Human Chromosome Variation Heteromorphism,

Polymorphism and Pathogenesis, 2nd Edition

Visit the link below to download the full version of this book:

https://medidownload.com/product/human-chromosome-variation-heteromorphism-polym
orphism-and-pathogenesis-2nd-edition/

Click Download Now

Herman E. Wyandt Vijay S. Tonk
Genesys Diagnostics, Inc. Department of Pediatrics
Oakdale, CT Texas Tech University Health Sciences
USA Center
Lubbock, TX
Golder N. Wilson USA
Department of Pediatrics
Texas Tech University Health Sciences
Center
Lubbock, TX
USA

ISBN 978-981-10-3034-5 ISBN 978-981-10-3035-2 (eBook)

DOI 10.1007/978-981-10-3035-2
Library of Congress Control Number: 2017930279

1st edition: © Springer Science+Business Media B.V. 2012

2nd edition: © Springer Nature Singapore Pte Ltd. 2017
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part
of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations,
recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission
or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar
methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this
publication does not imply, even in the absence of a specific statement, that such names are exempt from
the relevant protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this
book are believed to be true and accurate at the date of publication. Neither the publisher nor the
authors or the editors give a warranty, express or implied, with respect to the material contained herein or
for any errors or omissions that may have been made. The publisher remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.

Printed on acid-free paper

This Springer imprint is published by Springer Nature

The registered company is Springer Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore
Foreword

Early experience in medicine quickly teaches the importance and challenges of

knowing what is normal. Comparisons between symmetrical body parts, similar to
side-by-side chromosome pairs, may help distinguish the difference between nor-
mal variation and abnormal findings. The greater the depth of detail in chromosome
and copy number variant [CNV] analyses, the more difficult it has become to
differentiate the polymorphic from the pathogenic change. Many claims of patho-
genic variants have been revised and been re-classified as benign or of uncertain
significance. The key theme of this important text aims to focus on the key dis-
tinction between pathogenic CNVs and chromosomal polymorphisms.
Microdeletions, and less so for microduplications, may be associated with
diverse phenotypes, including intellectual disability, congenital malformation,
autism, schizophrenia, and epilepsy. The remarkable different manifestations of a
microdeletion at a specific location, when compared to a duplication at the identical
position, remain to be fully explained. It is also a salutary lesson that a pathogenic
variant may not necessarily be pathogenic in patients with different genomic
backgrounds. Confounding our understanding of chromosomal and molecular
biology is the observation of recurrence of autism in siblings with different CNV
abnormalities. Unanswered questions remain in this context about etiology and
pathogenesis and the possible role of epigenetic factors. In this edition, the authors
have added a very helpful sequential chromosome tabulation of known CNVs with
associated phenotypic features. While undoubtedly many more microdeletion/
duplication syndromes will be described in the future, it is likely that the authors
have captured the most common and important syndromes.
Burgeoning technology, beyond the use of microarrays, include the increasing
use of high resolution analyses by whole exome sequencing and whole genome
sequencing. Although these analyses enable identification of single nucleotide
sequence changes, they have also revealed a wealth of variations that will engage
the attention of geneticists for many years to come. A valuable addition to this
volume are Chaps. 9–12, that provide knowledge and insight into the increasingly

v
vi Foreword

complex involvement of CNVs in the etiology and pathogenesis of single gene

diseases.
Excellent information and data, enriched in this edition by the addition of the
chapters on CNVs, will be of inestimable value to molecular cytogeneticists and all
who endeavor to understand the variations that, to a lesser or greater degree, render
us healthy. After all, epigenetic issues notwithstanding, are we not simply the sum
of our variants, hopefully mostly normal!

Aubrey Milunsky, MB.B.Ch., D.Sc., F.R.C.P., F.A.C.M.G., D.C.H.

