The genetic cause for approximately 80% of
familial breast cancer patients is unknown. Here, by sequencing the entire exomes of nine early-onset
familial breast cancer patients without BRCA1/2 mutations (diagnosed with
breast cancer at or before the age of 35) we found that two index cases carried a potentially deleterious mutation in the RECQL gene (
RecQ helicase-like; chr12p12). Recent studies suggested that RECQL is involved in
DNA double-strand break repair and it plays an important role in the maintenance of
genomic stability. Therefore, we further screened the RECQL gene in an additional 439 unrelated
familial breast cancer patients. In total, we found three
nonsense mutations leading to a truncated
protein of RECQL (p.L128X, p.W172X, and p.Q266X), one mutation affecting
mRNA splicing (c.395-2A>G), and five missense mutations disrupting the helicase activity of RECQL (p.A195S, p.R215Q, p.R455C, p.M458K, and p.T562I), as evaluated through an in vitro helicase assay. Taken together, 9 out of 448 BRCA-negative
familial breast cancer patients carried a pathogenic mutation of the RECQL gene compared with one of the 1,588 controls (P = 9.14×10-6). Our findings suggest that RECQL is a potential
breast cancer susceptibility gene and that mutations in this gene contribute to
familial breast cancer development.