Oxford Desk Reference: Clinical Genetics and Genomics

Dr Helen Firth, DM FRCP DCH is a Consultant Clinical Geneticist at Cambridge University Hospitals, an Honorary Faculty Member of the Wellcome Trust Sanger Institute, and a Bye-Fellow of Newnham College, Cambridge. Her main research interests are in mapping the clinical genome and the matching of rare genomic variants to empower discovery and diagnosis in rare disease. In 2004, she initiated the DECIPHER project (http://decipher.sanger.ac.uk) that enables clinicians and scientists around the world to share information about rare genomic variants to facilitate diagnosis and help to elucidate the role of genes whose function is not yet known. In 2010 Dr Firth became Clinical Lead for the Deciphering Developmental Disorders study (DDD study) (http://www.ddduk.org), one of the world's largest nationwide, genome-wide sequencing projects in rare disease. The study aims to improve diagnosis and further understanding of the genomic architecture of severe developmental disorders.

Dr Jane Hurst is a clinician working full time as a clinical geneticist in the one of the leading children's hospitals in the world; a centre of excellence for the diagnosis and treatment of rare diseases. She moved to her current post in 2010 to lead the dysmorphology service after 18 years working in Oxford, UK. Although primarily a patient-focussed clinician, she has always worked closely with scientific colleagues by identifying families that give important clues to the genetic aetiology. Thus early in her career she identified the first family shown to have leptin deficiency and the two families that led to the cloning of the FOXP2 gene.

