Genetic disorders and the fetus : diagnosis, prevention, and treatment

Explore the latest edition of the definitive resource on prenatal genetic diagnosis In the newly revised eighth edition of Genetic Disorders and the Fetus, authors and acclaimed medical doctors, Aubrey and Jeff Milunsky, deliver a thorough and comprehensive reference perfect for academicians, students in post-graduate specialization courses, and working medical professionals. This book incorporates the knowledge, wisdom, perspectives, and recommendations from a renowned team of contributing authors, drawing upon their extensive experience in prenatal genetic diagnosis to present the definitive reference work used routinely around the world. In addition to fundamental information on established prenatal diagnosis and exhaustively referenced coverage of new techniques, you'll find new chapters on preconception genetic counselling, preimplantation genetic diagnosis, advances in fetal imaging, and gene therapy. Genetic Disorders and the Fetus is authored by a global team of internationally recognized contributors, all of whom are leading voices in the field The eighth edition also contains: A thorough discussion of the public policy and ethics of embryo editing, including mitochondrial replacement treatment, and gene patents, prenatal diagnosis, and polygenic disease risk prediction An exploration of preimplantation genetic diagnosis, pharmacogenetics and prenatal diagnosis, and whole genome sequencing A treatment of genetic disorders and pharmacologic therapy, including spinal muscular atrophy and fragile X syndrome A discussion of legal issues, including the fetus as plaintiff and the increasing liability of physicians due to advances in genetics Perfect for obstetricians, clinical geneticists, molecular and biochemical geneticists, and pediatricians, Genetic Disorders and the Fetus will also earn a place in the libraries of neonatologists, genetics counsellors, ethicists, radiologists, and professionals working in public policy and health departments. Cover Title Page Copyright Contents Preface Acknowledgments Contributors Chapter 1 Genetic Counseling: Preconception, Prenatal, and Perinatal The burden of genetic disorders and congenital malformations Incidence and prevalence of genetic disorders and congenital malformations Congenital malformations and infant morbidity and mortality Down syndrome The goal and purpose of prenatal diagnosis Prerequisites for genetic counseling Knowledge of disease Expertise in genetic counseling Ability to communicate Knowledge of ancillary needs Empathy Sensitivity to parental guilt Guiding principles for genetic counseling Accurate diagnosis Nondirective counseling Concern for the individual Truth in counseling Confidentiality and trust Timing of genetic counseling Parental counseling Counselee education Duty to recontact Do no harm Duty to warn Preconception genetic counseling Indications for preconception genetic counseling Identification of preconception options Genetic counseling as a prelude to prenatal diagnosis Informed consent Presymptomatic or predictive testing Expansion mutations and anticipation Disorders with anticipation Disorders with suspected anticipation Imprinting and uniparental disomy Genotype–phenotype associations Somatic mosaicism Genetic counseling when the fetus is affected Decision making Elective abortion: decision and sequel Testing the other children Perinatal genetic counseling Family matters The surviving children The efficacy of genetic counseling References Chapter 2 Preimplantation Genetic Testing Approaches to preimplantation genetic testing Polar body‐based preimplantation genetic testing Preimplantation genetic testing based on embryo biopsy Prospects for noninvasive preimplantation genetic testing Preimplantation genetic analysis Single‐gene disorders De novo mutations Late‐onset disorders HLA typing Chromosomal disorders Ethical and legal issues Conclusion References Chapter 3 Amniotic Fluid Constituents, Cell Culture, and Neural Tube Defects Introduction Amniotic fluid Formation and circulation Volume Origin Biochemical and other characteristics of amniotic