Researchers have identified a series of single nucleotide polymorphisms (SNPs) associated with acute lymphoblastic leukemia (ALL) in children with Down syndrome, according to an article published in Blood.

Down syndrome is a common genetic syndrome, and it confers a 10- to 20-fold increase in risk for ALL and an overall 2% lifetime risk for leukemia. In patients with Down syndrome, ALL is predominantly of B-cell lineage, and it carries poorer outcomes and higher rates of somatic chromosomal rearrangements. Previous genome-wide association studies have shown that IKZF1, CDKN2A, ARID5B, CEBPE, GATA3, BMI1, and PIP4K2A may be involved in ALL, though these studies did not specifically investigate germline susceptibility to ALL among children with Down syndrome.

Related Articles

For this study, researchers conducted a meta-analysis to determine whether any specific genetic variants conferred a higher risk for ALL in children with Down syndrome. They also compared the frequency of alleles associated with risk for ALL in patients with and without Down syndrome.

Continue Reading

The meta-analysis included 4 studies containing data from 542 patients with both Down syndrome and ALL and 1192 patients with Down syndrome alone. Nearly 7 million autosomal genetic variants, aside from those of chromosome 21, were analyzed.

The researchers identified 4 SNPs representing susceptibility to ALL in patients with Down syndrome: rs58923657 near IKZF1 (odds ratio [OR], 2.02), rs3731249 in CDKN2A (OR, 3.63), rs7090445 in ARID5B (OR, 1.60), and rs3781093 in GATA3 (OR, 1.73).

The association between CDKN2A and ALL in this population was maintained “in separate regression models, both adjusting for and stratifying on CRLF2 overexpression, high hyperdiploidy, ETV6-RUNX1, and B-other subgroups, indicating an increased penetrance of CDKN2A risk alleles in children with Down syndrome,” wrote the researchers.

IKZF1 knockdown also appeared to pose a greater risk for ALL in Down syndrome cell lines compared with control cell lines.

“Future, large-scale, collaborative studies of well-phenotyped cases are needed to further elucidate the role of inherited genetic variation in leukemia susceptibility in children with Down syndrome,” the researchers noted.


1.     Brown AL, de Smith AJ, Gant VU, et al. Inherited genetic susceptibility of acute lymphoblastic leukemia in Down syndrome [published online July 26, 2019]. Blood. doi:10.1182/blood.2018890764