Introduction
Adoption
Approach to the consultation with a child with dysmorphism, congenital malformation or developmental delay
Autosomal dominant (AD) inheritance
Autosomal recessive (AR) inheritance
Communication skills
Complex inheritance
Confidentiality
Confirmation of diagnosis
Consent for genetic testing
Genetic basis of cancer
Genetic code and mutations
Genomes and genomic variation
Genomic imprinting
Genomic sequencing and interpretation of data from WES or WGS analyses
Mitochondrial inheritance
Reproductive options
Testing for genetic status
Timing and origin of new dominant mutations
Useful resources
X-linked dominant (XLD), semi-dominant, pseudoautosomal and male sparing inheritance
X-linked recessive inheritance
Clinical Approach
Ambiguous genitalia (including sex reversal)
Anal anomalies (atresia, stenosis)
Anterior segment eye malformations
Arthrogryposis
Ataxic adult
Ataxic child
Brachydactyly
Broad thumbs
Cardiomyopathy in children under 10 years
Cataract
Cerebellar anomalies
Cerebral palsy
Chondrodysplasia punctata
Cleft lip and palate
Coarse facial features
Coloboma
Congenital heart disease
Congenital hypothyroidism
Corneal clouding
Deafness in early childhood
Developmental delay in the child with consanguineous parents
Developmental regression
Duane retraction syndrome
Dysmorphic child
Dystonia
Ear anomalies
Facial asymmetry
Failure to thrive
Floppy infant
Fractures
Generalized disorders of skin pigmentation (including albinism)
Hemihypertrophy and limb asymmetry
Holoprosencephaly
Hydrocephalus
Hypermobile joints
Hypoglycaemia in the neonate and infant
Hypospadias
Intellectual disability
Intellectual disability with apparent X-linked inheritance
Increased bone density
Intracranial calcification
Large fontanelle
Laterality disorders including heterotaxy and isomerism
Leukodystrophy/leukoencephalopathy
Limb reduction defects
Lissencephaly, polymicrogyria and neuronal migration disorders
Lumps and bumps
Macrocephaly
Microcephaly
Micrognathia and Robin sequence
Microphthalmia and anophthalmia
Minor congenital anomalies
Nasal anomalies
Neonatal encephalopathy and intractable seizures
Nystagmus
Obesity with and without developmental delay
Ocular hypertelorism
Oedema generalized or puffy extremeties
Oesophageal and intestinal atresia (including tracheo-oesophageal fistula)
Optic nerve hypoplasia
Overgrowth
Patchy hypo- or de-pigmented skin lesions
Patchy pigmented skin lesions (including café-au-lait spots)
Plagiocephaly and abnormalities of skull shape
Polydactyly
Prolonged neonatal jaundice and jaundice in infants below 6 months
Ptosis, blepharophimosis and other eyelid anomalies
Radial ray defects and thumb hypoplasia
Retinal dysplasia
Retinal receptor dystrophies
Scalp defects
Seizures with developmental delay/intellectual disability
Short stature
Skeletal dysplasias
Structural intracranial anomalies (agenesis of the corpus callosum, septo-optic dysplasia and arachnoid cysts)
Sudden cardiac death
Suspected non-accidental injury
Syndactyly (other than 2-3 toe syndactyly)
Unusual hair, teeth, nails and skin
Common consultations
Achondroplasia
Alpha1-antitrypsin deficiency
Alport syndrome
Androgen insensitivity syndrome (AIS)
Angelman syndrome
Autism and autism spectrum disorders
Autosomal dominant polycystic kidney disease (ADPKD)
Beckwith-Wiedemann syndrome (BWS)
Charcot-Marie-Tooth disorder (CMT)
Ciliopathies
Congenital adrenal hyperplasia (CAH)
Consanguinity
Craniosynostosis
Cystic fibrosis (CF)
Dementia early onset and familial forms
Diabetes mellitus
Dilated cardiomyopathy (DCM)
DNA repair defects
Duchenne and Becker muscular dystrophy (DMD and BMD)
Ehlers-Danlos syndrome
Epilepsy in infants and children
Epilepsy in adults
Fascioscapulo-humeral muscular dystrophy (FSHD)
Fragile X syndrome (FRAX)
Glaucoma
Haemochromatosis
Haemoglobinopathies
Haemophilia and other inherited coagulation disorders
Hereditary haemorrhagic telangiectasia (HHT)
Herediatry spastic paraplegia (HSP)
Hirschprung disease
Huntington disease (HD)
Hyperlipidaemias
Hypertrophic cardiomyopathy (HCM)
Immunodeficiency and recurrent infection
Incest
Leigh encephalopathy
Limb-girdle muscular dystrophies
Long QT and Brugada syndromes
Marfan syndrome
Mitochondrial DNA diseases
Myotonic dystrophy (DM1)
Neural tube defects
Neurofibromatosis type 1 (NF1)
Noonan syndrome and the RAS-MAPK pathway disorders
Parkinson disease
Retinitis pigmentosa (RP)
Rett syndrome
Sensitivity to anaesthetic agents
Spinal muscular atrophy (SMA)
Stickler syndrome
Thrombophilia
Tuberous sclerosis (TSC)
X-linked adrenoleukodystrophy (X-ALD)
Cancer
BRCA1 and BRCA2
Breast cancer
Cancer surveillance methods
Colorectal cancer (CRC)
Confirmation of diagnosis of cancer
Cowden syndrome (CS)
Familial Adenomatous Polyposis (FAP) and adenomatous polyposis (due to MUTYH, NTHL1, POLE & POLD1)
Gastric cancer
Gorlin syndrome
Juvenile polyposis syndrome (JPS)
Lynch syndrome
Lifestyle factors in cancer: smoking, alcohol, obesity, diet and exercise
Li-Fraumini syndrome (LFS)
Multiple endocrine neoplasia (MEN)
Neurofibromatosis type 2 (NF2)
Ovarian cancer
Peutz-Jeghers syndrome (PJS)
Phaeochromocytoma and Paraganglioma
Prostate cancer
Renal cancer
Retinoblastoma
von Hippel-Lindau (VHL) disease
Wilms tumour
Chromosomes
22q11 deletion syndrome
47,XXX
47,XXY
47,XYY
Autosomal reciprocal tranlsocations background
Autosomal reciprocal translocations familial
Autosomal reciprocal translocations postnatal
Autosomal reciprocal translocations prenatal
Cell division mitosis, meiosis and non-disjunction
Chromosomal mosaicism postnatal
Chromosomal mosaicism prenatal
Deletions and duplications (including microdeletions and microduplications)
Down syndrome (trisomy 21)
Edwards syndrome (trisomy 18)
Inversions
Mosaic trisomy 8
Mosaic trisomy 16
Patau syndrome (trisomy 13)
Prenatal diagnosis of sex chromosome aneuploidy
Ring chromosomes
Robertsonian translocations
Sex chromosome mosaicism
Supernumerary marker chromosomes (SMCs) postnatal
Supernumerary marker chromosomes (SMCs) prenatal
Triploidy (69,XXX, 69XXY or 69,XYY)
Turner syndrome, 45,X and variants
X-autosome translocations
Pregnancy and fertility
Anterior abdominal wall defects
Assisted reproductive technology: in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI) and pre-implantation genetic diagnosis (PGD)
Bowed limbs
Congenital cystic lung lesions, Currarino syndrome, and sacrococcygeal teratoma
Congenital diaphragmatic hernia
Cytomegalovirus (CMV)
Drugs in pregnancy
Female infertility and amenorrhoea: genetic aspects
Fetal alcohol syndrome (FAS)
Fetal anticonvulsant syndrome (FACS)
Fetal akinesia
Fetomaternal alloimmunisation (rhesus D and thrombocytopaenia)
Hyperechogenic bowel
Hyoplastic left heart
Imaging in prenatal diagnosis
Invasive techniques and genetic tests in prenatal diagnosis
Low maternal serum oestriol
Male infertility: genetic aspects
Maternal age
Maternal diabetes mellitus and diabetic embryopathy
Maternal phenylketonuria (PKU)
Miscarriage and recurrent miscarriage
Neonatal (newborn) screening (NS)
Non-invasive prenatal diagnosis/testing (NIPD/T)
Oedema increased nuchal translucency, cystic hygroma and hydrops
Oligohydramnios (Including Potter/ Oligohydramnios sequence)
Paternal age
Polyhydramnios
Posterior fossa malformations
Premature ovarian failure (POF)
Radiation exposure, chemotherapy, and landfill site
Rubella
Short limbs
Talipes (Club foot)
Toxoplasmosis
Twins and twinning
Urinary tract and renal anomalies (Congenital anomalies of the kidney and urinary tract - CAKUT)
Varicella
Ventriculomegaly
Appendix
Antenatal and neonatal screening timelines
Bayes theorem
Carrier frequency and carrier testing for autosomal recessive disorders
Centile charts for boys height and weight
Centile charts for girls height and weight
Centile charts for occipital-frontal circumference (OFC)
CK (Creatine kinase) levels in carriers of Duchenne muscular dystrophy (DMD)
Conversion charts from English to metric units for height and weight
Denver Developmental Screening Test
Distribution of muscle weakness in different types of muscular dystrophy
Dysmorphology examination checklist
Embryonic fetal development (overview)
Family tree sheet and symbols
Haploid autosomal lengths of human chromosomes
Investigation of lethal metabolic disorder or skeletal dysplasia
ISCN Nomenclature
Karyotypes
Normal range of aortic root dimensions
Paternity testing
Patterns of cancer
Radiological investigations including magnetic resonance imaging (MRI)
Skeletal dysplasia charts
Staging of puberty

