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

Abstract

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.

Inherited bone marrow failure syndromes: phenotype as a tool for early diagnostic suspicion at a major reference center in Mexico

“…Published information on cohorts of patients with IBMFS from LMICs, including Mexico, remains scarce. Comprehensive available data of Mexican patients with IBMFS are predominantly case reports or small case series, such as those for patients with FA ( García-de Teresa et al, 2019 ; Reyes et al, 2022 ), or case reports from a limited number of patients with DC or SCN ( López-Rodríguez et al, 2022 ; Picos-Cárdenas et al, 2022 ; Velez-Tirado et al, 2022 ).…”

“…Little is known about the prevalence and phenotypic spectrum of IBMFSs in the Mexican population, and available studies concentrate on FA ( García-de Teresa et al, 2019 ; Reyes et al, 2022 ). To address current genotyping limitations, we implemented a clinical approach to expedite clinical suspicion and diagnosis.…”

“…Frontiers in Genetics frontiersin.org concentrate on FA (García-de Teresa et al, 2019;Reyes et al, 2022).…”

Fanconi anemia and dyskeratosis congenita/telomere biology disorders: Two inherited bone marrow failure syndromes with genomic instability

“…A recent prospective study published that vertebrae anomalies are found in almost 50% of patients after intentional evaluation ( 245 ), which is in sharp contrast with the 4% described in the literature ( 37 , 133 ). Some reports have depicted less frequent anomalies, such as rib hypoplasia, Sprengel deformity, and hip dysplasia ( 149 , 225 , 261 – 264 ).…”