Understanding the Aging Chromosome Dance cont.

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1 Research Update Wnter 2006 Research Update News from the Emory Down Syndrome Project at Emory Unversty Understandng the Agng Chromosome Dance EMORY DOWN SYNDROME PROJECT Who we are The people behnd the research Stephane Sherman, PhD Emory Down Syndrome Project Drector Lora Bean, PhD Down Syndrome and Congental Heart Defects Project Drector Salle Freeman, PhD Down Syndrome Clnc Drector Shelley Dlls, MS Down Syndrome Clnc Coordnator Jeanne Vsootsak, MD Down Syndrome Clnc Medcal Drector Helen Smth, RN, MSN Nurse Researcher Elzabeth Sablón, BSW Project Coordnator Trace Rosser, PhD Project Coordnator Cndy Oxford-Wrght, MS, CRC Research Consultant How to reach us Emory Down Syndrome Project Attn: Helen Smth Department of Human Genetcs 2165 North Decatur Road Decatur, GA Phone: Fax: Emal: The process of formng an egg or a sperm ncludes a complcated, but fascnatng, dance of the chromosomes called meoss. Each cell of the human body typcally contans 23 pars of chromosomes, for a total of 46, and meoss s the process that ensures each egg or sperm contans only half that total number one from each of the 23 pars of chromosomes. The reason ths s so mportant s that when a sperm and an egg unte to form an embryo each usually brngs ther 23 chromosomes for the new cells of the embryo, and these are combned to provde the necessary 46 chromosomes carryng all the genes that form the buldng blocks of our bodes. If you magne that the chromosomes are beng led through a dance, ths s what they mght hear ther choreographer sayng: COPY: All 46 chromosomes, copy yourselves, but don t let go. Glue your new sster tght to your sde. PAIR: Fnd your chromosome partner and make 23 pars. To the two tall and sknny chromosomes, you get together. You two short ones, now move together. The rest of you get the dea. Insde ths ssue: Understandng the Agng Chromosome Dance 1&2 The Down Syndrome Clnc at Emory Q&A 3 The Emory Down Syndrome and Congental Heart Defects Study 4 Congental Heart Defects and Folc Acd 4 What s a complete AVSD? 5 Understandng Genetcs 6 Gettng Involved 6 Our Msson Statement 7

2 Understandng the Agng Chromosome Dance cont. LOCK: Lnk arms wth your partner. (Remember you have four arms now, yours and your ssters. So you have dfferent ways to lnk together). Hold on tght! (For you eggs, hold on really tght, because you have to stay ths way for at least 10 years!) As you can see, ths s a very complcated dance, wth a lot of props and a lot of precse movements. When chromosome pars or ther sster pars are not pulled to the approprate cell, too many or too few chromosomes can end up n the egg or sperm. In some cases, ths can lead to Down syndrome, whch s due to one extra copy of chromosome 21, for a total of three (trsomy). DIVIDE: On my sgnal, all pars move to the center of the cell. Once you re there, each partner needs to grab a rope that s ted to a pole at each sde of the cell. One member of the par grabs the rope ted to the rght pole, the other one grabs the rope ted to the left pole. Now, pull yourselves to the opposte sde of the cell. We are dvdng equally to form two cells. Each cell now has 23 chromosome sster pars. You have lost your glue, but that should be ok. You are n the last steps of the dance. DIVIDE AGAIN: One more tme, on my sgnal, all ssters move to the center of the cell. Now, each sster, grab a rope and separate yourselves! Pull to the other sde of the cell. We are dvdng nto two more cells. Now each cell has 23 chromosomes. One mportant safety measure n the dance s lnkng chromosome arms together tghtly to stablze chromosome pars. For eggs, ths s especally mportant, snce the chromosome dance begns durng the fetal lfe of a female. Then the musc stops for years and only starts up agan when that egg s ovulated. If the chromosome pars do not lnk at all, or f they are lnked only by ther fngertps, they could become unstable. We have studed ths dance n eggs and focused on those lnks that hold the chromosome arms together durng the frst dance steps. We now know that these lnks (recombnatons, for the experts) are very mportant and ther locaton on the chromosome s key. We have