"Review from previous edition: It is very refreshing to review a book written for clinicians by clinicians, which is in a format that reflects situations actually encountered in practice. Information provided by the referring doctor to a clinical geneticist or other specialist before a clinic or ward consultation is usually limited. This new text takes common referral indications and, in a standardized format that manages to be brief and clear without skimping on detail, reminds the clinician of diagnostic possibilities and strategies for investigation and management. This will allow the best possible use to be made of an individual consultation by both the patient and the doctor." - Dian Donnai, Professor of Medical Genetics, University of Manchester, Consultant Clinical Geneticist, Regional Genetics Service, St Mary's Hospital, Manchester, UK

"I have been impressed with the thoughtfulness of the topics. This should be a great help to many people who are part of the clinical genetics team....There are up-to-date summaries for the staff member who needs a refresher, as well as the glossary and the headings on fundamental topics, like AD inheritance, for those just starting out." - Lewis B. Holmes Professor of Pediatrics, Harvard Medical School and Chief, Genetics and Teratology Unit, Massachusetts General Hospital for Children, Boston, Massachusetts, USA

"This is going to be an extremely useful reference source. The authors have done an outstanding job of summarizing, in one or two pages, pertinent recommendations regarding diagnoses and management of specific disorders as well as practical approaches to a variety of problems that commonly present in real life." - Marilyn Jones, Adjunct Professor of Pediatrics, University of California, San Diego and Director, Dysmorphology and Genetics, Children's Hospital San Diego, USA

"...a comprehensive and highly focussed guide to clinical genetics that should certainly rank as an indispensable handbook for consultants in clinical genetics, genetic counsellors and paediatricians. However, it should also be extremely useful for PhD students in nearly all disciplines within medical and/or human genetics. Its major strength is the well-conceived and clearly laid out format which enables the reader to obtain a rapid yet quite substantial overview of a plethora of difficult topics..." - Human Genetics

"The authors of [this book] deserve to be congratulated for achieving the impossible...Overall this book is a winner and is a must for every clinical genetics department. This is arguably the most important book ever published for trainees in genetics...[but] can be considered as an extremely useful reference source to any genetics physician...this book is a 'peripheral brain' and 'lifesaver' for geneticists in many situations!" - Ulster Medical Journal Vol 75, no 3

"If there was a Booker Prize for new texts on clinical genetics, then the winner this year would be a foregone conclusion. No one else could possibly come up with and entry as good as this. ... the definitive hands-on guide to clinical genetics. ... The breadth and depth of information provided is remarkable. ... As a practical guide to the specialty of clinical genetics this book has no match, and overall it represents an awesome achievement. How did the authors manage to acquire and collate all this knowledge? Where did they find all this information? ... If your department can only afford one book this year, make it this one. Better still, buy your own copy and keep it hidden because it is going to be much in demand." - British Medical Journal

"This is an amazing compilation of genetic knowledge. It provides a fantastic tool for clinical geneticists who require a fast review of specific genetic subjects while performing clinical consultations. ... Condensation of the amount of information included in this wonderful book could not be done any better. ... This is a most-have tool for all clinical geneticists who require quick and specific reviews in clinical practice. ... Dr Firth and Hurst have achieved a tremendous goal. They have been able to summarize a tremendous amount of information in clinical genetics and convert it to an excellent tool for the practice of the specialty. It could not be done any better. The magnificent work done suggests that as the field of clinical genetics expands, further editions will be needed. This is a must have book, and a second edition would be expected." - Doody's Book Reviews