fluid Cell‐free DNA and RNA Proteins Proteomics Lipids Enzymes Amino acids Disaccharidases Miscellaneous biochemical constituents and other characteristics of amniotic fluid Blood group substances Immunoglobulins Antibacterial activity of amniotic fluid Bacteriostatic effect Isolation of infectious agents Hormones Drugs/toxicants Amniotic fluid cell culture Alternatives to cell culture and metaphase karyotype analysis Amniotic fluid cell types Cell culture and cell harvest Enhancement of amniotic fluid cell growth Testing and handling fetal bovine serum Defined growth factor supplements Culture failure Safety in the laboratory Mesenchymal stem cells in amniotic fluid References Chapter 4 Molecular Aspects of Placental Development Overview Placental structure Placental development and function Implantation Angiogenesis Nutrient delivery Immune function Placental insufficiency Fetal growth restriction Genetic causes of fetal growth restriction Developmental considerations in confined placental mosaicism Imprinting and fetal growth restriction Preeclampsia Early diagnosis of preeclampsia Genetics of preeclampsia Genetic findings associated with molar changes in the placenta Complete hydatidiform mole Partial hydatidiform mole Placental mesenchymal dysplasia DNA methylation studies in the placenta and their clinical application Epigenetic studies in the placenta and environment The placenta as a predictor of child health Further considerations References Chapter 5 Fetal Origins of Adult Health and Disease Introduction Epigenetics and programming Energy‐balance programming: under‐ and overnutrition Environmental toxins Maternal stress and anxiety Glucocorticoids and prematurity Organ‐specific programming effects Appetite and adiposity Hepatic programming Pancreas programming Cardiac programming Bone programming Brain programming Renal programming Immune system programming Endocrine programming Sexuality programming Conclusion References Chapter 6 Maternal Serum Screening for Chromosomal Abnormalities and Neural Tube Defects Chromosomal abnormalities Neural tube defects Screening and prenatal diagnosis Widely used markers Additional markers Marker distributions in Down syndrome, neural tube defect, and unaffected pregnancies Risk screening for Down syndrome Age‐specific Down syndrome risk at term Down syndrome risk at the time of the test Down syndrome likelihood ratios Modeling performance of Down syndrome screening Established multimarker Down syndrome policies Model performance of neural tube defect screening Prospective confirmation of the Down syndrome model Further multimarker Down syndrome strategies First‐trimester Contingent test Additional first‐trimester ultrasound markers Additional first‐trimester serum markers First‐trimester Triple and Quad tests Second‐trimester Combined test Genetic sonogram Repeat measures and highly correlated markers Two‐sample Combined test Ultrasound screening for OSB Second‐trimester lemon and banana signs Second‐trimester anomaly scan First‐trimester anomaly scan First‐trimester screening Other Down syndrome markers A disintegrin and metalloprotease 12s (ADAM12s) Pregnancy‐specific glycoprotein‐1 Urinary human chorionic gonadotropin species Serum invasive trophoblast antigen Serum thyroid‐stimulating hormone Clinical factors Maternal age Previous affected pregnancy Twins Assisted reproduction Maternal diabetes Renal transplant Previous false positive Smoking Ethnicity Maternal weight Other factors Edwards syndrome (trisomy 18) Other conditions associated with altered markers Other chromosome abnormalities X‐linked ichthyosis Smith–Lemli–Opitz syndrome Cornelia de Lange syndrome Abdominal wall defects Cardiac abnormalities Moles and placental mesenchymal dysplasia Fetal demise Adverse maternal–fetal complications of pregnancy Planning a program Conclusion Acknowledgments References Chapter 7 Noninvasive Screening for Aneuploidy Using Cell‐Free Placental DNA Introduction Cell‐free DNA Performance of cell‐free DNA screening Sex chromosome aneuploidy Cell‐free DNA screening approaches Cell‐free DNA test failures False‐positive cell‐free DNA results and incidental findings