Genotype-phenotype associations in Fanconi anemia: A literature review

doi:10.1016/j.blre.2019.100589

Blood Reviews

Volume 37, September 2019, 100589

https://doi.org/10.1016/j.blre.2019.100589 Get rights and content

Abstract

Fanconi anemia (FA) is a genomic instability syndrome with predisposition to congenital abnormalities, bone marrow failure, and cancer. Classical and most frequent congenital abnormalities include all those seen in VACTERL-H association and those described under the PHENOS acronym. Pathogenic variants in at least 22 genes are associated with FA, which code for proteins that comprise the FA/BRCA DNA repair pathway. We reviewed 187 publications and 1101 cases of FA in which the gene or complementation group was identified and analyzed those in whom physical findings were sought. We conducted genotype-phenotype analyses considering the specific gene, the location in the FA/BRCA DNA repair pathway, and the type of variant (null or hypomorphic) as exposures. The outcomes were the presence of any physical abnormality or specific categories of abnormalities. Seventy-nine percent of the patients had at least one physical abnormality. Pathogenic variants in FANCB, FANCD2, the ID complex and downstream genes were associated with several specific anomalies. Patients with biallelic or hemizygous null variants had a higher proportion of at least one abnormality, renal malformations, microcephaly, short stature and the combination of VACTERL-H compared with those with hypomorphic genotypes. VACTERL-H alone or in combination with PHENOS is highly associated with FA, but the absence of those features does not rule out the diagnosis of FA.

Introduction

Fanconi anemia (FA) is a genomic instability syndrome associated with congenital abnormalities, bone marrow failure (BMF) and cancer predisposition [1,2]. The first cases of FA were reported by Guido Fanconi, a Swiss pediatrician, who in 1927 described three brothers with short stature, physical abnormalities and anemia [3]. Cytopenias due to BMF are the most common presentation of FA. Hematological manifestations include aplastic anemia, myelodysplastic syndrome and leukemia [1,4]. The median age at diagnosis of FA is 7 years [2] although symptomatic and asymptomatic (family members) cases have been described from birth to >50 years of age. Patients with FA have an extremely high risk of developing malignancies at an early age; the most common are acute myeloid leukemia and squamous cell carcinomas of head and neck and of female genitalia [1].

The physical phenotype in patients with FA is extremely heterogenous and can affect multiple systems [2]. Classical congenital abnormalities include those described in the VACTERL-H (Vertebral, Anal, Cardiac, Tracheo-esophageal fistula, Esophageal atresia, Renal, upper Limb and Hydrocephalus) association (OMIM 192350) [5]. From 5 to 30% of patients with FA were reported to meet VACTERL-H criteria (presence of at least any 3 of 8 features) [6,7]. Other abnormalities common to FA but not part of VACTERL-H were recently grouped by us as PHENOS (skin Pigmentation, small Head, small Eyes, Nervous system, Otology, Short stature). At least four of the six PHENOS features were more frequent in the patients with FA who also had VACTERL-H [7].

Pathogenic variants in at least 22 genes (FANCA, FANCB, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCM, FANCN/PALB2, FANCO/RAD51C, FANCP/SLX4, FANCQ/ERCC4/XPF, FANCR/RAD51, FANCS/BRCA1, FANCT/UBE2T, FANCU/XRCC2, FANCV/REV7, and FANCW/RFWD3) have been identified in patients with FA [8]. All are autosomal recessive except FANCB which is X-linked, and FANCR which is autosomal dominant. The FA genes code for proteins that comprise a complex network for DNA damage repair (FA/BRCA DNA repair pathway) and other cellular processes [9,10]. The main function of the pathway is the removal of DNA interstrand crosslinks, which interfere with DNA replication and gene transcription [10]. The genes are grouped according to their function in the FA/BRCA DNA repair pathway as upstream genes (FANCA, B, C, E, F, G, L, M, and T), ID complex (FANCD2 and I), and downstream genes (FANCD1, J, N, O, P, Q, R, S, U, V, and W). The upstream gene products form the FA core complex upon DNA damage. This leads to monoubiquitination of the ID complex, which then activates the downstream genes, resulting in DNA repair.

Genotype-phenotype associations previously reported in FA include: 1) poor hematological outcomes due to severe cytopenia and increased frequency of leukemia in patients with FANCG and in those with biallelic null variants in FANCA compared with FANCC [11]; 2) less frequent congenital abnormalities in patients with FANCC compared with FANCA and G [11]; and 3) high risk and early age of cancer in patients with pathogenic variants in the downstream genes FANCD1/BRCA2 and FANCN/PALB2 [[12], [13], [14]].

We revisited the genotype-phenotype relationships in published cases of FA and proposed several questions: What is the association of at least one abnormality or specific groups of abnormalities (such as VACTERL-H or PHENOS) with the genotype? Does it depend on the gene, the location in the FA/BRCA DNA repair pathway, or the type of FA gene pathogenic variant?

