113 - The genetic etiology of renal anomalies presenting in the perinatal period

Poster Number: 113
Publication Number: 113.125

Thomas Hays, Columbia University Vagelos College of Physicians and Surgeons, Brooklyn, NY, United States; David Crosby, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Miles Bomback, Columbia University Division of Nephrology, Mount Kisco, NY, United States; Hila Milo Rasouly, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Jessica L. Giordano, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States; Ronald J. Wapner, Columbia University Medical Center, New York, NY, United States; Ali Gharavi, Columbia University Vagelos College of Physicians and Surgeons, New York, NY, United States

Background: Genetic disorders have been shown to cause a significant portion of congenital anomalies of the kidneys and urinary tract (CAKUT) in children and adults. Genetic disorders are prevalent in critically ill infants and in fetal disorders. However, the prevalence of genetic disease in perinatal CAKUT has not been well described.

Objective: We sought to determine the contribution of genetic disorders in fetuses and critically ill infants with CAKUT using whole exome sequencing (WES).

Design/Methods: Subjects were recruited from three cohorts: pregnancies affected by fetal CAKUT, infants admitted to the neonatal intensive care unit (NICU) found to have CAKUT, and children under the age of ten with CAKUT who had been admitted to the NICU in infancy. WES was used to diagnose genetic disorders. Data regarding demographics and clinical outcomes were also gathered.

Results: 141 cases were studied. Of fetal cases, 57% resulted in livebirth, 37% in termination, and 6% in demise or stillbirth. Of neonatal cases, 80% survived infancy. 49% of all cases had extrarenal anomalies. Single gene disorders were found in 27 (19%) of cases. These represented 24 unique diagnoses, with three genetic disorders found in two cases each. No characteristic was found to have a statistically significant association with the presence of genetic disorders. Similar proportions of cases were found to have genetic disorders across CAKUT categorization. 20 of 24 genetic diagnoses were associated with extrarenal manifestations that present in later childhood or adulthood. Conclusion(s): Our data indicate that genetic disorders are prevalent in this population. This prevalence is likely higher than in older populations presenting with CAKUT in part because of fetal loss and infant mortality. Congenital renal anomalies in this population may represent heralding features of underlying genetic disorders that include disease in later life. The genetic disorders found nearly all had implications for changed clinical management including counseling/prognosis, planning for future pregnancies, end-of-life decision making, referral to specialists, screening for syndromic manifestations, shortening diagnostic odyssey, and tailoring of therapy. Most genetic disorders predisposed to diseases in later life such as blindness, hearing loss, developmental delays, or diabetes. Most genetic diagnoses occurred in only one case, reflecting the complex genetic etiology of CAKUT. Further research is needed to study how clinical care of infants with CAKUT may be improved using genetic diagnostic techniques.
Figure 1. Forms of CAKUT presenting in perinatal cases.Congenital renal anomalies found in fetal, neonatal, and pediatric cohorts included a broad spectrum of malformations affecting the renal parenchyma, ureters, and lower urinary tract. The proportion of cases found to have genetic disorders by WES did not differ significantly across these categories.
Table 1. Demographic characteristics of CAKUT cases.Cases were recruited from fetal, neonatal, and pediatric cohorts. Similar distributions of CAKUT manifestations were found in all cohorts. There was a preponderance of male cases in part due to urinary tract dilation from posterior urethral valves. No features were found to confer a statistically significant higher risk of genetic disorder diagnosed by WES.