Genetic Drivers Discovered for DiGeorge Syndrome Kidney Defects

DiGeorge syndrome is a chromosomal disorder that can lead to malformations in multiple organs and it is the most common microdeletion syndrome, in which a portion of a chromosome is missing.

The DiGeorge syndrome is a debilitating, multisystemic condition that features, with variable expressivity, cardiac malformations, velopharyngeal insufficiency, hypoparathyroidism with hypocalcemia, and thymic aplasia with immune deficiency.

A large team of scientists led by those at Columbia University Medical Center performed genomic analyses in 2,666 children with congenital anomalies of the kidney and urinary tract which is the largest pediatric cohort of these disorders, and 22,094 controls to identify structural variants associated with these defects. They performed genomewide genotyping for analysis of copy-number variation by means of high-density single-nucleotide polymorphism (SNP) microarrays.

They performed high-throughput next-generation sequencing for eight genes in the 370-kb minimal region of overlap for the DiGeorge syndrome in samples obtained from an additional 526 patients using microfluidic polymerase-chain-reaction capture coupled with next-generation sequencing on the 2500 HiSeq system.

The scientists’ analysis identified deletions at the terminal portion of the 22q11.2 DiGeorge locus as the second most common microdeletion in patients with kidney malformations. This study mapped the candidate gene for kidney disease in DiGeorge syndrome to a smaller region containing only nine genes. The team resequenced all genes included in the critical 22q11.2 region identified five out of 586 patients with kidney and urinary tract defects that had novel heterozygous protein-altering variants, including a premature termination codon, in CRK-Like Proto-Oncogene, Adaptor Protein gene (CRKL). Inactivation of the same gene in mouse embryos finally proved its role as the main driver.

Simone Sanna-Cherchi, MD, an assistant professor of medicine and senior author of the study said, “This study represents a critical step forward in understanding the genetic basis of congenital kidney defects associated with DiGeorge syndrome and in the general population. Expanding our knowledge of the genetics of kidney development and malformations will give us additional tools needed to diagnose this variant of DiGeorge syndrome and gives us a potential therapeutic target.” The study was published on January 25, 2017, in The New England Journal of Medicine.