Comparison of the clinical phenotype and haematological course of siblings with Fanconi anaemia

Jung, Moonjung; Mehta, Parinda A.; Jiang, Caroline S.; Rosti, Rasim Özgür; Usleaman, Gabriel; Rosa, Joel Correa da; Lach, Francis P.; Goodridge, Erica; Auerbach, Arleen D.; Davies, Stella M.; Smogorzewska, Agata; Boulad, Farid

doi:10.1111/bjh.17061

Cited by 7 publications

(9 citation statements)

References 15 publications

(22 reference statements)

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“…All of them share height, radial and skin abnormalities, two also had microcephaly and ultrasonographic evaluations rule out renal malfomations. As expected, although these three patients share the same pathogenic FANCG genotype and a similar genetic background, their phenotypic presentation was not homogeneous, as has been evidenced in other cases [42]. Yet, they illustrate that clinical presentation in FA has a broad spectrum of severity that in this case goes from a florid presentation in FANC143 which includes five PHENOS features and uncommon findings like bifid uvula, to a more discreet presentation in patient FANC155 in whom her unilateral radial abnormality was only recorded after intentional evaluation by a dysmorphologist (Table 4).…”

Section: Discussionsupporting

confidence: 71%

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Reyes¹,

García-de-Teresa²,

Juárez³

et al. 2021

Preprint

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Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the FA/BRCA pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatics predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.

show abstract

Section: Discussionsupporting

confidence: 71%

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Reyes¹,

García-de-Teresa²,

Juárez³

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…As expected, although these three patients share the same pathogenic FANCG genotype and a similar genetic background, their phenotypic presentation was not homogeneous, as evidenced in other cases [40]. Yet, they illustrate that clinical presentation in FA has a broad spectrum of severity that in this case goes from a florid presentation in FANC143, which includes five PHENOS features and uncommon findings like bifid uvula, to a more discreet presentation in patient FANC155 in whom her unilateral radial abnormality was only recorded after intentional evaluation by a dysmorphologist (Table 4).…”

Section: Discussionsupporting

confidence: 62%

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Reyes

Teresa

Juárez

et al. 2022

IJMS

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Fanconi anemia (FA) is a rare genetic disorder caused by pathogenic variants (PV) in at least 22 genes, which cooperate in the Fanconi anemia/Breast Cancer (FA/BRCA) pathway to maintain genome stability. PV in FANCA, FANCC, and FANCG account for most cases (~90%). This study evaluated the chromosomal, molecular, and physical phenotypic findings of a novel founder FANCG PV, identified in three patients with FA from the Mixe community of Oaxaca, Mexico. All patients presented chromosomal instability and a homozygous PV, FANCG: c.511-3_511-2delCA, identified by next-generation sequencing analysis. Bioinformatic predictions suggest that this deletion disrupts a splice acceptor site promoting the exon 5 skipping. Analysis of Cytoscan 750 K arrays for haplotyping and global ancestry supported the Mexican origin and founder effect of the variant, reaffirming the high frequency of founder PV in FANCG. The degree of bone marrow failure and physical findings (described through the acronyms VACTERL-H and PHENOS) were used to depict the phenotype of the patients. Despite having a similar frequency of chromosomal aberrations and genetic constitution, the phenotype showed a wide spectrum of severity. The identification of a founder PV could help for a systematic and accurate genetic screening of patients with FA suspicion in this population.

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“…Previous reports have shown that there is not a clear correlation between specific FANCA mutations (i.e., homozygous null variants versus hypomorphic gene product) and the severity of the clinical phenotype with respect to congenital abnormalities and age at which hematologic abnormalities arise ( Castella et al 2011 ). Hematological progression significantly correlated between siblings harboring the same mutations in a recent study ( Jung et al 2020a ). However, siblings may also present with widely dissimilar phenotypes ( Faivre et al 2000 ), suggesting that other, lesser understood factors, such as environmental exposures or modifying genetic variants, may also play a role in disease manifestation.…”

Section: Introductionmentioning

confidence: 70%

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

Lach

Singh

Rickman

et al. 2020

Cold Spring Harb Mol Case Stud

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Fanconi anemia (FA) is a clinically heterogenous and genetically diverse disease with 22 known complementation groups (FA-A to FA-W), resulting from the inability to repair DNA interstrand cross-links. This rare disorder is characterized by congenital defects, bone marrow failure, and cancer predisposition. FANCA is the most commonly mutated gene in FA and a variety of mostly private mutations have been documented, including small and large indels and point and splicing variants. Genotype–phenotype associations in FA are complex, and a relationship between particular FANCA variants and the observed cellular phenotype or illness severity remains unclear. In this study, we describe two siblings with compound heterozygous FANCA variants (c.3788_3790delTCT and c.4199G > A) who both presented with esophageal squamous cell carcinoma at the age of 51. The proband came to medical attention when he developed pancytopenia after a single cycle of low-dose chemotherapy including platinum-based therapy. Other than a minor thumb abnormality, neither patient had prior findings to suggest FA, including normal blood counts and intact fertility. Patient fibroblasts from both siblings display increased chromosomal breakage and hypersensitivity to interstrand cross-linking agents as seen in typical FA. Based on our functional data demonstrating that the c.4199G > A/p.R1400H variant represents a hypomorphic FANCA allele, we conclude that the residual activity of the Fanconi anemia repair pathway accounts for lack of spontaneous bone marrow failure or infertility with the late presentation of malignancy as the initial disease manifestation. This and similar cases of adult-onset esophageal cancer stress the need for chromosome breakage testing in patients with early onset of aerodigestive tract squamous cell carcinomas before platinum-based therapy is initiated.

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Comparison of the clinical phenotype and haematological course of siblings with Fanconi anaemia

Cited by 7 publications

References 15 publications

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG

Esophageal cancer as initial presentation of Fanconi anemia in patients with a hypomorphic FANCA variant

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