Center for Human Genetics
Cambridge, MA, USA
and
Department of Obstetrics & Gynecology
Tufts University School of Medicine
Boston, MA, USA
Preface

In the Atlas of Human Chromosome Heteromorphisms, we emphasized the rapid

change in standards of care in clinical cytogenetics—“that today’s research almost
immediately becomes tomorrow’s clinical test. What was once unsolvable becomes
approachable with new technologies, almost before the… clinician or laboratory
director may be aware they are available.” This statement has proven remarkably
prophetic as microarray analysis and whole exome sequencing technologies have
been co-opted for clinical genetic testing, the former now endorsed as a standard of
care. The problems that justified survey of heteromorphic regions on chromosomes
to help distinguish benign from clinically significant variation have now been
extrapolated to high resolution DNA analyses. Just as the previous Atlases did not
provide a panacea for such problems, neither does the present volume, but we do
now add clinical genetic principles and case examples that help address the poly-
morphic versus pathogenic dilemma.
Standard methods of identifying most human chromosome abnormalities and
variants (heteromorphisms) have been in use for more than four decades. The
benign nature of heteromorphism of certain chromosomal regions was established
in early population studies and information has not been much improved since.
Although laboratories strove for longer chromosomes with higher band resolution,
these advancements did not significantly add new variants or aid in interpretation of
known variants detectable by standard light microscopy. Fluorescence in situ
hybridization (FISH) in the 1990s allowed better characterization of some variants
and revealed a few new variants that were not detectable by standard cytogenetic
methods. Likewise, however, they did not necessarily improve on the distinction
between variants that are clinically significant and those that are not.
Improved chip (array) technologies can detect copy number variants (CNVs) that
are widely dispersed throughout the human genome and are not detectable by
standard microscopy. CNVs are often produced by unequal crossing over at
“hotspots” with flanking repetitive DNA sequences. These submicroscopic
microdeletions and microduplications can be specified in exact numbers of

vii
viii Preface

nucleotides since the human genome project has specified the nucleotide sequence
for every chromosome (e. g., 1 to *250 million for chromosome 1). Large scale
personalized DNA sequencing defines another type of submicroscopic chromosome
change in the form of single nucleotide substitutions, alterations of several
nucleotides (like the 3-base pair deltaF508 mutation in cystic fibrosis), or complex
repetitive DNA rearrangements like the expanding triplet repeats associated with
the fragile site at Xq27. Deciding if these precisely specified CNVs or the single
nucleotide changes detected by massive parallel (NextGen) sequencing are poly-
morphic (benign CNVs or SNPs) or pathogenic remains difficult, and we supple-
ment clinical examples with conceptual criteria and database references to address
this problem.
Another example of chromosome change now explained by DNA sequence
difference are the “common” and “rare” chromosomal fragile sites, first observed in
the 1970s and given renewed interest by clinical relevance. Fragile sites on chro-
mosomes have been observed to occur in specific bands, under a variety of in vitro
conditions, including low folic acid, inhibition of folic acid metabolism, etc.
Molecular characterization of the fragile Xq27.3 site associated with X-linked
mental retardation provided a new mechanism for genetic disease (expanding DNA
repeats), but most fragile sites have no direct clinical association. Common or rare
(<5% of individuals) fragile sites can be induced in cultured cells from most people,
and it is well known that they occur at sites frequently involved in chromosome
rearrangement that arise in people or cancers. More recent molecular characteri-
zation has uncovered proto-oncogenes at several such fragile sites, and screening
for haplo-insufficient tumor suppressor genes (by microarray) or germline oncogene
mutations is an important thrust of modern genetic testing.
Just as the previous volumes changed the title from “Atlas of Human Chromosome
Heteromorphism” to “Human Chromosome Variation: Heteromorphism and
Polymorphism,” so has this volume morphed to Human Chromosome Variation:
Heteromorphism, Polymorphism, and Pathogenesis to consider all levels of chro-
mosomal DNA variation and to provide some examples of clinical correlation. We
have retained intact as Part I the core of prior volumes: Pictorial representations of
common and not so common heteromorphisms. Part II concerns the advances in
molecular cytogenetics and DNA diagnosis, including review of the common and
rare fragile sites and discussion of polymorphisms and copy number variations
(CNVs) that cannot be detected except at the molecular level, the latter expanded
from the previous volume. Part I covers variations seen by routine karyotype or direct
analysis of cells and chromosomes by fluorescence in situ hybridization (FISH).
Part II includes information on chip-based technologies, and (briefly, as a guide to the
future) approaches to genome sequencing, as well as the clinical genetic approach, the
latter because discrimination of benign from clinically significant variation is much
easier when the genetic test is appropriate to the category of potential genetic disease.
Case studies illustrate how the distinction between benign or pathogenic variant, the
major objective of this work, is carried out in practice, increasingly challenging as the
Preface ix

