Preventive Genetics Sharad Gogate
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1Preventive Genetics
Editor Sharad Gogate MD DGO DFP FCPS FICS Director Surlata Hospital and Fetal Medicine Consultancy Services Mahim, Mumbai 400 076, India Forewords Joe Leigh Simpson Rustom P Soonawala
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Preventive Genetics
© 2006, Sharad Gogate
All rights reserved. No part of this publication should be reproduced, stored in a retrieval system, or transmitted in any form or by any means: electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the editor and the publisher.
This book has been published in good faith that the material provided by contributors is original. Every effort is made to ensure accuracy of material, but the publisher, printer and editor will not be held responsible for any inadvertent error(s). In case of any dispute, all legal matters to be settled under Delhi jurisdiction only.
First Edition: 2006
9788180617669
Typeset at JPBMP typesetting unit
Printed at Gopsons Paper Ltd, Noida
3This book is humbly dedicated to those countless women who are burdened with most difficult task of bearing, rearing and managing physically and mentally challenged children!
4Contributors 7Foreword
Genetics was once not preventive at all. It was only reactive. Other than avoiding pregnancy, no reproductive options existed for women having an affected offspring. Antenatal management was unimaginable. If a child with a genetic problem was born within a given family, recurrence risks may or may not have been available. If they were, there was little else a physician could do except provide succor.
The first step toward true genetic prevention was neonatal screening for phenylketonuria, introduced in the 1950s. Although this constituted proof of principle that genetic screening could be conducted and its ancillary problems handled, it was not until invasive antenatal diagnosis through amniocentesis was initiated a decade later (1968) that preventive genetics would become a practical reality for the obstetrician-gynecologist. Second trimester amniocentesis was followed some 15 years later by first trimester chorion villous sampling, now increasingly the preferred approach. Invasive prenatal diagnosis was soon accompanied by therapeutic attempts in utero, biochemical as well as surgical. Concurrently, efforts began before conception to identify couples at increased risk for autosomal recessive disorders. Heterozygote identification in selected ethnic groups was thus offered for Tay Sachs disease, β- and α-thalassemias and sickle cell anemia. Overall, it became feasible to identify couples at risks not simply after birth of an affected child, but rather before. That is, survey the entire population.
In this volume, Sharad Gogate encompasses the field of prenatal preventive genetics, with particular emphasis on advances in India. As an obstetrician-gynecologist and a prenatal diagnostician skilled in invasive procedures and therapeutic management, Dr. Gogate is ideally suited to edit this volume. His own preface takes us chapter by chapter over what the reader can expect. It is necessary only that I point out a few unique aspects of this volume, offered by a Western observer.
Early in the book Drs. Verma and Sankaranarayanan enumerate the impressive contributions of Indian scientists. A rich legacy of genetics has emanated from India, particularly in botany. This has now been leveraged into medical (preventive) genetics. The 2-3% frequency of major birth defects in India is not different from that in Western countries, but is confounded by advanced maternal age and consanguinity in some locations. Highly accurate data is being gathered concerning specific 8malformations in different regions, and will influence public policy. Birth defects registers are being set up, pioneered by Dr. Suresh.
Preventive genetics next covers the principles of counseling, pivotal for all genetic screening programs: aneuploidy, neural tube defects, β-thalassemia and metabolic diseases. Technical details are next provided in sections IV and V: ultrasound, cytogenetics, preimplantation genetics, recovery of fetal cells and cell-free DNA. Antenatal and postnatal management of genetic conditions is next discussed by international authorities in their respective field.
The value of preventive genetics has long been clear to the individual couple. To them a diagnosis is either zero or 100%. Statistical nuances are of little comfort if their child is affected. Using preventive genetics, not just the individual couple but the entire population becomes involved. Fortunately, offering genetic services to the entire population is now occurring in more and more countries. As the standard of living rises in developing countries, the focus changes from individual medical advances applicable to individuals having resources to the broader public. When the infant mortality rate remains 100 per 100,000 births or greater, a country’s priority naturally must involve preventing neonatal morbidity and mortality caused by infections and childbirth. High rates of maternal mortality typically accompany high infant mortality rates. As infant and maternal mortality rates fall, priorities change. When the infant mortality rate becomes 20-40/100,000, the relative contribution of birth defects to a country’s health burden becomes greater. It is now cost effective to screen for genetic disorders and treat neonates with birth defects. This yields productive citizens rather than ostracized children. Preventing birth defects through prenatal genetic diagnosis and treatment is likewise appropriate. Parents confident that their offspring will not only survive but usually be normal will restrict their family size, relieving population pressure. Resources then can be diverted to improve the citizenry as a whole.
