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 GARDNER AND SUTHERLAND’S
CHROMOSOME ABNORMALITIES
AND GENETIC COUNSELING

2
OXFORD MONOGRAPHS ON MEDICAL GENETICS
General Editors:
JUDITH G. HALL PETER S. HARPER LOUANNE HUDGKINS EVAN EICHLER CHARLES J.
EPSTEIN (DECEASED 2011) ARNO G. MOTULSKY (RESIGNED 2011)

1. R. B. McConnell: The genetics of gastrointestinal disorders

2. A. C. Kopéc: The distribution of the blood groups in the United Kingdom
3. E. Slater and V. A. Cowie: The genetics of mental disorders
4. C. O. Carter and T. J. Fairbank: The genetics of locomotor disorders
5. A. E. Mourant, A. C. Kopéc, and K. Domaniewska-Sobezak: The distribution
of the human blood groups and other polymorphisms
6. A. E. Mourant, A. C. Kopéc, and K. Domaniewska-Sobezak: Blood groups and
diseases
7. A. G. Steinbert and C. E. Cook: The distribution of the human immunoglobulin
allotypes
8. D. Tills, A. C. Kopéc, and R. E. Tills: The distribution of the human blood
groups and other polymorphisms: Supplement I
10. D. Z. Loesch: Quantitative dermatoglyphics: Classification, genetics, and
pathology
11. D. J. Bond and A. C. Chandley: Aneuploidy
12. P. F. Benson and A. H. Fensom: Genetic biochemical disorders
13. G. R. Sutherland and F. Hecht: Fragile sites on human chromosomes
14. M. d’A Crawfurd: The genetics of renal tract disorders
16. C. R. Scriver and B. Child: Garrod’s inborn factors in disease
18. M. Baraitser: The genetics of neurological disorders
19. R. J. Gorlin, M. M. Cohen, Jr., and L. S. Levin: Syndromes of the head and
neck, third edition
21. D. Warburton, J. Byrne, and N. Canki: Chromosome anomalies and prenatal
development: An atlas
22. J. J. Nora, K. Berg, and A. H. Nora: Cardiovascular disease: Genetics,
epidemiology, and prevention
24. A. E. H. Emery: Duchenne muscular dystrophy, second edition
25. E. G. D. Tuddenham and D. N. Cooper: The molecular genetics of haemostasis
and its inherited disorders
26. A. Boué: Foetal medicine
27. R. E. Stevenson, J. G. Hall, and R. M. Goodman: Human malformations
28. R. J. Gorlin, H. V. Toriello, and M. M. Cohen, Jr.: Hereditary hearing loss and
its syndromes
29. R. J. M. Gardner and G. R. Sutherland: Chromosomes abnormalities and
genetic counseling, second edition
30. A. S. Teebi and T. I. Farag: Genetic disorders among Arab populations
31. M. M. Cohen, Jr.: The child with multiple birth defects
32. W. W. Weber: Pharmacogenetics

3
33. V. P. Sybert: Genetic skin disorders
34. M. Baraitser: Genetics of neurological disorders, third edition
35. H. Ostrer: Non- Mendelian genetics in humans
36. E. Traboulsi: Genetic factors in human disease
37. G. L. Semenza: Transcription factors and human disease
38. L. Pinsky, R. P. Erickson, and R. N. Schimke: Genetic disorders of human
sexual development
39. R. E. Stevenson, C. E. Schwartz, and R. J. Schroer: X- linked mental
retardation
40. M. J. Khoury, W. Burke, and E. Thomson: Genetics and public health in the
21st century
41. J. Weil: Psychosocial genetic counseling
42. R. J. Gorlin, M. M. Cohen, Jr., and R. C. M. Hennekam: Syndromes of the head
and neck, fourth edition
43. M. M. Cohen, Jr., G. Neri, and R. Weksberg: Overgrowth syndromes
44. R. A. King, J. I. Rotter, and A. G. Motulsky: Genetic basis of common
diseases, second edition
45. G. P. Bates, P. S. Harper, and L. Jones: Huntington’s disease, third edition
46. R. J. M. Gardner and G. R. Sutherland: Chromosome abnormalities and genetic
counseling, third edition
47. I. J. Holt: Genetics of mitochondrial disease
48. F. Flinter, E. Maher, and A. Saggar- Malik: Genetics of renal disease
49. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn errors of
development: The molecular basis of clinical disorders of morphogenesis
50. H. V. Toriello, W. Reardon, and R. J. Gorlin: Hereditary hearing loss and its
syndromes, second edition
51. P. S. Harper: Landmarks in medical genetics
52. R. E. Stevenson and J. G. Hall: Human malformations and related anomalies,
second edition
53. D. Kumar and S. D. Weatherall: Genomics and clinical medicine
54. C. J. Epstein, R. P. Erickson, and A. Wynshaw-Boris: Inborn errors of
development: The molecular basis of clinical disorders of morphogenesis,
second edition
55. W. Weber: Pharmacogenetics, second edition
56. P. L. Beales, I. S. Farooqi, and S. O’Rahilly: The genetics of obesity syndromes
57. P. S. Harper: A short history of medical genetics
58. R. C. M. Hennekam, I. D. Krantz, and J. E. Allanson: Gorlin’s syndromes of
the head and neck, fifth edition
59. D. Kumar and P. Elliot: Principles and practices of cardiovascular genetics
60. V. P. Sybert: Genetic skin disorders, second edition
61. R. J. M. Gardner, G. R. Sutherland, and L. C. Shaffer: Chromosome
abnormalities and genetic counseling, fourth edition
62. D. Kumar: Genomics and health in the developing world
63. G. Bates, S. Tabrizi, and L. Jones: Huntington’s disease, fourth edition

