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MUTATIONS IN HUMAN GENETIC DISEASE

MUTATIONS IN HUMAN GENETIC DISEASE
Edited by David N. Cooper and Jian-Min Chen . 
304 pages . 

Just over 30 years ago, the first heritable human gene mutations were characterized at 
the DNA level: gross deletions of the human α-globin and β-globin gene clusters 
giving rise to α- and β-thalassaemia (1978) and a nonsense mutation in the human β- 
globin (HBB) gene causing β-thalassaemia (1979). With the number of known germline 
mutations in human nuclear genes either underlying or associated with inherited 
disease now exceeding 125,000 in ~5,000 different genes (Human Gene Mutation 
Database; http://www.hgmd.org; October 2012), the characterization of the spectrum 
of human germ-line mutations is proceeding apace. Such information is beginning to 
shed new light on longstanding questions such as the nature of disease predisposition, 
the determinants of the genotype-phenotype relationship, the molecular basis of 
reduced penetrance and the measurement of the human gene mutation rate, as well as 
posing profound questions pertaining to how we conceptualise genetic disease. Thus, 
from data generated by the 1000 Genomes Project, it has become clear that an average 
human genome typically contains ~100 loss-of-function variants, with ~20 genes being 
completely inactivated. In addition, even apparently healthy individuals harbour 
many tens or even hundreds of potentially deleterious variants in their genomes 
whose impact on the phenotype is usually still unknown.
Mutations are also likely to play a role in many complex genetic diseases (such as 
heart disease, neuropsychiatric disease or diabetes). These are conditions that do not 
display simple Mendelian patterns of inheritance even although genes may exert an 
important influence; hence close relatives of individual patients will often have an 
increased risk of developing the condition. These disorders are thought to be due to 
the combined effects of genetic variants at multiple gene loci, interacting with the 
environment. Complex disease has a very significant impact on human health because 
of the high population incidence of these conditions (unlike most Mendelian disorders 
which tend to be individually rare).
The advent of next-generation sequencing has also made possible the detailed 
characterization of whole cancer genomes, allowing for the first time a comprehensive 
assessment of the lexicon of somatic mutations driving tumorigenesis in a given cell or 
tissue. It has become clear that cancer genomes often constitute an intricate patchwork 
of clustered, or even overlapping, somatic lesions. Next-generation sequencing has the 
major advantage of being capable of simultaneously detecting genome/exome-wide, 
deletions, insertions, copy number alterations and translocations as well as nucleotide 
substitutions (including hot-spot mutations in known cancer-related genes). Such 
studies are transforming our knowledge of oncogenic pathways and providing novel 
molecular targets of use in diagnosis, prognostic and therapeutic contexts. The 
ultimate goal is to provide a personalized treatment regime for both solid tumours and 
hematologic malignancies by tailoring health care to the individual patient using their 
own genetic information. Significant challenges remain to be addressed, such as the 
dissection of intra-tumoral DNA sequence heterogeneity and the development of 
powerful new bioinformatic tools with which to differentiate reliably between driver 
and passenger mutations.
It should be abundantly clear from the above that the study of mutation is relevant to 
all of us, not just the minority of individuals who may be afflicted in a very immediate 
way by inherited disease or cancer. In this volume, the interested reader will find 14 
chapters on different aspects of mutation as it impacts human genetic disease. It is 
hoped that this book will not only be of practical assistance to those scientists and 
clinicians already working in the field but will also serve to encourage others to make 
their own unique contribution to understanding the nature and pathological 
consequences of mutation in the human genome.

David N. Cooper
Department of Medical Genetics, Haematology and Pathology, Cardiff University
School of Medicine, Institute of Medical Genetics Building Heath Park, Cardiff,
Wales

Jian-Min Chen
Directeur de Recherche, Institut National de la Santé et de la Recherche Médicale
(INSERM), U613, Brest, France;
Etablissement Français du Sang (EFS)- Bretagne, Brest,
France

CONTENTS :

Chapter 1 Missense Mutation in AR-CGD 1
M. Yavuz Köker and Hüseyin Avcilar

Chapter 2 Missense Mutations in GDF-5 Signaling: 
Molecular Mechanisms Behind Skeletal Malformation 11
Tina V. Hellmann, Joachim Nickel and Thomas D. Mueller

Chapter 3 Missense Mutation in the LDLR Gene: 
A Wide Spectrum in the Severity  of Familial Hypercholesterolemia 55
Mathilde Varret and Jean-Pierre Rabès

Chapter 4 Missense Mutation in Cancer 
in Correlation to Its Phenotype – VHL as a Model 75
Suad AlFadhli

Chapter 5 Genotype-Phenotype Disturbances 
of Some Biomarkers in Colorectal Cancer 91
Mihaela Tica, Valeria Tica, Alexandru Naumescu, Mihaela Uta, Ovidiu Vlaicu and Elena Ionica

Chapter 6 Genetic Causes of Syndromic and 
Non-Syndromic Congenital Heart Disease 119
Akl C. Fahed and Georges M. Nemer

Chapter 7 The Prototype of Hereditary Periodic Fevers: 
Familial Mediterranean Fever 149
Afig Berdeli and Sinem Nalbantoglu

Chapter 8 Pathophysiological Roles of Mutations in 
the Electrogenic Na+-HCO3
- Cotransporter NBCe1 167
George Seki, Shoko Horita, Masashi Suzuki, Osamu Yamazaki and Hideomi Yamada

Chapter 9 The Mutations and Their Relationships 
with the Genome and Epigenome, RNAs Editing and Evolution in Eukaryotes 181
Daniel Frías-Lasserre

Chapter 10 Screening of Gene Mutations in Lung Cancer for 
Qualification to Molecularly Targeted Therapies 201
Paweł Krawczyk, Tomasz Kucharczyk and Kamila Wojas-Krawczyk

Chapter 11 Clinical and Genetic Heterogeneity of Autism 217
Yu Wang and Nanbert Zhong

Chapter 12 Bioinformatics Approaches to the Functional 
Profiling of Genetic Variants 233
Biao Li, Predrag Radivojac and Sean Mooney

Chapter 13 Anderson’s Disease/Chylomicron Retention 
Disease and Mutations in the SAR1B Gene 251
A. Sassolas, M. Di Filippo, L.P. Aggerbeck, N. Peretti and M.E. Samson-Bouma

Chapter 14 Activating Mutations and Targeted Therapy in Cancer 273
Musaffe Tuna and Christopher I. Amos .


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