found that lnks formed near the mddle of the chromosome protect the chromosome par from agng effects (sometmes referred to as maternal age effects ). There s evdence that some lnks become weaker and the ssters start comng unglued as they age that s, the glue degrades over tme. Lnks that occur closer to the rope attachment pont where the chromosome pars are pulled apart are susceptble to these agng effects. But a lnk formed n the mddle holds the chromosomes together better and protects those ssters from comng apart too early n the dance. On the other hand, lnks located at the end of the chromosomes (at ther fngertps ) are very weak. These weak lnks ncrease the chance that the ssters wll separate too early n the frst cell dvson, no matter how old the egg may be. We are now usng resources developed through the Human Genome Project to determne whether there are dfferences between these lnks other than just ther locaton. Ths research wll help us better understand the steps nvolved n egg formaton. Informaton gathered through our studes may be used to nvestgate fertlty problems that are related to the age of the egg. To reach ether goal would mean major advances n reproductve bology. We would lke to thank all those who have gracously partcpated n our studes for helpng us answer these mportant questons. RESEARCH UPDATE WINTER 2006 Page 2

3 The Down Syndrome Clnc at Emory: Questons and Answers The Down Syndrome Clnc at Emory Unversty celebrated ts fourth brthday n January To date, our clnc has scheduled over 250 new famly vsts. What age chldren are you currently seeng n your Down Syndrome Clnc? Whle our longrange goal s to see ndvduals of any age who have Down syndrome, we currently see chldren from brth to age fve years. How do I make a clnc appontment? To make an appontment call Shelley Dlls, Clnc Coordnator, at Spansh-speakng famles can call Elzabeth Sablon, our medcal nterpreter at We thnk t s mportant that parents make the appontment because that ntal phone call gves us the opportunty to explan the clnc and determne f there s nformaton about Down syndrome that the famly needs mmedately. If so, we can often provde t by phone or mal pror to ther clnc appontment. How s a vst to the Down Syndrome Clnc dfferent from a vst to a pedatrcan? We are not a substtute for a pedatrcan. As for any chld, your goal should be to select a pedatrcan whom you trust to provde all the best general pedatrc care and who wll be avalable for those nevtable mdnght earaches! Read on to fnd out more about our clnc. What does a clnc vst nclude? A revew of your chld s medcal hstory. When parents schedule an appontment, we ask for permsson to get ther chld s medcal records. Informaton from the brth hosptal, pedatrcan, and any specalsts helps us get to know your chld. For example, we can make sure that all recommended tests such as a hearng screen, thyrod test, and cardac evaluaton have been completed adequately. A dscusson of your chld s chromosome report. Parents often want to know more about how Down syndrome occurs, what an extra chromosome 21 means for ther chld, and f there s an ncreased chance of another chld n the famly havng Down syndrome A physcal exam. We complete a basc physcal exam of your chld and make a specal effort to answer any questons you have about features characterstc of Down syndrome. A developmental evaluaton. Our medcal drector, Dr. Jeanne Vsootsak, s a board-certfed developmental pedatrcan. After conductng a developmental screenng she dscusses her fndngs wth parents and makes recommendatons for the tmng and frequency of early nterventonal therapy (physcal, occupaton, speech/language). Each chld s an ndvdual wth developmental strengths and challenges. Our goal s to dentfy these strengths and challenges and In 2003, the Department of Human Genetcs at Emory Unversty establshed the Down Syndrome Center. make recommendatons to maxmze each chld s potental. An explanaton of the Healthcare Gudelnes for Chldren wth Down Syndrome. These natonal gudelnes provde parents and physcans wth a concse outlne of specal tems of care and ther tmng (e.g., cardac evaluaton, vson and hearng exams, thyrod tests.) Referrals. Based on each chld s medcal hstory, physcal examnaton, and developmental