Brook's Clinical Pediatric Endocrinology

Mehul T. Dattani, Charles G. D. Brook, Mehul T. Dattani, Charles G. D. Brook

• Publisher: Wiley-Blackwell
• Year: 2019
• ISBN:
  9781119152705
• Edition: 7
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The seventh edition of Brook's Clinical Pediatric Endocrinology has been compiled by an experienced editorial team and internationally renowned contributors; it presents basic science and clinical management of endocrine disorders for all involved in the care of children and adolescents. It provides treatments for a variety of hormonal diseases, including diabetes and hypoglycaemia, growth problems, thyroid disease and disorders of puberty, sexual differentiation, calcium metabolism, steroid metabolism and hypopituitarism.

1
Genetics and Genomics

Anu Bashamboo and Ken McElreavey

Human Developmental Genetics, Institut Pasteur, Paris, France

Introduction

The Human Genome Project was completed in 2003 but it is only now that we are truly in the genomic era. Next‐generation sequencing (NGS), which allows genome‐wide detection of variants, is transforming on an unprecedented scale our understanding of pediatric and endocrine diseases by identifying mutations that are pathogenic or confer disease risk: new genes that cause human disease are being identified at the rate of 3 per week. We all differ in our DNA sequence and medical geneticists aim to understand the significance of this genetic diversity in health and disease, which has led to the age of genomic medicine.

Understanding genetic diversity is essential to understanding the biology of diseases of various kinds, from simple Mendelian or monogenic disorders to more complex multifactorial disease, and how we respond to treatment at both population and individual levels. We have the capacity to study the human genome as an entity rather than one gene at a time and medical and clinical genetics has become part of the broader field of genomic or precision medicine, which seeks to apply a large‐scale analysis of the human genome to provide an individual and knowledge‐based approach to medical care.

Many web resources and web‐based tools have been developed to help the clinicians navigate and interpret the tremendous amount of genomic data that are being generated (Table 1.1).

Table 1.1 Commonly used databases in human genetic and genomic analysis.

Site	Content	URL
National Center for Biotechnology Information	A portal that provides access to a wealth of biomedical and genomic information. Includes PubMed, OMIM, dbSNP, Clinvar, expression data sets. Suite of tools for data and sequence analysis (e.g. BLAST)	http://www.ncbi.nlm.nih.gov
Mendelian Inheritance in Man (MIM)	A comprehensive database of human genes and genetic disorders	http://www.ncbi.nlm.nih.gov/omim
ClinGen	Authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research	https://www.clinicalgenome.org
Ensembl	Genome browser for vertebrate genomes that supports research in comparative genomics, evolution, sequence variation and transcriptional regulation. Annotates genes, computes multiple alignments, predicts regulatory function and collects disease data	http://www.ensembl.org
University California, Santa Cruz (UCSC), genome browser	Genome browser offering access to genome sequence data from vertebrate and invertebrate species and major model organisms. Integrated with a large collection of analysis tools	https://genome.ucsc.edu
GeneCards	Provides comprehensive information on all human genes. It integrates gene data from ~125 web sources, including genomic, transcriptomic, proteomic, genetic, clinical and functional information	http://www.genecards.org
Human Gene Mutation Database (HGMD)	Collates published gene lesions responsible for human inherited disease	www.hgmd.cf.ac.uk/ac
Mouse Genome Informatics at the Jackson Laboratories	International database resource for the laboratory mouse, providing integrated genetic, genomic, and biological data to facilitate the study of human health and disease	http://www.informatics.jax.org
DECIPHER database	Collects clinical information about rare genomic variants and displays this information on the human genome map	https://decipher.sanger.ac.uk
Database of Genomic Variants (DGV)	A curated catalogue of human genomic structural variation	http://dgv.tcag.ca/dgv/app/home
Exome Aggregation Consortium (ExAC) browser	Exome data set >60,000 unrelated individuals. Provides both a reference set of allele frequencies and constraint metrics giving information on whether a gene is tolerant or intolerant to variation	http://exac.broadinstitute.org
ClinVar	Aggregates information about genomic variation and its relationship to human health.	http://www.ncbi.nlm.nih.gov/clinvar
Sequence Variant Nomenclature	Provides guidelines for sequence variation nomenclature	http://varnomen.hgvs.org
dbSNP	Genetic variation within and across different species. Not limited to SNPs, it contains a range of molecular variation	http://www.ncbi.nlm.nih.gov/SNP
F‐SNP	Provides integrated information about the functional effects of SNPs obtained from 16 bioinformatics tools and databases. Helps identify and focus on SNPs with potential pathological effect to human health	http://compbio.cs.queensu.ca/F‐SNP
Biological General Repository for Interaction Datasets (BioGRID)	Database of protein–protein interactions, genetic interactions, chemical interactions, and post‐translational modifications	http://thebiogrid.org
PhenomicDB	A multi‐organism phenotype–genotype database including human, mouse, fruit fly, C. elegans, and other model organisms	http://www.phenomicdb.de
Phencode	Connects human phenotype and clinical data in various locus‐specific mutation databases with data on genome sequences, evolutionary history and function in the UCSC Genome Browser	http://phencode.bx.psu.edu
Human Epigenome Atlas	Includes human reference epigenomes and the results of their integrative and comparative analyses. Provides details of locus‐specific epigenomic states like histone marks and DNA methylation across tissues and cell types, developmental stages, physiological conditions, genotypes and disease states	http://www.genboree.org/epigenomeatlas
Encyclopedia of DNA Elements (ENCODE)	Catalogue of functional elements in the human genome, including elements that act at the protein and RNA levels and regulatory elements that control cells and circumstances in which a gene is active	https://www.encodeproject.org
Genomics England 100,000 Genomes Project	The project will sequence 100,000 genomes from around 70,000 people. Participants are National Health Service (UK) patients with a rare disease, plus their families, and patients with cancer	www.genomicsengland.co.uk/the‐100000‐genomes‐project

The term ‘‐omics’ aims at the collective characterization and quantification of pools of biological molecules that translate into the structure, function and dynamics of an organism. Genomics can be divided into comparative genomics, the study of the relationship of genome structure and function across different biological species or strains; functional genomics, which describes gene and protein functions and interactions; metagenomics, the study of genetic material recovered directly from environmental samples; and epigenomics, which is the study of the complete set of epigenetic modifications on the gen...