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Background: Accessory breast tissue is a developmental abnormality characterised by extra breast tissue along the milk line. It has a prevalence of ~2-6% in humans, being more common in African and Asian ancestries, and in women. It has profound physical and psychosocial effects on affected individuals. Strikingly, research into the genetic aetiology of accessory breasts is limited, especially among Ghanaians. This research sought to decipher the genetic aetiology of bilateral accessory breasts in a Ghanaian multiplex family.
Methods: Six individuals from a multiplex family were recruited, comprising three unaffected males and three affected females. Ultrasound and histopathology were conducted to confirm the diagnosis. Whole-exome sequencing was conducted at 100X. Bioinformatics analysis utilised the Sentieon workflow and GRCh38. Called variants were annotated with Ensembl VEP, followed by filtering out variants with MAF > 0.01. Subsequently, pathogenicity of variants was deduced using ACMG guidelines. This included employing 12 tools in dbNSFP and VarElect.
Results: Ultrasound examination was suggestive of bilateral accessory breasts. Histopathology of the accessory breast tissues showed breast lobules and ductal structures with areas of fibrous tissue with no atypia. After segregation analysis and examining the inheritance pattern, 12 candidate genes (PRSS50, SLC7A7, NDE1, DIP2B, ADGRG6, CHDH, OR2W1, FANCC, ACKR2, OR4Q3, MYO1H) were selected. From the 12 candidate genes selected, PRSS50 and FANCC genes have been implicated in breast diseases. FANCC is a DNA repair protein that participates in post-replication repair and serves as a cell cycle checkpoint function – this gene has been associated with hereditary breast and ovarian disease. It is also implicated in DNA repair pathways, being regulated by the tumour suppressor gene TP53, and is co-expressed with the BRCA1 gene.
Conclusion: Two dominant frameshift variants in FANCC are causal for familial accessory breasts. This observation is crucial for genetic counselling, molecular diagnostics and pathophysiology of the condition.