1007A Abramson Research Center The Children's Hospital of Philadelphia 3615 Civic Center Blvd.

CytoGenomic Diagnostics, copy number variation, cytogenetics

Etiology of pediatric disease, molecular analysis of Alagille syndrome (currently identifying modifiers of liver disease severity), genetic basis of biliary atresia, molecular analysis of ring chromosome 20.

Research Interests
Human Genetics, Notch signaling in human disease, Alagille syndrome, SNP array analysis, copy number variation, human disease gene identification by mapping deletions,

Key words: Jagged1, Notch Signaling, Alagille syndrome, chromosome deletions.

Description of Research
Our lab is interested in identifying genes that contribute to congenital disease. We have a long standing interest in Alagille syndrome, a genetic disorder that affects the heart and liver. We have demonstrated that this disorder is caused by two genes in the Notch Signaling Pathway, and have continued to study the effect of these mutations, and understand the clinical spectrum of defects in these disorders. Currently, we have begun a study to identify the genetic factors that influence the variation in liver disease severity seen in this disorder.

We are working on understanding the molecular basis of the clinical features observed in patients with ring chromosome 20 syndrome. We are working with Dr. Harold Riethman to clone the fusion points of the ring chromosomes to determine the mechanism of formation, and develop a molecular diagnostic test. We are looking to determine the mechanism by which ring chromosomes lead to human disease, especially for those rings with no deletions or duplications.

We have recently begun to utilize SNP array technology to identify genomic alterations associated with several phenotypes including biliary atresia, fetal death, and a variety of clinical abnormalities diagnosed in infancy or early childhood. We are interested in defining the range of genomic abnormalities that are disease causing.

Rotation Projects for 2009-2010

(possible examples, exact projects subject to discussion with PI)

1. Cloning of fibroblasts from a chimeric XX/XY individual suspected of having the XX cell line derived maternally (uniparental inheritance).
2. Expression analysis of chromosome 20 genes in cells from ring 20 patients.

Lab personnel:
Rob Bauer--grad student (GGR)
Ellen Tsai-grad student (GCB)
Laura Conlin, PhD, Fellow
Xia Li, PhD, Research Associate
Melissa Leyva-Veyga, MD, Fellow
Moira Crowley, MD, Fellow
Jennifer Gerfen, Technician
Annie Hutchinson, Project Coordinator

Professor of Pediatrics at the Children's Hospital of Philadelphia (2004 – 2009)
Professor of Pathology and Laboratory Medicine at the Children's Hospital of Philadelphia (2010– present)
Professor of Genetics at University of Pennsylvania School of Medicine (2004– present)
Assistant Professor of Genetics at University of Pennsylvania School of Medicine (1991 – 1998)
Assistant Professor of Pediatrics at the Children's Hospital of Philadelphia (1991 – 1998)
Associate Professor of Genetics at University of Pennsylvania School of Medicine (1998 – 2000)
Associate Professor of Pediatrics at the Children's Hospital of Philadelphia (1998 – 2004)
Ph.D., Genetics, University of California at Berkeley/San Diego State (1984)
B.A., Anthropology, Brandeis University (1975)
Selected Publications
Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K, O'Hara R, Casalunovo T, Conlin LK, D'Arcy M, Frackelton EC, Geiger EA, Haldeman-Englert C, Imielinski M, Kim CE, Medne L, Annaiah K, Bradfield JP, Dabaghyan E, Eckert A, Onyiah CC, Ostapenko S, Otieno FG, Santa E, Shaner JL, Skraban R, Smith RM, Elia J, Goldmuntz E, Spinner NB, Zackai EH, Chiavacci RM, Grundmeier R, Rappaport EF, Grant SF, White PS, Hakonarson H.. High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications.. Genome Research. Vol 19(9) . 2009 July:1682-90.
DeScipio C, Spinner NB, Kaur M, Yaeger D, Ambrosini, A, Hu S, Shan S, Conlin LK, Krantz ID, Riethman, H. Fine-Mapping Subtelomeric Deletions and Duplications by Comparative Genomic Hybridization in 42 Individuals.. Am J Med Genet A.. Vol 146. 2008:730-739.
Krantz ID and Spinner NB. (2007) Novel Microdeletion Syndromes.. Am J Med Genet C Semin Med Genet.. Vol 145C(4). 2007 Oct 1:323-326.
McDaniell R, Warthen DM, Piccoli DA, Sanchez-Lara M, Pai A, Krantz ID, Spinner NB. NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the Notch Signaling Pathway. Am J Hum Genet. Vol 79. 2006:19-173.
Venditti, CP, Hunt P, Donnenfeld A, Zackai E and Spinner NB. Mosaic paternal uniparental (iso)disomy for chromosome 20 associated with multiple anomalies. Am J Med Genet. Vol 124A. 2004:274-279.
Kamath BM, Bason L, Piccoli DA, Krantz ID, Spinner NB. Consequences of JAG1 mutations. J Med Genet. Vol 40(12) . 2003:891-5.
Lu, F-M, Morrissette, JJD, Spinner, NB. Conditional JAG1 mutation shows the developing heart is more sensitive than developing liver to JAG1 dosage. Am J Hum Genet. Vol 72. 2003:1065-68.
Morrissette, J.J.D., Colliton, R.P., Spinner, N.B.. Defective intracellular transport and processing of JAG1 missense mutation in Alagille syndrome. Hum Molec Genet. Vol 10. 2001:405-13.
Spinner, N.B.. Alagille syndrome and the Notch Signaling Pathway; New Insights into Human Development. Gastroenterology. Vol 116. 1999:1257-60.