4
64. B. Lee and F. Scaglia: Inborn errors of metabolism: From neonatal screening
to metabolic pathways
65. D. Kumar and C. Eng: Genomic medicine, second edition
66. R. Stevenson, J. Hall, D. Everman, and B. Solomon: Human malformations
and related anomalies, third edition
67. R. Erickson and A. Wynshaw-Boris: Epstein’s inborn errors of development:
The molecular basis of clinical disorders of morphogenesis, third edition
68. C. Hollak and R. Lachmann: Inherited metabolic disease in adults: A clinical
guide
69. V. P. Sybert: Genetic skin disorders, third edition
70. R. J. M. Gardner and D. J. Amor: Gardner and Sutherland’s chromosome
abnormalities and genetic counseling, fifth edition

5
 GARDNER AND SUTHERLAND’S

Chromosome Abnormalities and

Genetic Counseling
FIFTH EDITION

R. J. McKinlay GARDNER
ADJUNCT PROFESSOR
CLINICAL GENETICS GROUP
UNIVERSITY OF OTAGO, DUNEDIN, NEW ZEALAND

David J. AMOR
LORENZO AND PAMELA GALLI CHAIR
UNIVERSITY OF MELBOURNE
VICTORIAN CLINICAL GENETICS SERVICES
MURDOCH CHILDREN’S RESEARCH INSTITUTE
ROYAL CHILDREN’S HOSPITAL, MELBOURNE, AUSTRALIA

6
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Published in the United States of America by Oxford University Press

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© Oxford University Press 2018

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted, in any form or by any means, without the prior permission in writing of Oxford
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You must not circulate this work in any other form and you must impose this same condition on any
acquirer.

Library of Congress Cataloging-in-Publication Data

Names: Gardner, R. J. M., author. | Amor, David J., author.
Title: Gardner and Sutherland’s chromosome abnormalities and genetic counseling / R. J. McKinlay
Gardner, David J. Amor.
Other titles: Chromosome abnormalities and genetic counseling | Oxford monographs on medical
genetics ; no. 70.
Description: Fifth edition. | Oxford ; New York : Oxford University Press, [2018] |
Series: Oxford monographs on medical genetics ; no. 70 | Preceded by Chromosome abnormalities
and genetic counseling / R.J. McKinlay Gardner, Grant R. Sutherland, Lisa G. Shaffer. c2012. |
Includes bibliographical references and index.
Identifiers: LCCN 2017034126 | ISBN 9780199329007 (hardcover : alk. paper) | ISBN
9780199329021 (epub)
Subjects: | MESH: Chromosome Aberrations | Genetic Counseling
Classification: LCC RB155.7 | NLM QS 677 | DDC 616/.042—dc23 LC record available at
https://lccn.loc.gov/2017034126

This material is not intended to be, and should not be considered, a substitute for medical or other
professional advice. Treatment for the conditions described in this material is highly dependent on
the individual circumstances. And, while this material is designed to offer accurate information with
respect to the subject matter covered and to be current as of the time it was written, research and
knowledge about medical and health issues is constantly evolving and dose schedules for
medications are being revised continually, with new side effects recognized and accounted for
regularly. Readers must therefore always check the product information and clinical procedures
with the most up-to-date published product information and data sheets provided by the
manufacturers and the most recent codes of conduct and safety regulation. The publisher and the
authors make no representations or warranties to readers, express or implied, as to the accuracy or
completeness of this material. Without limiting the foregoing, the publisher and the authors make
no representations or warranties as to the accuracy or efficacy of the drug dosages mentioned in the
material. The authors and the publisher do not accept, and expressly disclaim, any responsibility for
any liability, loss or risk that may be claimed or incurred as a consequence of the use and/or
application of any of the contents of this material.

