The aims of this project are to apply genetic approaches to elucidate the molecular mechanisms underlying human renal agenesis/hypodysplasia. Renal developmental disorders are the most common causes of cases of end stage renal disease (ESRD) in children. Familial aggregation of renal hypoplasia/agenesis suggests that genetic factors are important in the development of this disorder. We have recruited 15 large kindreds ascertained via an index case with agenesis/ hypoplasia;these kindreds demonstrate transmission consistent with autosomal dominant inheritance with reduced penetrance. We have performed a genome-wide scan and analysis of linkage and have detected linkage to chromosome 1p32-33 and another locus under a model of dominant inheritance with locus heterogeneity (peak lod score 3.9 with 45% of families linked). Importantly, the first family (K100) supports linkage to the 1p33-32 interval on its own. Fine mapping of the interval with 26 microsatellite markers confirmed the trait locus to a 7 Mb interval containing 52 genes. In a second large dominant pedigree, we have also localized a second gene for this phenotype on chromosome three. We have also recruited additional patients with sporadic forms of disease to study the role of genes in such cohorts. In the current proposal, we will continue to characterize and recruit patients with familial and sporadic renal hypoplasia. We will also annotate and prioritize genes in the chr 1 and chr 3 interval and proceed with sequencing of the positional candidates to identify underlying gene(s). Once the gene has been identified, we will examine the contribution of this gene to sporadic forms of renal hypoplasia. In addition, we will search for chromosomal structural variations as a underlying cause of sporadic disease. Identification of the gene(s) for hypoplasia will provide insight in the biology of urogenital development. Moreover, it will provide the opportunity to develop novel diagnostic and therapeutic tools for this common clinical disorder.
| Sanna-Cherchi, Simone; Westland, Rik; Ghiggeri, Gian Marco et al. (2018) Genetic basis of human congenital anomalies of the kidney and urinary tract. J Clin Invest 128:4-15 |
| Winawer, Melodie R; Griffin, Nicole G; Samanamud, Jorge et al. (2018) Somatic SLC35A2 variants in the brain are associated with intractable neocortical epilepsy. Ann Neurol 83:1133-1146 |
| Groopman, Emily E; Rasouly, Hila Milo; Gharavi, Ali G (2018) Genomic medicine for kidney disease. Nat Rev Nephrol 14:83-104 |
| Sanna-Cherchi, Simone; Khan, Kamal; Westland, Rik et al. (2017) Exome-wide Association Study Identifies GREB1L Mutations in Congenital Kidney Malformations. Am J Hum Genet 101:789-802 |
| Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754 |
| Verbitsky, Miguel; Kogon, Amy J; Matheson, Matthew et al. (2017) Genomic Disorders and Neurocognitive Impairment in Pediatric CKD. J Am Soc Nephrol 28:2303-2309 |
| Verbitsky, Miguel; Sanna-Cherchi, Simone; Fasel, David A et al. (2015) Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest 125:2171-8 |
| Prakash, Sindhuri; Gharavi, Ali G (2015) Diagnosing kidney disease in the genetic era. Curr Opin Nephrol Hypertens 24:380-7 |
| Materna-Kiryluk, Anna; Kiryluk, Krzysztof; Burgess, Katelyn E et al. (2014) The emerging role of genomics in the diagnosis and workup of congenital urinary tract defects: a novel deletion syndrome on chromosome 3q13.31-22.1. Pediatr Nephrol 29:257-67 |
| Sanna-Cherchi, Simone; Sampogna, Rosemary V; Papeta, Natalia et al. (2013) Mutations in DSTYK and dominant urinary tract malformations. N Engl J Med 369:621-9 |
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