Genotype-phenotype associations in Fanconi anemia: A literature review

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.

Keywords: Congenital abnormality; Fanconi anemia; Gene; Genotype-phenotype association; PHENOS; VACTERL-H.

Fig. 1.

Study Flow Chart. We identified 1101 reports of individual patients in which the complementation group or gene related to FA was reported from 1982 through September 2017. Phenotype information was provided for 561 patients (51%); 443 (79%) of these had a physical abnormality and 118 (21%) did not. The type of pathogenic variant (null or hypomorphic) could be classified in 380 patients (68%) with phenotype information; 237 (62%) of these had a null genotype and 143 (38%) a hypomorphic genotype. For the rest of the patients, the authors did not mention molecular details enabling variant classification.

Fig. 2.

Types of Abnormalities. TEF, trachea-esophageal fistula; Esoph/duod, esophageal or duodenal atresia; neuro, neurological; dev, developmental; FA, Fanconi anemia; GI, gastrointestinal. Upper limb includes abnormal thumb +/− abnormal radius. Neuro structure includes structural brain malformations other than hydrocephalus. Otology comprises ear malformations and/or hearing loss. The heading “Other findings” includes anomalies not contained in VACTERL-H or PHENOS. Gray: any or no abnormality; solid blue or orange: VACTERL-H or PHENOS; horizontal stripes: individual findings. Horizontal axis: abnormalities analyzed; vertical axis: percent of total cases with that abnormality. VACTERL-H association (≥3/8 features) was present in 12% and PHENOS (≥4/6 features) in 9% of patients. The most frequent features (unrelated to criteria for VACTERL-H or PHENOS) were: short stature (43%), upper limb (radial ray) abnormalities (40%), skin pigmentary changes (37%), renal malformations (27%), and small head (27%). The rest of the abnormalities were less than 20%.

Fig 3.

Combinations of the most common VACTERL-H features. C: cardiac structural anomalies; R: renal malformations; L: upper limb anomalies (radial ray). Solid: patients with gene and phenotype described (n=561); horizontal stripes: patients who had ≥3/8 VACTERL-H features (n=69); white: patients who had only 2/8 VACTERL-H features (n=78). Horizontal axis: combinations; vertical axis: percent of cases with each combination. The frequencies of the combinations in the patients with gene and phenotype described were RL 19.6%, CL 9.6%, CR 9.1%, and CRL 7.7%; whereas in those who met criteria for VACTERL-H the frequencies were 91.3%, 63.8%, 63.8%, 62.3%, respectively. Eighty-two percent of patients who did not met criteria for VACTERL-H (with only 2 features) had the RL (60.3%), CL (12.8%), or CR (9%) combinations.

Fig 4.

Type of Pathogenic Variants according to Gene. Gray: null genotype; white: hypomorphic genotype. Horizontal axis: gene, number of patients; vertical axis: percent of cases within each gene. *p<0.05. The type of variant could be determined in 380 out of 561 cases (68%) based on available information; 62% of patients had null variants. The frequency of null and hypomorphic variants varied among the genes. FANCB, G, J, and N were more frequently associated with null variants (p≤0.03); FANCC with hypomorphic variants (p=0.004); and, null and hypomorphic variants were equally distributed in the rest of the genes.

Fig. 5.

Presence or Absence of at least one Abnormality. Gray: abnormality; white: no abnormality. A and B) Horizontal axis: gene, number of patients; vertical axis: percent of cases within each gene. C and D) Horizontal axis: location in the pathway, number of patients; vertical axis: percent of cases within each location in the pathway. *p<0.05. (A) More than 70% of patients in each gene group had at least one of the abnormalities reported in Figure 2, except for FANCP (56%). Approximately 90% of patients with FANCB, D1, D2, J and N had at least one abnormality. A higher proportion of patients with FANCD2 had at least one abnormality compared with all other genes combined (p=0.01), in contrast with a smaller proportion of patients with FANCA (p=0.01). (B) More than 75% of the patients with a null genotype and more than 65% of the patients with a hypomorphic genotype had at least one abnormality. A higher proportion of patients with a null genotype compared with those with a hypomorphic genotype in FANCA and B had at least one abnormality (p≤0.0001); whereas for FANCC a higher proportion of patients with a hypomorphic genotype compared with biallelic null variants had any abnormality (p=0.01). (C) Presence of any abnormality was more frequent in the ID complex, followed by downstream and then upstream genes (p<0.05). (D) Patients with biallelic or hemizygous null variants were more likely to have any abnormality than those with hypomorphic variants independent of the location in the pathway (p<0.05).

Fig. 6.

Presence or absence of VACTERL-H and/or PHENOS. Blue, VACTERL-H alone; orange, PHENOS alone; gray, VACTERL-H plus PHENOS; white, neither VACTERL-H nor PHENOS. A and B) Horizontal axis: gene, number of patients; vertical axis: percent of cases within each gene. C and D) Horizontal axis: location in the pathway, number of patients; vertical axis: percent of cases within each location in the pathway. *p<0.05. (A) 9% of all patients had VACTERL-H alone, 5% had PHENOS alone, 4% had VACTERL-H plus PHENOS, and 82% had neither VACTERL-H nor PHENOS. A higher proportion of patients with FANCB and I had VACTERL-H (irrespective of PHENOS) (p<0.001 and p=0.02, respectively). A higher proportion of patients with FANCD2 and I had PHENOS (irrespective of VACTERL-H) (p=0.01 for FANCD2). A higher proportion of patients with FANCB had VACTERL-H alone (without PHENOS) (p<0.001). VACTERL-H plus PHENOS was more frequent in patients with FANCI (p=0.03). VACTERL-H and/or PHENOS was rare in patients with FANCA (p<0.0001). (B) Overall, VACTERL-H (irrespective of PHENOS) was more frequent in patients with biallelic or hemizygous null variants than in those with at least one hypomorphic allele (p=0.01). Gene by gene, VACTERL-H (irrespective of PHENOS) and at least one of the two (VACTERL-H or PHENOS) were more frequent in patients with biallelic or hemizygous null variants in FANCB (p<0.05) and I. (C) VACTERL-H and/or PHENOS were less frequent in patients with pathogenic variants in upstream genes (p<0.0001). A higher proportion of patients with pathogenic variants in ID complex genes had PHENOS (irrespective of VACTERL-H) (p=0.001), both VACTERL-H plus PHENOS (p=0.003), or at least one of the two (p=0.01) compared with patients with pathogenic variants in upstream and downstream genes. (D) Patients with biallelic or hemizygous null variants in upstream genes had a higher proportion of PHENOS (irrespective of VACTERL-H) and at least one of the two (VACTERL-H or PHENOS) than those with hypomorphic genotype (p<0.02); these associations were not seen in ID or downstream genes.