Pathogenic FANCC Variants Are Associated with Accessory Breasts in a Sub-Saharan African Multiplex Family

TL;DR

This study identifies genetic variants in FANCC linked to accessory breasts in a Sub-Saharan African family, offering new insights into the condition's genetic basis.

Contribution

The study reports novel pathogenic FANCC variants associated with familial accessory breasts in a Sub-Saharan African population.

Findings

Pathogenic FANCC variants c.360del and c.355_358del were identified as likely causes of familial accessory breasts.

Twelve candidate genes, including PRSS50 and FANCC, were found to be potentially involved in accessory breast formation and comorbidities.

Secondary findings in TTR and RYR1 suggest additional genetic contributions to comorbid conditions.

Abstract

Accessory breasts denote the formation of extra breast tissue along the milk line, and are known to be more prevalent among Black and Asian populations, affecting both genders. This first-ever study aimed to determine the genetic aetiology of accessory breasts in a multiplex family, where all female siblings present with bilateral accessory breasts. The study also ascertained secondary findings (SFs) responsible for comorbidities. Clinical data and saliva samples were obtained from all family members. Ultrasound and histopathology confirmed the diagnosis. Whole-exome sequencing was conducted on DNA samples obtained from the saliva, with variant calling conducted utilising the Sentieon workflow. Variant classification was based on American College of Medical Genetics and Genomics guidelines. After segregation analysis, 12 candidate genes emerged. Among these, PRSS50 and FANCC emerged as top candidates, being implicated in breast diseases. However, two variants in FANCC (c.360del; p.His120GlnfsTer24 and c.355_358del; p.Ser119IlefsTer24) were selected as the most probable causal variants because of the role of this gene in hereditary breast and ovarian cancer syndromes. The remaining ten genes were reported as potentially accounting for comorbidities segregating with accessory breasts. Reported SFs involve TTR and RYR1. In conclusion, pathogenic variants in FANCC cause familial accessory breasts. These novel observations impact pathophysiology, genetic counselling, and personalised medicine.

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