17q12 Family Meeting families from 9 states

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1 8/5/04 7q Family Meeting 04 families from 9 states Genetics of the 7q Region Christa Lese Martin, PhD, FACMG August 8, 04 Many developmental issues have a genetic basis (learning, behavior, motor skills) Many developmental issues have a genetic basis (learning, behavior, motor skills) Single gene, Mendelian (fragile X FMR; PTEN) 0% Chromosomal 5-0% Unknown cause (unidentified genes, multiple gene interactions, environment) Single gene, Mendelian (fragile X FMR; PTEN) 0% Chromosomal 5-0% Unknown cause (unidentified genes, multiple gene interactions, environment) G-banded Karyotype Analysis Genetic material (DNA) is organized into chromosomes G-banded chromosome analysis: Each chromosome (-,X,Y) equal to a state Karyotype image courtesy of N. Chia, ISCN 005

2 8/5/04 Example of Common Chromosome Abnormality Trisomy Down syndrome Each chromosome is made up of multiple bands which can be rearranged, deleted or duplicated G-banded chromosome analysis: Each band equal to the larger cities in each state chromosome band q3 Could see if something is wrong with Philadelphia or Pittsburgh but not Lewisburg. Examples of Common Chromosome Abnormalities A new technology, chromosomal microarray, allows us to look at each city for every state across the U.S.! q Deletion q Deletion Resolution: Up to 00x s greater than G-banding. One of the first clinically relevant successes of the Human Genome Project Increasing the Resolution for Detecting Chromosome Imbalances Whole Genome by Microarray Whole Genome by G-banding 7q (only detectable using microarray) Array image source Agilent Technologies Ledbetter, NEJM 008

3 8/5/04 7q Deletion Microarray Results 7q Region.4 Mb 7q Region.4 Mb similar DNA sequences similar DNA sequences 3

4 8/5/04 7q Duplication 7q Deletion 7q Duplication 7q Deletion and 7q Region.4 Mb 7q Region.4 Mb Since dels and dups of 7q are mediated by this recurrent mechanism, all individuals with these rearrangements have the EXACT same region deleted or duplicated. (This is in contrast to most chromosome rearrangements that have random, rather than recurrent breakpoints) 5 genes deleted or duplicated Del and dup cause different clinical features 4

5 8/5/04 7q Genes How does knowing the genetic cause help? ZNHIT3 MY09 PIGW GGNBP DHRS MRM LHX AATF ACACA C7orf78 TADAA DUSP4 SYNRG DDX5 HNFB Only gene in region associated with defined clinical features: Renal cysts and diabetes (RCAD) 5 Building bridges for a complete diagnosis A behavioral diagnosis alone only tells you WHAT not WHY image modified from hrvoice.org Behavioral vs. Etiological Diagnosis Goals of 7q Initiative Identify medical, cognitive, neural and behavioral profiles shared by this genetically well defined group to inform and improve treatment and care. Some questions to be explored: Autism Autism Autism Fragile X syndrome q. del 7q del Define etiology Targeted medical monitoring Develop etiology specific interventions What explains the phenotypic heterogeneity within the group of individuals with deletion or duplication of 7q? What other genes are contributing to the phenotype? What is the natural history and longitudinal course? Acknowledgements David Ledbetter, PhD Tom Challman, MD Inoka Devapriya, MD Megan Epler, BA David Evans, PhD Andy Faucett, MS Brenda Finucane, MS Geisinger Health System Barb Haas-Givler, MEd Laina Lusk, BS Steve Martin, BS Marissa Mitchel, MS Scott Myers, MD Erin Riggs, MS Missy Slane, MS Yale Daniel Moreno De Luca, MD Grant Support NIH/NIMH RO MH Simons Foundation SFARI Awards 4043,