NEW YORK (GenomeWeb) – Some forms of congenital kidney disease appear to stem from recurrent deletions affecting the same chromosome 22 locus implicated in DiGeorge syndrome, perhaps explaining some of the kidney complications that can occur in individuals with the syndrome.
A team led by Columbia and Duke University used array-based genotyping to scrutinize structural variant patterns in nearly 2,100 individuals with congenital kidney and urinary tract conditions. Compared with almost 22,100 unaffected control individuals, the kidney disease patients had more deletions involving one copy of the chromosome 22q11.2 locus.
The researchers unearthed the same heterozygous deletion in five more individuals who were profiled by targeted or exome sequencing, while their animal model experiments suggested that only a few of the nine genes in this 370-kilobase region directly contributed to the kidney disease in DiGeorge syndrome or the congenital kidney conditions.
"Of the nine genes at this locus, SNAP29, AIFM3, and CRKL appear to be critical to the phenotype, with haploinsufficiency of CRKL emerging as the main genetic driver," the researchers wrote in a paper published yesterday in the New England Journal of Medicine.
De novo heterozygous deletions spanning up to 2.5 million bases at 22q11.2 are the main genetic alterations implicated in DiGeorge syndrome, a condition characterized by developmental defects in multiple organ systems — from heart malformations to neurodevelopmental or urogenital problems. As the team explained, the long arm of chromosome 22 contains multiple segmental duplications that confer a predisposition to genomic rearrangements.
Using high-density Illumina or Affymetrix arrays, the researchers profiled copy number patterns in samples from 2,080 individuals with congenital kidney and urinary tract abnormalities and 22,094 unaffected controls.
After narrowing in on the heterozygous chromosome 22 deletions — which turned up in 14 kidney cases, but just three controls (including one individual found to have undiagnosed DiGeorge syndrome) — the team used the Illumina 2500 HiSeq to perform targeted or exome sequencing on 526 kidney disease cases, 1,152 IgA nephrology patients, and 576 controls. That search led to loss-of-function mutations affecting genes in the 22q11.2 deletion region, including CRKL.
The researchers' gene editing experiments on zebrafish embryos suggested alterations affecting the nine genes at the 22q11.2 locus contributed to renal problems that could be improved by adding back versions of the SNAP29, AIFM3, or CRKL genes. Meanwhile, their gene and protein expression experiments indicated that CRKL may be particularly important to kidney and urinary tract development in mice and humans.
"[O]ur approach provides support for the causal role of CRKL in the pathogenesis of kidney development defects," they wrote. "Such defects occur specifically in the context of the DiGeorge syndrome and 22q11.2 deletions and, more broadly, in sporadic congenital kidney and urinary tract abnormalities."