To this Western observer, India is at the fulcrum of widespread genetic application. The future is bright for screening and preventive genetics. This volume is thus timely and authoritative. The editor and his contributors are to be congratulated.
Joe Leigh Simpson MD
Ernst W. Bertner Chairman and Professor
Department of Obstetrics and Gynecology
Professor, Department of Molecular and Human Genetics
Baylor College of Medicine
Houston, Texas, USA
9Foreword
It gives me great pleasure to write this foreword for this book edited by Dr Sharad Gogate on the vital topic of “Preventive Genetics”.
It is the duty of every doctor, particularly an obstetrician, to ensure that every pregnant woman goes through the process of pregnancy and child birth in the most comfortable, safe manner and gives birth to a healthy baby. Though a comprehensive Maternal Child Health program can prevent and treat complications like anaemia, malnutrition, prematurity, we cannot prevent the morbidity and mortality due to birth defects and genetic disorders. There is a 1-2% risk of such defects at birth, considering that huge and over populated country of over 1 billion and annual birth of over 25 million babies, it is a huge burden on the society. This causes a huge pregnancy wastage, increases infant mortality and morbidity. Some of these disorders like Intra Uterine Growth Restriction can have far reaching effects like Diabetes mellitus, Obesity, Cardiac diseases and Certain cancers. This can be a serious public health hazard. In India and other developing countries, where maternal malnutrition and lack of high quality antenatal care in remote rural areas this problem is assuming huge proportions.
The only way to avoid such catastrophic situation is to spread the awareness of genetic disorders and birth defects in all strata of society, entire nations and make facilities for screening, early diagnosis and management of these genetic problems available freely at affordable cost. This is possible only by incorporating component of preventive genetics in the maternal and child health program at all levels of health care.
It is no more a search and destroy birth defects policy! It is more like suspect screen/diagnose, treat and (if possible), prevent genetic disorders/birth defects!
This publication “Preventive Genetics” should find a prominent place in this endeavor as it is a well conceived and well written reference book. Most of the aspects screening, prevention and management of genetic disorders, and birth defects, at all stages of life are extensively covered by a galaxy of eminent specialists who have penned these chapters.
The introductory chapter, written by the editor himself, effectively conveys the basic concept of Preventive Genetics, it’s applicability at macro-level as well as individual patient evaluation and how it can be effectively implemented in holistic manner.
10First section on population genetics has been ably covered by eminent authors. It elaborates on public health concerns about genetic defects, gravity of burden of genetic disorders and the vital role of Birth Defects registry in the program.
The section on Genetic counseling is also very useful and covers all aspects of genetic counseling.
Section of screening programs covers major diseases of clinical concern viz. Down’s and NTD, Thalassemia and Inborn Errors of Metabolism. This will be useful to us for evolving screening programs.
All important section on Ultrasonography and other imaging modalities is very well written and illustrated by three very senior and internationally renowned from Greece, Italy and Singapore.
Fifth section covers various laboratory technologies used in diagnosis of genetic disorders like Cytogenetics, Molecular genetics and pre-implantation genetic diagnosis, these are ably covered by very senior scientists. The emphasis is on clinical applications and interpretation of these technologies. The new areas in genetics like Fetal cells and cell-free DNA and impact of Human Genome Project are written by senior stalwarts like Prof Simpson and Prof Pergament and are very informative. How onco-genetics can help in prevention or more efficient management of various cancers is well elucidated in the chapter written by one of our young but dynamic scientists from Mumbai. Topic of congenital microbial infections gives good guidelines for screening, early diagnosis of congenital infections.
Next two sections deal with antenatal and post-natal management of genetic disorders. Importance of multi-specialty approach for efficient management is explained by Dr Deka, the difficult topic of Recurrent Pregnancy Loss is handled comprehensively by Dr Pankaj Desai, who is an authority on this topic. Prof Rodeck, pioneer in the Fetal therapy has contributed an excellent chapter on recent advances in Fetal therapy.
In India the era of Fetal therapy is just dawning! As of now we have to manage most of the fetal anomalies after delivery. Two well known pediatric surgeons from Mumbai have nicely shown the surgical management of birth defects.
The essay by Dr Snehalata Deshmukh, a highly decorated pediatric surgeon and academician, on Antenatal Learning is very exciting and holds great promise.
In the epilogue, future of Preventive genetics initiative is envisaged enthusiastically by Sharad.
Now a little bit about the editor!