evaluaton, we suggest approprate specalsts f needed. Answer questons. Ths s perhaps the most mportant part of your vst. We urge parents to come wth ther questons. Each famly who vsts our clnc s n a dfferent place n terms of ther knowledge of Down syndrome and ther acceptance of the dagnoss for ther chld. We try to talor vsts to each famly s needs. Where s the Down Syndrome Clnc located? The clnc s located n our faclty just off the Emory Unversty campus near the corner of North Decatur and Clarmont Roads. The address s 2165 North Decatur Rd., Decatur, GA and parkng s easy! How do I fnd out more about the clnc? Shelley Dlls, Clnc Coordnator, wll be glad to answer questons related to the clnc ( , sdlls@genetc.emory.edu). Page 3 RESEARCH UPDATE WINTER 2006

4 The Emory Down Syndrome and Congental Heart Defects Study For several years researchers at Emory Unversty n the Departments of Human Genetcs and Pedatrcs have been workng together to understand why some chldren born wth Down syndrome also have a heart defect. We have worked wth the Sbley Heart Center and Chldren s Healthcare of Atlanta (CHOA) to dentfy chldren wth Down syndrome and an atroventrcular septal defect (AVSD or AV canal). Ths type of heart defect s rare n the general populaton but common among chldren wth Down syndrome. A study focused on the causes of heart defects s possble due to the network that we have bult through the Atlanta Down Syndrome Project ( ), Natonal Down Syndrome Project ( ) and Emory Down Syndrome Project (2005-present). Through these three studes, we have offered famles n the 5-county metro Atlanta area, as well as natonwde, the opportunty to partcpate n research. Dr. Ken Dooley, a pedatrc cardologst at the Sbley Heart Center, has worked wth our group to document the types of heart defects seen n chldren wth Down syndrome. Although many of the chldren n these studes are elgble for the heart study, addtonal famles needed to be dentfed. In 2004 fundng was granted by the Cardac Research Commttee at CHOA to dentfy chldren treated n Atlanta who were not elgble for the ongong metro-atlanta based studes. The response from Georga famles has been amazng. To date, 50 famles wth a chld who was treated at CHOA have completed the study. We have recently expanded our project to nclude famles wth a chld who has been treated at Columbus Chldren s Hosptal n Columbus, OH. Wth the help of pedatrc cardologst Dr. Clff Cua, an addtonal 14 famles from Oho have completed the study. More than 30 famles have been recruted through collaboraton wth Dr. George Capone at the Kennedy Kreger Insttute Down Syndrome Clnc. Congental Heart Defects and Folc Acd Last July representatves from our study attended the Down Syndrome Congress Conventon held n Atlanta. Nearly 30 famles from around the country expressed an nterest n partcpatng n our study. Overall, approxmately 150 famles wth a chld who has Down syndrome and an AVSD are partcpatng n our project. We have started to use varous genetcs methods to dentfy rsk factors for heart defects. Understandng why heart defects occur n chldren wth Down syndrome wll also help us to understand why heart defects occur n persons wthout Down syndrome. A research study cannot be successful wthout support from the medcal communty, ntensve efforts by researchers, and most mportantly the tme and effort of motvated famles. We are contnually mpressed by and thankful for the wllngness of busy famles to make tme for a study that wll someday beneft others. Thank you to all who have partcpated. For more nformaton, contact Dr. Lora Bean at (404) or lbean@genetcs.emory.edu. Folc acd, or folate, s a vtal detary nutrent. Insuffcent ntake of folc acd durng pregnancy ncreases the rsk of neural tube defects n the fetus. Snce 1998 the US food supply has been supplemented wth folc acd and women who are pregnant or plannng to become pregnant have been advsed to take folc acd supplements, usually n the form of prenatal vtamns. The process by whch folc acd s broken down and used n the body s complex. Folc acd s needed both durng fetal development and throughout lfe to make and repar DNA. Many genes contan nformaton for protens that play a role n folc acd processng. Human DNA s made up of long