resolution of genetic testing extends from chromosome band to the DNA segment and
nucleotide level. A summary closes by emphasizing that clinical judgment in
ordering and interpreting genetic tests is the fulcrum for balancing variation versus
disease.

Oakdale, USA Herman E. Wyandt

Lubbock, USA Golder N. Wilson
Lubbock, USA Vijay S. Tonk
Acknowledgements

This is a review of the work of many investigators spanning more than five decades
of cytogenetic research, and now including nearly two decades of microarray and
whole genome sequencing data. It is not possible to adequately represent the early
efforts of investigators such as A. Craig-Holms, J.P. Geraedts, P. Jacobs, H. Lubs,
W.H. MacKenzie, R.E. Magenis, A.V.N. Mikelsaar, H.J. Muller, S. Patil,
P. Pearson, M. Shaw, and many others who perceived the need to study chromosome
heteromorphisms in populations and who attempted to give order to a complicated
topic. For specific examples of common and rare heteromorphisms, in the Atlas of
Human Chromosome Heteromorphisms, individual contributions from colleagues
around the world were an essential ingredient.
Contributors of figures or other substantive materials to the Atlas were listed and
annotated in a format that was retained in the subsequent edition of Human
Chromosome Variation: Heteromorphism and Polymorphism, and is retained again
in this edition. Once again, we acknowledge (1) the contribution of Lauren Jenkins
at Kaiser Permanente Medical Group (San Jose), who provided us a significant
number of excellent examples of chromosome heteromorphisms in the original
volume, and (2) the use of archived material from our respective laboratories. The
cytogenetic technologists and associates who helped provide examples for the Atlas
from these sources include: Xin Li Huang, Alex Dow, Agen Pan, Zhen Kang, Xiao
Wu, and Hong Shao in the Center for Human Genetics at Boston University, and
Caro E. Gibson, Manju G. Jayawickrama, Eun Jung Lee, Jee Hong Kyhme,
Eun-Hee Cho, Pam Nye and Vhung-Hwan Yuk in the Cytogenetics Laboratory at
Texas Tech University. Sun Han Shim (postdoctoral fellow), in the Center for
Human Genetics, also helped provide key examples of FISH variants. We must also
acknowledge the large amount of published material for which we obtained per-
mission to reproduce in this and previous volumes.
The information and format relating to heteromorphism has, for the most part,
been retained in its entirety in the present edition, and we continue to be grateful for
the early support by the following individuals in the Department of Pediatrics,

xi
xii Acknowledgements

Texas Tech University Health Sciences Center in Lubbock, TX: Richard M.