11I know Sharad for last three decades as he was my student in medical school and I have seen him mature into an excellent clinician, capable research worker and a good human being! He is keenly interested in the field of prenatal diagnosis and fetal medicine. He was one of the key figures, who foresaw the future of these important streams in clinical medicine and showed great foresight in founding the “Indian Society for Prenatal Diagnosis and Therapy” in 1989. He has played a major role, not only in setting up and nurturing this organization to it’s present national and international stature (he is the founder Secretary General of Indian Society for Prenatal Diagnosis and Therapy), but also in spreading the message of Fetal medicine and Genetic diagnosis and therapy at national and international levels.
I feel that this book will be an excellent reference material for persons, from various educational streams, who want to contribute toward the goal of Healthy Mother and Healthy Child.
I wish this book a great success!
Dr Rustom P Soonawala
MD FRCS FRCOG
Dr Soonawala Clinic
Pashmina, Pedder Road
Mumbai, India
12Preface
My sojourn with Prenatal Diagnosis and Fetal medicine started way back in 1973-74. I had just passed my postgraduate exams in Obstetrics and Gynaecology. One of my respected teachers Dr Shirish Sheth, who is the past President of FIGO, inducted me in a research project on prenatal diagnosis of chromosomal anomalies by amniotic fluid culture. Being a rather unknown and not so popular topic at that time, I was ridiculed for wasting my time by my colleagues! But I persisted and actually enjoyed the project. I was fascinated by this new area and continued to work in the field. In 1984 I attended an international workshop on Laboratory Techniques in Prenatal Diagnosis at New Delhi and this really motivated me to make a lifetime career in the field of clinical genetics and fetal medicine.
To learn more I went to King’s College, London, UK in 1985 for a short fellowship and came in close contact with Prof. Charles Rodeck, Prof. Kypros Nicolides and learned the techniques of Fetoscopy and other interventional procedures. As a result they became my role models! As the field of prenatal diagnosis and therapy was quite unknown and neglected in India, many of the workers in this field like Dr Rustom Soonawala (an internationally known, highly decorated clinician and my guide and mentor), Dr Hema Purandare, Dr Amit Chakravarty, myself and others formed a national forum “Indian Society for Prenatal-Diagnosis and Therapy” (ISPAT) in 1989 in Mumbai. The society became a rallying point for the nascent specialty of Fetal Medicine and Prenatal Diagnosis and attracted all the workers trying to promote this speciality. The society has organized till date several national conferences, workshops and seminars across the country with a galaxy of international and national clinicians and scientists as the faculty. We also hosted the conference of “International Society for Prenatal Diagnosis” (ISPD) in 1996 at Goa, India which was highly acclaimed for it’s high scientific contents and excellent organization. All of these activities focused attention and popularized the fields of Prenatal Diagnosis and Fetal Medicine all over the country.
I was inducted in the “International Foetoscopy Working Group” by Prof. Joe Leigh Simpson, an eminent scientists and clinician from Baylor College of Medicine, Houston, USA, in 1994. This really broadened my horizons and I could present local and national data as well as learn from 13the rich interaction with the stalwarts from the field, this has been a great learning experience! I am grateful to Prof. Joe Leigh for giving this opportunity.
All through out this period I have been feeling the need for a comprehensive reference book for clinicians, laboratory personnel and undergraduate and postgraduate students and lay public. Which will cover the different aspects of screening, diagnosis and comprehensive management of complex genetic disorders and birth defects, with special emphasis on prevention. So I conceived the idea last year of editing a book on “Preventive Genetics” and was heartened to get a positive response from many of my colleagues in India and abroad.
 
ORGANIZATION OF THE BOOK
In the opening chapter I have taken an overview of the concept and practice of Preventive Genetics, both at macro and micro levels. I have also elaborated on how we can implement preventive genetics program at all stages of our life so as to make a concerted effort to down-stage the genetic disorders (whereever possible). So as to avoid the risk of recurrence.
The first section covers important topic of “Burden of Genetic Disorders in India” written by Dr IC Verma, one of the pioneers in the country in the field of clinical and laboratory genetics. The chapter on Public health aspect of preventive genetics is effectively covered by Dr S Sankaranarayanan, a Senior Professor in Preventive Medicine from Mumbai. Dr S Suresh, who has set-up the first national registry in the country, covers the important topic of role of birth defects registry in prevention of genetic defects.
Second section deals with genetic counseling, a core activity in the program; this is effectively covered by Prof David Chitayat from Toronto, Canada, covering pre-conception counseling and Dr Leena Gole from Singapore, who covers pre-testing and pre-procedure counseling. Other aspects of counseling are covered by other authors in their respective chapters.
Section three covers screening programs for genetic disorders, with Prof H Cuckle, a pioneer in the maternal serum screening scenario, covering Down’s and NTD screening. Dr Amit Chakravarty, my close personal friend, covers population screening and prevention of Thalassemia with overview of Indian scenario. The vital aspect of population screening of Inborn Errors of Metabolism is covered by Prof Taranath Shetty from NIMHANS, Bangalore.