Maternal malignancy Vanishing twins False‐negative cell‐free DNA results Cell‐free DNA screening for microdeletion syndromes Genome‐wide cell‐free DNA screening Pretest counseling Post‐test screening Comparison of cell‐free DNA screening to traditional screening Cost‐effectiveness Contingent screening Cell‐free DNA screening following a positive traditional screening test Use of prenatal ultrasound in the setting of cell‐free DNA First trimester Ultrasound soft markers and cell‐free DNA screening Discordance between fetal sex on ultrasound and cell‐free DNA screening Multiple gestations Cell‐based noninvasive prenatal testing Conclusion References Chapter 8 Noninvasive Prenatal Diagnosis and Screening for Monogenic Disorders Using Cell‐Free DNA Introduction Biology and characteristics of cell‐free DNA in maternal blood Origin of fetal cell‐free DNA Importance of the fetal fraction General approaches for testing of single‐gene disorders by fetal cell‐free DNA analysis Identification of de novo or paternally inherited variants Identification of maternally inherited variants Laboratory techniques used for cfDNA‐based single‐gene disorder analysis Limitations of cfDNA‐based detection of single‐gene disorders Current status of noninvasive single‐gene testing by cell‐free DNA analysis Overview Noninvasive fetal sex determination Fetal RHD and other blood group genotyping Noninvasive prenatal diagnosis of monogenic disorders Skeletal dysplasias Duchenne and Becker muscular dystrophy Cystic fibrosis Spinal muscular atrophy Congenital adrenal hyperplasia Hemoglobinopathies Noninvasive prenatal screening using panels of single‐gene disorders by cell‐free DNA analysis Clinical implementation: ethical and social issues Summary and future directions References Chapter 9 Amniocentesis, Chorionic Villus Sampling, and Fetal Blood Sampling Introduction Amniocentesis Prerequisites Timing Technique Ultrasound guidance during amniocentesis Amniocentesis in multiple gestations Rh isoimmunization in amniocentesis Significance of amniotic fluid discoloration Safety of genetic amniocentesis Pregnancy losses Early amniocentesis Third‐trimester amniocentesis Chorionic villus sampling Technique of chorionic villus sampling Complications of chorionic villus sampling Safety of chorionic villus sampling in multiple pregnancies Reliability of results from chorionic villus sampling Fetal abnormalities following chorionic villus sampling Fetal blood sampling Fetal hematologic disorders Fetal infection Fetal therapy Technique of fetal blood sampling Safety of fetal blood sampling Fetal blood sampling in multifetal pregnancies Fetal blood sampling in fetuses with single umbilical arteries First‐trimester fetal blood sampling Cardiocentesis References Chapter 10 Prenatal Diagnosis of Neural Tube Defects Biology of α‐fetoprotein Amniotic fluid α‐fetoprotein Multiple pregnancy Causes of elevated (or low) levels of AFAFP in the absence of NTDs Likely mechanism/condition Leakage through skin Urinary tract leakage Leakage of placental origin Leakage of pulmonary origin Reduced intestinal AFP clearance or leakage Unknown site of “leakage” Problems and pitfalls Amniotic fluid acetylcholinesterase Experience with AFAChE Recommendations for prenatal diagnosis of NTDs using AFAFP and AChE assays Other techniques to detect neural tube defects Primary prevention of neural tube defects Genetic counseling Nutritional supplementation Complications and life expectancy References Additional references Chapter 11 Prenatal Diagnosis of Chromosomal Abnormalities through Chorionic Villus Sampling and Amniocentesis The incidence of chromosomal abnormalities detected by conventional cytogenetics Data from livebirths Data from adult biobanks Data from amniocentesis Data from chorionic villus sampling Data from spontaneous abortuses Data from induced abortuses Data from stillbirths Indications for prenatal cytogenetic diagnosis Noninvasive prenatal testing and trisomy 21, trisomy 18, and trisomy 13 Noninvasive prenatal testing and sex chromosome abnormalities Noninvasive prenatal testing and microdeletion syndromes Genome‐wide noninvasive prenatal testing