Lampe, M.D., Chairman; Surendra K. Varma, M.D., Vice Chairman; John A.
Berry, Administrator. We are similarly grateful to Aubrey Milunsky, M.D., D.Sc.,
F.R.C.P, F.A.C.M.G., D.C.H (formerly Professor of Human Genetics, Pediatrics,
Pathology and Obstetrics & Gynecology and Director of the Center for Human
Genetics, Boston University School of Medicine, Boston, MA), now Founder and
Co-Director, Center for Human Genetics Cambridge, MA, and Adjunct Professor of
Obstetrics and Gynecology, Tufts University School of Medicine, Boston, MA, and
to Jeff Milunsky, M.D. (formerly Associate Professor of Pediatrics, Genetics and
Genomics and Associate & Clinical Director of the Center for Human Genetics),
now Co-Director, Center for Human Genetics, Cambridge, MA.
For this latest edition, Human Chromosome Variation: Heteromorphism,
Polymorphism and Pathogenesis, this project would not have been completed
without the support of the Pediatrics department at Texas Tech University Health
Sciences Center and the Texas Tech University Health Sciences Center Clinical
Research Institute in Lubbock Texas. A fundamental contribution to this book was
by Division Administrator Cortney Becker, whose Microsoft Excel database of
aCGH results provided the Texas Tech data summarized in the chromosome
chapters of Chap. 10. We are also grateful to the following individuals in the
department of Pediatrics at Texas Tech University Health Sciences Center in
Lubbock, Texas: Richard M. Lampe, M.D.—Chairman, John A Berry—Chief
Administrator, Jill Johnston—Lead Cytogenetic Technologist and Tejaswini Reddy,
M.D./Ph.D. student at Texas A&M University, College Station, Texas. We owe
special thanks to Sahil S. Tonk for the many hours spent in the daunting task of
checking the accuracy of the many hundreds of references in this latest edition. Last
but not least, we want to acknowledge the many families whose sharing of concern
and information makes medical advances possible.
We also owe specials thanks for critical review of the manuscript to Dr. Roger
Schultz and Dr. Ankita Patel. We must also thank Peter Butler and staff at Springer
Science+Business Media for taking a personal interest, in the Atlas of Human
Chromosome Heteromorphisms and in Human Chromosome Variation:
Heteromorphism and Polymorphism. We are similarly grateful to Thijs van
Vlijmen, senior publishing editor, Hema Suresh, production editor, and Sara
Germans at Springer Nature for help with the present edition.
Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......... 1
1.1 Genome and Chromosome Structure as Examined
by Genetic Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 Scanning the Human Genome: A Text Analogy . . . . . . . . . . . . 4
1.3 Microscopic Chromosome Variation . . . . . . . . . . . . . . . . . . . . . 5
1.4 Submicroscopic Chromosome Variation . . . . . . . . . . . . . . . . . . 6
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

Part I Human Chromosome Methods and Nomenclature

2 Chromosome Heteromorphism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.1 Chromosome Banding Techniques and Mechanisms . . . . . . . . . 15
2.1.1 Q-banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.1.2 G-banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.1.3 R-banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.1.4 C-banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.1.5 Cd Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.1.6 G-11 Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.1.7 Silver Staining (Ag-NOR) . . . . . . . . . . . . . . . . . . . . . . 21
2.2 Other DNA-Binding Fluorochromes . . . . . . . . . . . . . . . . . . . . . 22
2.3 Sister Chromatid Exchange Staining (SCE) . . . . . . . . . . . . . . . 23
2.4 Replication Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.5 High Resolution Banding and Special Treatments . . . . . . . . . . 26
2.6 Satellite DNA in Heteromorphic Regions . . . . . . . . . . . . . . . . . 26
2.6.1 Alpha Satellite DNA . . . . . . . . . . . . . . . . . . . . . . . . . . 27
2.6.2 Satellites I–IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.6.3 Beta Satellite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.6.4 Minisatellites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.6.5 Microsatellites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

xiii
xiv Contents

2.7 Single Nucleotide Polymorphisms (SNPs) . . . . . . . . . . . . . . . . 30

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3 Frequencies of Heteromorphisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.1 By Q- and C-Banding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.1.1 The New-Haven Study . . . . . . . . . . . . . . . . . . . . . . . . 40
3.1.2 Study Comparisons . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.1.3 Additional Studies of Racial or Ethnic Differences . . . 43
3.2 Specialized Banding Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
4 Clinical Populations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4.1 Spontaneous Abortions and Reproductive Failure . . . . . . . . . . . 47
4.2 Nucleolar Organizing Regions and Non-disjunction . . . . . . . . . 48
4.3 Satellite Association . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
4.4 Mobile Elements and Cryptic Translocations Involving
Acrocentrics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 50
4.5 Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 51
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 53
5 Euchromatic Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
6 Chromosome Heteromorphism (Summaries) . . . . . . . . . . . . . . . . . . . 63
6.1 Chromosome 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64
6.2 Chromosome 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
6.3 Chromosome 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72
6.4 Chromosome 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
6.5 Chromosome 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
6.6 Chromosome 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78
6.7 Chromosome 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
6.8 Chromosome 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
6.9 Chromosome 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
6.10 Chromosome 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
6.11 Chromosome 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
6.12 Chromosome 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.13 Chromosome 13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
6.14 Chromosome 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
6.15 Chromosome 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
6.16 Chromosome 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
6.17 Chromosome 17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 112
6.18 Chromosome 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113
6.19 Chromosome 19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115
6.20 Chromosome 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Contents xv