Section snippets

Patients and methods

We searched PubMed for publications limited to human subjects from October 1982 through September 2017 using the terms “Fanconi” and “anemia”. We began with 1982 because this was the year of the first patient report was associated with a specific FA complementation group [15,16]. We identified all cases that reported the FA gene or complementation group. We selected cases that had clinical information on the presence or absence of physical abnormalities. We sought genotype-phenotype

Cases analyzed

We identified 1101 reports of individual patients in which the complementation group or gene related to FA was reported from a review of 187 articles from 26 countries (Fig. 1). The male to female ratio was 1:0.91 (p = .5). We excluded 540 patients for whom data regarding the presence or absence of any phenotypic abnormality were not stated. Phenotype information was available for 561 patients (51%), of whom 443 (79%) had at least one abnormality and 118 were stated to have none. Two hundred

Discussion

This is the largest comprehensive review of the literature describing the association of congenital abnormalities with the gene, location in the FA/BRCA DNA repair pathway, and the type of pathogenic variant in patients with FA. The lack of information about physical findings in nearly half of the patients with reported genotype data (mostly patients with FANCA, C and G), may be due to a recent bias towards describing phenotypes in patients with rare genotypes.

The percentage of patients with at

Strengths and limitations

There are some limitations to this study. Nearly half of the reports in the literature lacked phenotype information. Approximately one third of the reports did not provide sufficient details to classify the type of variant. Patients who were stated to lack physical abnormalities were assumed to have no anomalies. We did not analyze hematological and oncological features. Strengths of this study include that the genotype-phenotype analysis included 561 patients. In addition to gene by gene

Conclusions and future directions

Congenital abnormalities in patients with FA are variable and multisystemic. The majority of patients in whom the genotype and phenotype are described have at least one abnormality. Patients with pathogenic variants in FANCB, D2, ID complex, and downstream genes as well as biallelic or hemizygous null variants have the highest frequency of associations with congenital abnormalities. The most common abnormalities are part of VACTERL-H and PHENOS. The presence of VACTERL-H alone or with PHENOS is

Practice points

•
The spectrum of physical abnormalities in patients with Fanconi anemia is variable and multisystemic.
•
The most frequent anomalies are: short stature, upper limb structural abnormalities, pigmentary skin changes, renal malformations, and microcephaly; all are included in either VACTERL-H or PHENOS.
•
FA should be considered in any patient with one or more of the congenital abnormalities listed above.
•
The clinician should suspect FA even if the patient does not meet criteria for VACTERL-H or PHENOS.
•

Research agenda

•
Explore the relation between canonical and non-canonical gene functions and the variability of congenital abnormalities [33,34].
•
Extend the genotype-phenotype analyses to include hematologic and oncologic outcomes.
•
Compare the various physical scoring systems for the strength of their association with proven cases with FA: i.e. adding anomalies [35], the CABS (congenital abnormality score) [36], VACTERL-H, PHENOS [7].
•
Determine the frequency of FA among patients with VACTERL-H.

Declaration of Competing of Interest

The authors declare no conflicts of interest.

Funding

This research was funded in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute, and a grant from the Fanconi Anemia Research Fund, Inc.

Author Statement

MOFR: Data curation, Formal analysis, Methodology, Writing: Original Draft, Review and Editing.

NG: Conceptualization, Data curation, Formal analysis, Methodology, Supervision, Validation, Writing: Review and Editing.

LJM: Methodology, Writing: Review and Editing.

AFB: Methodology, Writing: Review and Editing.

BPA: Conceptualization, Data curation, Formal analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Writing: Review and Editing.

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Published by Elsevier Ltd.

ReviewGenotype-phenotype associations in Fanconi anemia: A literature review

Abstract

Introduction

Section snippets

Patients and methods

Cases analyzed

Discussion

Strengths and limitations

Conclusions and future directions

Practice points

Research agenda

Declaration of Competing of Interest

Funding

Author Statement

Blood Rev

Best Pract Res Clin Haematol

Cell.

Eur. Fanconi Anemia Res. Group Blood

BioData Min

Am J Hum Genet

Am J Hum Genet

Blood.

Cancer Genet

Blood.

Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up

Haematologica.

Familiäre infantile perniziosaartige Anämie (pernizioses Blutbild und Konstitution)

Jahrbuch für Kinderheilkunde

Clinical geneticists' views of VACTERL/VATER association

Am J Med Genet A

Should chromosome breakage studies be performed in patients with VACTERL association?

Am J Med Genet A

Thinking of VACTERL-H? Rule out Fanconi Anemia according to PHENOS

Am J Med Genet A

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia

J Clin Invest

Fanconi anemia pathway

Curr Biol

The clinical phenotype of children with Fanconi anemia caused by biallelic FANCD1/BRCA2 mutations

Pediatr Blood Cancer

Review
Genotype-phenotype associations in Fanconi anemia: A literature review