Renal gene panel testing holds diagnostic value

Nearly 800,000 Americans have kidney failure (KF) and need dialysis or a kidney transplant. Yet, for about one-quarter of KF patients, an underlying diagnosis remains unknown. Although the prevalence of causative monogenic diseases in patients with chronic kidney disease (CKD) may be as high as 30%, genetic testing of patients waitlisted for kidney transplant is not routine. As reported in this issue, Schrezenmeier and colleagues used a comprehensive next-generation sequencing (NGS) panel to identify diagnostic variants in KF patients waitlisted for kidney transplant. The findings demonstrate the diagnostic value of genetic testing among patients with CKD of undetermined etiology. The researchers screened 635 patients on the Eurotransplant kidney waiting list at Campus Charité Mitte Berlin. Most patients (54%) had an undetermined diagnosis at screening. Of the 137 patients who met inclusion criteria for genetic testing, 126 gave consent. Using a targeted NGS panel of 600 genes described or associated with kidney disease or related disorders, the researchers detected diagnostic variants in 26 patients, more than half of whom (14/26) had likely pathogenic or pathogenic or variants in one or more of the genes in the panel. Most variants that classified as pathogenic or likely pathogenic (8/14) were in genes encoding the α3-, α4-, or α5-chains of type IV collagen. The analysis also uncovered variants of unknown significance (VUS) in another 12 patients as well as a pathogenic variant and a VUS in two patients suspicious for atypical hemolytic uremic syndrome. Altogether, genetic testing reduced the number of waitlisted patients with undetermined kidney disease etiology from 390 to 376 cases and bumped the number of clear monogenic cases up to 21%. Together, the results indicate that renal gene panel testing of waitlisted KF transplant patients may be cost-effective and have direct clinical consequences for affected individuals. —V. L. Dengler, News Editor

Newborn screening and exome sequencing are complementary

Newborn screening (NBS) to diagnose severe, early-onset disorders is routine. The screening includes point-of-care tests for hearing and critical congenital heart disease as well as tests for disorders with a Mendelian genetic basis, including cystic fibrosis, sickle cell disease, and many others using a dried blood spot for biochemical analysis. However, traditional NBS may miss disorders that are not included in the Recommended Uniform Screening Panel and that exome or genome sequencing (ES/GS) may detect. Yet, few studies have compared traditional NBS with complementary ES/GS. Wojcik and colleagues report incongruous results from the two screening modalities. The findings indicate that the two methods may provide complementary information. The researchers evaluated screening results from more than 300 infants enrolled in the BabySeq Project, a randomized clinical study. About half of the infants received a standard NBS report and a family history report. The remaining infants received the same care plus an ES report that included monogenic disease variants, pediatric pharmacogenomic-associated variants, heterozygous status for genes associated with autosomal recessive childhood-onset disorders, and a limited number of actionable adult-onset-only disorders. Most infants (84%) were both NBS and ES negative. Three infants were NBS and ES positive; however, only one was positive for the same disorder by both methods. Although 9 infants were NBS positive and ES negative, the NBS was false positive in 7 cases. In contrast, results for 15 infants were ES positive and NBS negative, all of which indicated risk for genetic conditions such as cardiomyopathy that are not included in the NBS. Altogether, the findings indicate that NBS and ES screening each have strengths and weaknesses. The authors conclude that the two modalities may complement each other in determining disease risk. —V. L. Dengler, News Editor