7
 This book is dedicated to Jocelyn, Geoffrey, and Craig, their
parents, and all other families who seek our “chromosomal
advice.”

Jocelyn and Geoffrey (with lamb) have a partial trisomy for

chromosome 4 long arm, and Craig, the youngest, had a 46,XY
result on amniocentesis. Their father is a translocation carrier (see
Fig. 5–1, lower). Craig, since married, came to the genetic clinic

8
for confirmatory advice about his low genetic risk.

9
Heredity
Inescapably, this is me—the diagnosis
is cause for anger at those
who brightly say we choose our destinies.
There is no store
of courage, wit or will
can save me from myself and I must face
my children, feeling like
that wicked fairy, uninvited
at the christening, bestowing on my own,
amidst murmurs of apprehension, a most
unwanted gift—that
of a blighted mind. No one
could tell me of this curse when I
was young and dreamt of children
and the graces they would bear. Later,
it seemed that a chill morning
revealed deeper layers
of truth. For my romancing
there is a price to pay—
perhaps my children’s children
will pass this tollgate after me.
My grandmothers gaze down from their frames
on my wall, sadly wondering.
—Meg Campbell

Dear DNA
In real life you’re just
a tangle of white filaments
captured in a test-tube,
and your first photo is not flattering:
grey smudges like tractor tracks,
or a rusty screw. Yet
many say you are beautiful.
Online for a night
with a hundred fantastic portraits

10
and I’m head over heels
In love with you, DNA,
bewitched by your billions
coiled in my cells, transcribing,
replicating, mutating.
I see your never-ending dance.
A length of twisted ladder
briefly unwinds,
both strands duplicate,
each copy drifts away
on its secret mission
to make a thought, feel sunshine,
or digest this morning’s porridge.
Two winding parallel threads,
a tiny tangle of gossamer
designing my life.
DNA, you are astonishing
and I am yours truly.
—Winifred Kavalieris

Genes pass on our kind

But our selves are transmitted
In words left behind.
—J. Patrick Gookin

Curiosity is a virtue, perhaps an unsung and undervalued virtue, which

should be the energizing fuel to the thinking geneticist.
—Willie Reardon

Where is the wisdom we have lost in knowledge?

Where is the knowledge we have lost in information?
—T. S. Eliot

11
 PREFACE TO THE FIFTH EDITION

Chromosomal disorders have been, and will always be, with us; that is a
given. What is changing is our ability to recognize and detect them:
detection both in terms of the subtlety of abnormalities and of the means
we can use to find them. Classical cytogenetics has now well and truly
given way to “molecular karyotyping,” and this has been the extraordinary
development of the early twenty-first century. Readers will now be as
accustomed to molecular nomenclature in defining a segment, such as
chr5:1-18,500,000, as they had been to the classical description,
5p14.1→pter.
The very small deletions and duplications which molecular karyotyping
can now reveal have become familiar to the clinicians and counselors who
see patients and families in the clinic. A large number of these are now on
record, many attracting the nomenclature “copy number variant”: Some
are very well understood, others becoming so, and yet quite a few—
variants of uncertain significance, the acronym “VOUS” in daily parlance
—whose roles in human pathology are imperfectly appreciated. Many are
not in the same mold as the deletions and duplications of classical
cytogenetics, in which the single defect sufficed to cause a particular
phenotype, and always did so: We now need to take account of the concept
of incomplete penetrance, with some microdeletions or duplications not, of
themselves, always leading to an abnormal phenotype. Apparently
clinically normal parents may carry the same alteration as their child with
an abnormal phenotype. Digenic, or “two-hit,” mechanisms may now
require consideration. These were not formerly notions much entering into
the assessment of chromosomal disorders; discussion apropos in the clinic
presents a new challenge.
The number of “new” del/dup syndromes increases almost with each
issue of the clinical genetic journals. We include a mention of a
considerable number of these here (Chapter 14), not intending to create an
encyclopedic resource per se but believing that such a record may provide
a useful first point of contact when these cases are encountered in the
clinic. Copy number variants of uncertain significance, on the other hand,
we mostly take only a broad rather than a detailed view (Chapter 17); the