14 Fourth section deals with imaging for screening for genetic disorders and birth defects and we have Prof Aris Antsaklis from Athens, Greece and Dr Anandkumar from Singapore, both well known authorities on the topic. Dr Brambati Bruno from Milan, Italy, who has been a pioneer in first trimester invasive techniques and a close friend, covers various fetal tissue sampling procedures comprehensively.
The fifth section includes chapters on different laboratory techniques. Dr Hema Purandare, my colleague for last two and half decades, shares her vast experience in Cytogenetic testing and clinical interpretation. Dr Leena Gole from Singapore elaborates on the Molecular Genetic tests. While Dr Vincenzo Trengia, a young but talented worker in prenatal diagnosis and fetal therapy, covers important area of Preimplantation Genetic Diagnosis with special reference to Thalassemia prevention. Prof Joe Leigh Simpson, who has done pioneering work in field of study of Fetal cells in maternal blood, elaborates on this vital topic. Rapidly expanding field of Onco-Genetics is tackled by Dr Pratibha Amare, eminent scientist from Tata Memorial Hospital, Mumbai. Microbial infections are not actually part of genetic disorders, but they are important causes of pregnancy loss, well-defined anomaly syndromes and significant fetal morbidity and mortality. Hence, I have included them in this book. This chapter is contributed by Prof Alka Gogate, my better half, from Mumbai. The exciting topic of Human Genome Project is covered by Prof. Eugene Pergament, who has been closely associated with the project.
Sixth section is about antenatal management of birth deformities and genetic disorders. Prof Deepika Deka stresses the important of multi-specialty approach in seamless management of high-risk disorders. Pankaj D Desai The emerging Fetal Therapy is covered by Prof Charles Rodeck, who has been a pioneer in the field of Fetoscopic therapy. We have two senior Pediatric Surgeons Dr Mathure and Dr Rege from Mumbai penning the chapter of surgical management of fetal anomalies. The ancient Indian concept of “Garbha Sanskar” (antenatal learning) is presented by Dr Snehalata Deshmukh, who has been working on this concept for last several years.
Seventh section is about the neonatal evaluation and management. Newborn screening and evaluation of IEMs and other genetic disorders is covered by Dr BN Apte, who has over two decades of experience in this area. Dr Sudha Sane, a senior Perinatal Pathologist from Mumbai, stresses the importance of perinatal pathology and postmortem study. Lack of proper antenatal care and maternal malnutrition leads to risk of Intra-Uterine 15Growth Restriction (IUGR), especially in developing countries. The association between fetal growth disorders and adult diseases like Diabetes, Coronary heart disease, Obesity is discussed by Dr RD Potdar, who is closely associated with on-going evaluation and prevention of this phenomenon.
Vexing ethical and philosophical dilemmas in pre- and postnatal genetic management is tackled by Dr Mahendra Parikh, an authority on this topic.
Eighth section is an epilogue in which I have taken a bird’s eye view of the future scenario in the newly evolved faculty of “preventive genetics” and how it will shape the way we will practice clinical medicine in the future.
As this is a multi-authored book it reflects different perspectives of each individual, his/her unique style. Some amount of duplication is but in-evitable in such a multi-authored book. This should re-emphasize those points for the reader.
I wish to close my preface with this ancient Sanskrit invocation, which says
It means “Leteverybody in the universe be happy, free of diseases anddiscomfort, see and perceive only good things and be free of any sorrow”.
Sharad Gogate
16Acknowledgments
I would like to thank Prof Joe Leigh Simpson and Dr Rustom Soonawala for sparing valuable time to write the foreword for the book as well as constantly encouraging me to bring out this book.
I would also express my sincere thanks to all the contributors who not only wrote the excellent chapters in spite of their heavy schedules but also for good naturedly tolerated my constant hounding for timely dispatch of their manuscripts.
I would also appreciate the high quality printing as well as cooperation and patience shown by my Publishers M/s Jaypee Brothers Medical Publishers Pvt Ltd. I would take this opportunity to express my sincere thanks to Mr Tarun Duneja, General Manager Publishing, Ms Yashu Kapoor, Ms Geeta Srivastava, Ms Anju Saxena and Ms Mubeen Bano, who helped me in compiling and editing this book.
I am also grateful to my family Adheet, Sonal and especially my wife Alka, who has been constantly pushing me to take on new challenges and always aim high. If not for her constant prodding and encouragement, I would have not achieved this ambition of editing this book on such an important topic so close to my heart!