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 [...] 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) [...] 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 and 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...