12
reader will need to consult other repositories for fuller information, as their
interpretations evolve.
The new (or now, established) laboratory methodologies blur the
boundaries between what might have been regarded as the classic
chromosomal abnormalities and Mendelian conditions. Some disorders
recorded as being due not only to segmental deletion/duplication affecting
a single locus but also to point mutation at that locus we continue to treat
as “chromosomal”; and for most, their place in this book is secure. But one
major category, the fragile X syndromes, are now seen as essentially
Mendelian disorders, their historic cytogenetic-based nomenclature
notwithstanding, and they no longer claim their chapter.
Peripheral blood and skin have been the tissues in common usage for
chromosome analysis, with an increasing role for cells got from the
convenient and painless “spit sample.” Prenatal diagnosis has been based
on amniocentesis and chorionic villus sampling, but latterly blastomeres
from early embryos, and fetal DNA in the maternal circulation, have
become targets for testing. Now we can anticipate the potential for whole
genome analysis to be applied to the prenatal diagnosis of the classic
aneuploidies, from a simple maternal blood sample, and this would widen
such testing very considerably. Questions such as these raise ethical issues,
and a literature on “chromosomal ethics” is accumulating.
As we have previously written, however marvelous may be these new
ways to test for chromosomes, the concerns of families remain essentially
the same. We may reproduce here the final paragraph of the Preface of the
first edition of this book, from 1989, as valid now as then:
Families pursue genetic counseling in an effort to demystify the mysterious.
If they did not want to “hear it all,” they would not bother with genetic
counseling. Families want an honest evaluation of what is known and what is
unknown, a clear explanation of all possibilities, both good and bad, and a
sensitive exploration of all available information with which they can make
knowledgeable decisions about future family planning. Thus, Bloch et al.
(1979) succinctly convey the essence of why people go to the genetic
counselor. We hope this book will assist counselors in their task.

Dunedin R.J.M.G.
Melbourne D.J.A.
February 2018

13
 ACKNOWLEDGMENTS

We thank John Barber, Rachel Beddow, Amber Boys, Cyril Chapman,

Jane Halliday, Jan Hodgson, Caroline Lintott, Nicole Martin, Belinda
McLaren, Fiona Norris, Mamoru Ozaki, Mark Pertile, Jenny Rhodes,
Sharyn Stock-Myer, and Jane Watt for their critical advice. We
acknowledge Lisa Shaffer, who was a co-author of the previous edition,
and much of whose work has flowed over into this edition. We have made
much use of the ideograms created by Nicole Chia. The length of the
Reference list, and the frequency with which we acknowledge, in legends
to figures, the courtesy of colleagues whose work we use, speaks for the
debt we owe to our colleagues in clinical cytogenetics worldwide.
Belatedly, R.J.M.G. thanks Ngaire Adams and Dianne Grimaldi, whose
need for chromosomal teaching at Dunedin Hospital in the 1980s provided
the germination for writing this book. We have appreciated the wise
guidance, and the patience and forbearance of Oxford University Press,
from Jeff House when this book made its first appearance, through to Chad
Zimmerman and Chloe Layman in this fifth edition. R.J.M.G. thanks his
wife Kelley for her patient help, once again, in document management;
and the front cover art, and most of the new illustrations in this edition,
have been drawn, or redrawn, by her.

14
 CONTENTS

PART ONE: BASIC CONCEPTS

1. Elements of Medical Cytogenetics
2. Chromosome Analysis
3. The Origins and Consequences of Chromosome Pathology
4. Deriving and Using a Risk Figure

PART TWO: PARENT OR CHILD WITH A CHROMOSOMAL

ABNORMALITY
5. Autosomal Reciprocal Translocations
6. Sex Chromosome Translocations
7. Robertsonian Translocations
8. Insertions
9. Inversions
10. Complex Chromosomal Rearrangements
11. Autosomal Ring Chromosomes
12. Centromere Fissions, Complementary Isochromosomes,
Telomeric Fusions, Balancing Supernumerary Chromosomes,
Neocentromeres, Jumping Translocations, and Chromothripsis
13. Down Syndrome, Other Full Aneuploidies, Polyploidy, and the
Influence of Parental Age
14. Autosomal Structural Rearrangements: Deletions and
Duplications
15. Sex Chromosome Aneuploidy and Structural Rearrangement
16. Chromosome Instability Syndromes

PART THREE: CHROMOSOME VARIANTS

15
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