

et al. 2020

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Inherited bone marrow failure (IBMF) syndromes are rare blood disorders characterized by hematopoietic cell dysfunction and predisposition to hematologic malignancies. Despite advances in the understanding of molecular pathogenesis of these heterogeneous diseases, genetic variant interpretation, genotype–phenotype correlation, and outcome prognostication remain difficult. As new IBMF and other myelodysplastic syndrome (MDS) predisposition genes continue to be discovered (frequently in small kindred studies), there is an increasing need for a systematic framework to evaluate penetrance and prevalence of mutations in genes associated with IBMF phenotypes. To address this need, we analyzed population-based genomic data from >125 000 individuals in the Genome Aggregation Database for loss-of-function (LoF) variants in 100 genes associated with IBMF. LoF variants in genes associated with IBMF/MDS were present in 0.426% of individuals. Heterozygous LoF variants in genes in which haploinsufficiency is associated with IBMF/MDS were identified in 0.422% of the population; homozygous LoF variants associated with autosomal recessive IBMF/MDS diseases were identified in only .004% of the cohort. Using age distribution of LoF variants and 2 measures of mutational constraint, LOEUF (“loss-of-function observed/expected upper bound fraction”) and pLI (“probability of being loss-of-function intolerance”), we evaluated the pathogenicity, tolerance, and age-related penetrance of LoF mutations in specific genes associated with IBMF syndromes. This analysis led to insights into rare IBMF diseases, including syndromes associated with DHX34, MDM4, RAD51, SRP54, and WIPF1. Our results provide an important population-based framework for the interpretation of LoF variant pathogenicity in rare and emerging IBMF syndromes.

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Genotype-phenotype associations in Fanconi anemia: A literature review

Cited by 132 publications

References 34 publications

Fanconi anemia: a single center experience of a large cohort

Fanconi anemia: a single center experience of a large cohort

DNA Repair Syndromes and Cancer: Insights Into Genetics and Phenotype Patterns

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes

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