6.21 Chromosome 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

6.22 Chromosome 22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
6.23 Chromosome X . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
6.24 Chromosome Y . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129

Part II Genomics and DNA Polymorphism: Molecular

Cytogenetics and DNA Diagnosis
7 Fragile Sites . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
8 Chromosome Variation Detected by Fluorescent In Situ
Hybridization (FISH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
8.1 Types of FISH Probes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
8.2 FISH Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
8.3 Studies of Heteromorphisms by FISH . . . . . . . . . . . . . . . . . . . . 178
8.4 FISH Variants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
8.4.1 FISH Results with Centromeric Repeats . . . . . . . . . . . 180
8.4.2 Subtelomeric Deletions/Duplications: Normal
Variation or Chromosome Abnormality? . . . . . . . .... 182
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 187
9 Array-Comparative Genomic Hybridization/Microarray
Analysis: Interpretation of Copy Number Variants . . . . . . . . . .... 191
9.1 Human Genome Structure . . . . . . . . . . . . . . . . . . . . . . . . . .... 191
9.1.1 The Human Genome Project . . . . . . . . . . . . . . . . .... 192
9.1.2 Copy Number Variation: An Aspect of Genomic
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194
9.2 Mechanisms and Limitations aCGH . . . . . . . . . . . . . . . . . . . . . 195
9.2.1 Example of aCGH Methodology . . . . . . . . . . . . . . . . . 196
9.2.2 aCGH Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
9.3 Pathogenesis Versus Polymorphism: A Dilemma
Compounded by aCGH. . . . . . . . . . . . . . . . . . . . . . . . . . . .... 200
9.3.1 aCGH Examples That Support Single-Gene
Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 201
9.3.2 Examples Where Single Gene Dosage Does not
Explain Phenotype . . . . . . . . . . . . . . . . . . . . . . . . .... 203
9.3.3 A Stochastic Approach to Chromosomal
Phenotypes and Aphorisms for Chromosomal
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 206
9.4 Clinical Approach to Genetic Testing . . . . . . . . . . . . . . . . .... 210
9.4.1 Pediatric Genetics . . . . . . . . . . . . . . . . . . . . . . . . .... 211
9.4.2 Reproductive Genetics: Infertility, Recurrent
Pregnancy Loss, and Prenatal Diagnosis . . . . . . . .... 218
xvi Contents

9.5 Case Examples of aCGH Results . . . . . . . . . . . . . . . . . . . . . . . 219

9.5.1 Cases Where the Interpretation of Clinical
Significance Is Clear and the Diagnosis Provides
Good Prognostic Information . . . . . . . . . . . . . . . . . . . . 219
9.5.2 Cases Deemed Clinically Significant with Uncertain
Prognoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
9.5.3 Cases of Unclear Significance or Prognosis . . . . . . . . . 228
9.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229
10 A CNV Catalogue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235
10.1 Chromosome 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248
10.2 Chromosome 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254
10.3 Chromosome 3 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
10.4 Chromosome 4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266
10.5 Chromosome 5 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271
10.6 Chromosome 6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
10.7 Chromosome 7 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282
10.8 Chromosome 8 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 290
10.9 Chromosome 9 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 298
10.10 Chromosome 10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302
10.11 Chromosome 11 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 309
10.12 Chromosome 12 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314
10.13 Chromosome 13 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 318
10.14 Chromosome 14 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
10.15 Chromosome 15 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
10.16 Chromosome 16 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 334
10.17 Chromosome 17 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
10.18 Chromosome 18 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
10.19 Chromosome 19 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
10.20 Chromosome 20 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 363
10.21 Chromosome 21 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 368
10.22 Chromosome 22 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 371
10.23 X Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
10.24 Y Chromosome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
11 Gene and Genome Sequencing: Interpreting Genetic
Variation at the Nucleotide Level . . . . . . . . . . . . . . . . . . . . . . . . .... 419
11.1 DNA Diagnosis by Targeted DNA Sequencing . . . . . . . . .... 419
11.1.1 From Inheritance Pattern to DNA Diagnosis . . . . .... 420
11.1.2 Examples of Targeted DNA Sequencing for
Mendelian Disorders . . . . . . . . . . . . . . . . . . . . . . .... 424
Contents xvii