strngs of buldng blocks referred to as A, G, RESEARCH UPDATE WINTER 2006 C, and T. If, at a partcular poston n the DNA, some people have a C whle others have a T, the ste s called a varant. In the human populaton there are varants n genes that speed up or slow down folc acd processng. These varants are common and have been assocated wth many dseases ncludng congental heart defects. To nvestgate whether varants n folc acd processng genes play a role n heart defects n Down syndrome, DNA from approxmately 125 chldren wth Down syndrome and a complete atroventrcular septal defect (AVSD) and ther parents s beng compared to DNA from approxmately 125 chldren wth Down syndrome and no heart defect and ther parents. Varants n several genes necessary for folc acd processng are beng tested to determne whch varants each person has (a process called genotypng). The frequency of varants from two groups, those wth an AVSD and those wthout a heart defect, wll be compared. If one verson of a varant (.e. C ) occurs more often n cases than controls compared to the other verson of the varant (.e. T ), ths could ndcate that the C varant confers a hgher rsk for havng a heart defect wth Down syndrome. Ths genotypng study was made possble by an award from SeattleSNPs, a government-funded genotypng servce at the Unversty of Washngton, Seattle, WA. Results from ths study are expected soon. Page 4

5 What s a complete atroventrcular septal defect? The human heart s dvded nto four chambers the left and rght atra and the left and rght ventrcles - by a combnaton of septa (parttons) and valves. Ths heart structure ensures that blood enterng the heart from the body s pumped to the lungs to pck up oxygen, returned to the heart, and pumped back to the body for oxygen delvery. Rght Atrum Septum Valve Left atrum Valve Left Ventrcle Rght Ventrcle Septum Effcent heart functon s dependent upon the heart structures developng properly before brth. An atroventrcular septal defect (AVSD) occurs when both septa and both valves do not develop properly. The resultng underdeveloped heart has dffculty pumpng oxygen-carryng blood to the rest of the body. Ths heart defect requres surgcal repar. Dd you know? 40% of chldren born wth Down syndrome (or trsomy 21) have a congental heart defect (CHD). The most common form of CHD n Down syndrome s an atroventrcular septal defect (or AVSD) Chldren born wth Down syndrome are 2,000 tmes more lkely to have a complete AVSD than chldren wthout Down syndrome Page 5 RESEARCH UPDATE WINTER 2006

6 Study update Recrutment for the Natonal Down Syndrome Project (NDSP) has concluded and the frst artcle from ths collaboratve effort has been publshed (See abstract below.) The project nvolved sx states: Arkansas, Calforna, Georga, Iowa, New Jersey, and New York, and durng the four years of actve recrutment, NDSP enrolled 1884 famles n the study. We are contnung to analyze the data collected from ths ntatve and wll have further publcatons soon. Although the recrutment for the natonal project has ended, Emory s contnung to enroll study partcpants through ther new Emory Down Syndrome Project. Ths project began actvely recrutng n 2005 and has currently enrolled 68 famles. One new part of ths project s the Famly Study. We nvte sblngs and grandparents of chldren wth Down syndrome to partcpate. The goal s to understand more about the lnks, or recombnaton, between chromosomes (see "Understand the Agng "Chromosome Dance"). We are also contnung our efforts to dentfy rsk factors for congental heart defects among ndvduals wth Down syndrome. We have just receved fundng from the Natonal Heart, Lung and Blood Insttute and are collaboratng wth Johns Hopkns Unversty (Dr. Reeves, Wlhour and Brenner), Kennedy Kreger Insttute n Baltmore (Dr. Capone) and Oregon Health Scence Unversty (Dr. Maslen). We wll expand enrollment of ndvduals wth Down syndrome and a complete atrventrcular septal defect and those wth a structurally normal heart at all three stes. Ths combned effort wll enhance our ablty to dentfy genetc rsk factors and understand the mechansms that lead to abnormal heart development. Our Latest Publcaton The Natonal Down Syndrome Project: Desgn and Implementaton SB Freeman, PhD; EG Allen, PhD; CL