Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

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

Version 1 : Received: 24 December 2021 / Approved: 29 December 2021 / Online: 29 December 2021 (19:28:49 CET)

How to cite: Reyes, P.; García-deTeresa, B.; Juárez, U.; Pérez-Villatoro, F.; Fiesco-Roa, M.O.; Rodríguez, A.; Molina, B.; Villarreal-Molina, M.T.; Melendez-Zajgla, J.; Carnevale, A.; Torres, L.; Frias, S. Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG. Preprints 2021, 2021120473 (doi: 10.20944/preprints202112.0473.v1). Reyes, P.; García-deTeresa, B.; Juárez, U.; Pérez-Villatoro, F.; Fiesco-Roa, M.O.; Rodríguez, A.; Molina, B.; Villarreal-Molina, M.T.; Melendez-Zajgla, J.; Carnevale, A.; Torres, L.; Frias, S. Fanconi Anemia Patients from an Indigenous Community in Mexico Carry a New Founder Pathogenic Variant in FANCG. Preprints 2021, 2021120473 (doi: 10.20944/preprints202112.0473.v1).

Abstract

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.

Keywords

Fanconi anemia; Chromosome instability; FANCG; splicing; founder pathogenic variant; Mixe indigenous group.

Subject

MEDICINE & PHARMACOLOGY, Other

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