11.1.3 Examples of DNA Sequencing Panels

for Mendelian Disorders Conferring
Particular Clinical Symptoms . . . . . . . . . . . . . . . . .... 428
11.2 DNA Diagnosis by Whole Exome Sequencing . . . . . . . . . .... 430
11.2.1 WES Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 431
11.2.2 Approaches to Determining Pathogenesis
for WES Results . . . . . . . . . . . . . . . . . . . . . . . . . .... 433
11.3 Case Examples of WES Analysis . . . . . . . . . . . . . . . . . . . .... 436
11.3.1 Examples of Mutations in Genes Previously
Highlighted by ACGH . . . . . . . . . . . . . . . . . . . . . .... 437
11.3.2 Examples of Mutations in Genes Previously
Associated with Neurobehavioral Phenotypes . . . .... 441
11.3.3 Examples of Novel Mutations with Variable
Evidence for Clinical Relevance . . . . . . . . . . . . . .... 443
11.4 DNA Risk Modification, Pharmacogenomics,
and Precision Medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 447
11.4.1 DNA Markers Predicting Drug Metabolism
(Pharmacogenomics) . . . . . . . . . . . . . . . . . . . . . . .... 447
11.4.2 DNA Markers Predicting Disease Risks . . . . . . . .... 451
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .... 452
12 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 458
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 489
Figure Contributors

Arturo Anguiano, M.D. (c17, c29) Quest Diagnostics Incorporated, San Juan,
Capistrano, CA, USA
Petr Balicek, M.D. (c16) Division of Medical Genetics, University Hospital,
Kraklove, Czech Republic
Peter A. Benn, Ph.D. (c1, c11, c41) Division of Human Genetics, University of
Connecticut Health Center, Farmington, CT, USA
Center for Human Genetics, Boston University School of Medicine, Boston,
MA, USA (c1)
Cytogenetics Laboratory, Division of Cytogenetics and Medical Genetics,
Texas; Tech University Health Sciences Center, Lubbock, TX, USA (c43)
J.J.M. Engelen, Ph.D. (c40) Department of Molecular Cell Biology and
Genetics, Universiteit Maastricht, Maastricht, The Netherlands
James M. Fink, M.D., Ph.D. (c37, c38) Hennepin County Medical Center,
Minneapolis, MN, USA
Cheong Kum Foong (c31, c32) Cytogenetic Laboratory, Kandang Kerbau
Women’s and Children’s Hospital, Singapore
Steven L. Gerson, Ph.D. (c18) Dianon Systems, Stratford, CT, USA
Patricia N. Howard-Peebles, Ph.D. 323 Wrangler Dr, Fairfax, TX, USA
Syed M. Jalal, Ph.D. (c42) Cytogenetics Laboratory, Division of Laboratory
Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic and
Mayo Foundation, Rochester, MN, USA
Lauren Jenkins, Ph.D. (c2) Kaiser Permanente Medical Group, San Jose, CA,
USA
Rhett P. Ketterling, M.D. Division of Laboratory Genetics, Department of
Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation,
Rochester, MN, USA
Roger V. Lebo, Ph.D. Department of Pathology, Children’s Hospital Medical
Center of Akron, Akron, OH, USA
James Lespinasse, M.D. (c10) Laboratoire de Cytogenetique, Centre
Hospitalier, Chambery cedex, France

xix