Oxford-Wrght, MS; SW Tnker; C Druschel, MD, MPH; CA Hobbs, MD, PhD; LA O Leary, PhD; PA Romtt, PhD; MH Royle, PhD; CP Torfs, PhD; SL Sherman, PhD See complete artcle n: Publc Health Reports Jan-Feb; 122(1): Objectve. The Natonal Down Syndrome Project (NDSP), based at Emory Unversty n Atlanta, Georga, represents a mult-ste, populaton-based, case/control study wth two major ams: (1) to dentfy molecular and epdemologcal factors contrbutng to chromosome nondsjuncton and the consequent packagng of an extra chromosome nto an egg or sperm, and (2) to dentfy rsk factors for Down syndrome-assocated brth defects. Methods. The sx natonal stes represent approxmately 11% of U.S. brths. Cases were newborns wth Down syndrome (trsomy 21), and controls were nfants wthout major brth defects randomly selected from the same brth populatons. Bologcal samples were collected from case nfants and ther parents, and genetc markers were typed to determne the parental orgn of chromosome 21 nondsjuncton. Each ste ntervewed parents of case and control nfants addressng pregnancy, medcal and famly hstory, occupaton, and exposures. Stes collected medcal nformaton on case nfants. Results. The NDSP enrolled 907 nfants as cases and 977 nfants as controls (partcpaton rates: 60.7% for cases; 56.9% for controls). Partcpaton rates vared wdely by ste as dd mportant demographc factors such as maternal age, race, and educaton. Nondsjuncton durng oogeness accounted for 93.2% of the cases. Errors n spermatogeness were found n 4.1%, and 2.7% were post-zygotc errors. Conclusons. Ths exceptonal complaton of questonnare, clncal, and molecular data makes the NDSP a unque resource for ongong studes of the etology and phenotypc consequences of trsomy 21. The combned approach ncreases study power by defnng subgroups of cases by the orgn of nondsjuncton. Ths report descrbes the desgn and successful mplementaton of the NDSP. The Down Syndrome Center at Emory Unversty Announces our new webste: Please vst our webste for nformaton regardng: RESEARCH CLINICAL EDUCATION Down syndrome research at Emory Unversty The Emory Down Syndrome Clnc Educatonal resources For more nformaton, please call RESEARCH UPDATE WINTER 2006 Page 6

7 Understandng Genetcs Genotype & Phenotype Genotype: The genetc makeup of an ndvdual. Phenotype: Our anatomcal and physcal characterstcs. The nstructons contaned n the genotype determne the characterstcs that make us each unque ndvduals. In archtectural terms, the genotype s a set of buldng plans, and the phenotype s the fnshed buldng. Gettng Involved Enjoyng the Buddy Walk. (L to R) Alex Bean, Lora Bean, and Helen Smth Staffng the Down Syndrome Center booth at the Down Syndrome Congress Conference n Atlanta. (L to R) Helen Smth, Stephane Sherman, and Lora Bean. RESEARCH UPDATE WINTER 2006 Page 7

8 EMORY DOWN SYNDROME PROJECT Emory Unversty, Department of Genetcs 2165 North Decatur Road Decatur, GA Phone: Fax: Emal: Return Servce Requested Our Msson Statement Trsomy 21, the leadng cause of Down syndrome, occurs when a chld receves three copes of chromosome 21 nstead of the usual two copes. Ths s almost always due to a chromosome error durng the formaton of ether the egg or the sperm (see fgure at rght). Our frst goal s to dscover how these errors occur and dentfy rsk factors that affect ths process. Secondly, we want to understand why an extra chromosome 21 causes Down syndrome. We hope to dentfy specfc genes on chromosome 21 that alter development and produce the mental retardaton, congental heart defects, and other health problems assocated wth Down syndrome. Our hope s that ncreasng knowledge about Down syndrome wll beneft famles, educators, and health professonals. Both father and mother have the usual number of chromosomes, ncludng 2 copes of chromosome 21. Here we show only chromosome 21. The father s sperm have 1 copy of each par of chromosomes, ncludng chromosome 21. Occasonally, an egg or sperm s formed wth an extra copy of chromosome 21. The mother s eggs have 1 copy of each par of chromosomes, ncludng chromosome 21. Ths example shows the extra chromosome formng n the egg. Unon of ths egg wth an normal sperm leads to a chld wth 3 copes of chromosome 21 - trsomy 21 Down syndrome.