Noninvasive prenatal testing and low fetal fraction The first‐trimester Combined test Second‐trimester maternal serum screening Elevated maternal serum α‐fetoprotein Abnormal ultrasound findings The “genetic sonogram” or “anomaly scan” Advanced maternal age Advanced paternal age Multiple gestation pregnancy Carrier of a balanced structural rearrangement Previous child with trisomy Previous child with a de novo unbalanced rearrangement: isochromosome 21q and others Genetic variation in folate metabolism and previous child with a neural tube defect History of repeated fetal losses: parents' karyotype unknown History of fetal loss: fetal karyotype considerations Fetal demise, current pregnancy Male or female subfertility, cytogenetic causes Reduced ovarian complement Abnormal parental karyotype (other than a balanced structural rearrangement) Prenatal sex determination for X‐linked disorders Prenatal diagnosis for a nonchromosomal disorder Miscellaneous Interpretation issues: chromosome mosaicism and pseudomosaicism General considerations Diagnosing mosaicism in chorionic villus sampling Diagnosing mosaicism in amniotic fluid cell cultures Mosaicism involving gain of an autosome: data for individual chromosomes Autosomal monosomy mosaicism Mosaicism involving an autosomal structural abnormality (excluding supernumerary marker chromosomes) in CVS Mosaicism involving an autosomal structural abnormality (excluding supernumerary and marker chromosomes) in AFC Sex chromosome mosaicism in chorionic villus sampling Sex chromosome mosaicism in amniotic fluid cells Other types of mosaicism Guidelines for the diagnosis of mosaicism Genetic counseling and chromosome mosaicism Interpretation issues: chromosome rearrangements Familial structural rearrangements De novo structural rearrangements Uniparental disomy in familial and de novo rearrangements Summary conclusions and recommendations for chromosome rearrangements Interpretation issues: chromosome polymorphisms, common inversions, and other structural variations Polymorphisms of chromosomes 1, 9, 16, and Y Polymorphisms of acrocentric chromosomes Polymorphism of other chromosomes, “common” inversions, and translocations Summary conclusions and recommendations for polymorphisms and other variations Interpretation issues: maternal cell contamination Maternal cell contamination in chorionic villus sampling Maternal cell contamination in amniotic fluid cell culture Factors affecting diagnostic success rate and accuracy Twin pregnancy Mycoplasma contamination of cell cultures Toxic syringes or tubes Other causes of culture failure Technical standards for prenatal cytogenetics laboratories Error rates in prenatal cytogenetic diagnosis Discordance between karyotyping and molecular genetic testing Conclusion Acknowledgments References Chapter 12 Prenatal Diagnosis of Sex Chromosome Abnormalities Incidence Ascertainment bias Patterns of inheritance Prenatal diagnosis Turner syndrome Diagnosis and management Cognitive/psychologic development Karyotype variations Prenatal counseling for Turner syndrome 45,X mosaicism Klinefelter syndrome Clinical features and management Cognitive/psychologic development Prenatal counseling for 47,XXY 47,X,i(Xq),Y 47,XXY mosaicism 48,XXYY 48,XXXY 49,XXXXY 49,XXXYY Triple X and poly‐X syndromes Clinical features and medical management Cognitive/psychologic development Prenatal counseling for 47,XXX 47,XXX mosaicism 48,XXXX 49,XXXXX 47,XYY males Historical perspective Clinical features and medical management Cognitive/psychologic development Prenatal counseling for 47,XYY 46,XY/47,XYY mosaicism Polysomy Y karyotypes 48,XYYY 49,XYYYY 49,XXYYY Structural abnormalities of the X chromosome Xp deletions: del(Xp) or Xp2 Xq deletions: del(Xq) or Xq2 Xp duplications: dup(Xp) Xq duplications: dup(Xq) Isochromosome Xp: i(Xp) Isochromosome Xq: i(Xq) Marker X Inversion X: inv(X) X;autosome translocations X;X translocations Structural abnormalities of the Y chromosome Yp deletions: del(Yp) Yq deletions: del(Yq) Isochromosome Yp: i(Yp) Isochromosome Yq: i(Yq) Isodicentric Yp: idic(Yp) Isodicentric Yq: idic(Yq) Ring Y: r(Y) Marker Y: mar(Y) Inversion Y: inv(Y) Satellited Yq: Yqs Y;autosome translocations X;Y translocations Y;Y translocations Disorders of sex development 46,XX males 45,X males 47,XXX males 46,XY females Other sex reversal syndromes Ovotesticular disorders of sex development Conclusion References Chapter 13 Prenatal Diagnosis of Chromosomal Abnormalities: From Karyotype to Microarray The study and impact of chromosome abnormalities in humans Traditional cytogenetic testing: analysis of the G‐banded metaphase Incidence and spectrum of chromosome abnormalities observed in prenatal diagnosis Rapid identification of the common aneuploidies Fluorescence in situ hybridization Quantitative fluorescence polymerase chain reaction Multiplex ligation‐dependent probe amplification Chromosome microarray analysis adds diagnostic yield over karyotyping and rapid aneuploidy techniques Types of microarrays Array comparative hybridization Single‐nucleotide polymorphisms arrays Microarray design for clinical testing Interpreting and reporting of CMA results Cytogenomic tools and tips for interpreting CNVs Factors affecting CMA diagnostic yield Number of probes on the array and CNV size cutoff Impact on variants of uncertain significance The benefit of SNPs CMA in routine pregnancies CMA in pregnancies with ultrasound anomalies CMA versus karyotyping: additional points to consider CMA and genetic counseling Conclusion References Chapter 14 Molecular Genetics and Prenatal Diagnosis Diagnostic methods: use, limitations, and pitfalls Source of DNA for analysis Methods of analysis Clinical databases In silico tools Carrier detection Presymptomatic/predictive DNA tests Mutation detection Clinical caveats, cautions, limitations, and pitfalls Dynamic mutations and anticipation Mosaicism Imprinting and uniparental disomy Genotype–phenotype correlations Additional cautions and considerations Prenatal diagnosis of mitochondrial disorders Reporting incidental (secondary) results Ethical considerations in prenatal testing References Chapter 15 Prenatal Diagnosis of Cystic Fibrosis Genetics and epidemiology Clinical features Diagnosis Treatment Discovery of the cystic fibrosis gene The CFTR gene and its protein product CFTR mutations and variants Genotype–phenotype correlation Congenital bilateral absence of the vas deferens Modifier genes Ethnic variation in mutation frequencies Development and implementation of public policy for CF population carrier screening and the core mutation panel Laboratory methods Expanded panels Outcomes of the CF carrier screening program Special prenatal diagnosis situations Positive–negative couples Positive family history Echogenic bowel Assisted reproduction and preimplantation diagnosis Newborn screening Future directions References Chapter 16 Prenatal Diagnosis and the Spectrum of Involvement from Fragile X Mutations Introduction Epidemiology Clinical involvement in those with the full mutation Clinical phenotype in the premutation Pathogenesis of the premutation‐associated disorder FXTAS Neuropathology Molecular pathogenesis Molecular prenatal diagnosis methodology Preimplantation genetic testing and polar body analysis Neurobiologic advances and targeted treatment in the full mutation Genetic counseling Acknowledgments References Chapter 17 Prenatal Diagnosis of Fetal Malformations by Ultrasound Introduction Craniospinal defects Neural tube defects Acrania–exencephaly–anencephaly sequence Open spina bifida Encephalocele Ventriculomegaly – hydrocephaly Hydranencephaly Holoprosencephaly Microcephaly Corpus callosum agenesis Posterior fossa malformations Mega cisterna magna Blake's pouch cyst Vermian hypoplasia Dandy–Walker malformation Fetal face Cleft lip and/or palate Micrognathia and retrognathia Pulmonary and thoracic abnormalities Congenital pulmonary airway malformation Congenital diaphragmatic hernia Pleural effusions Congenital high airway obstruction syndrome Fetal hydrops (immune and nonimmune) Cardiovascular defects Cardiac anomalies Ventricular septal defect Atrioventricular septal defect Transposition of the great arteries Tetralogy of Fallot Abdominal wall defects Omphalocele (exomphalos) Gastroschisis Body stalk anomaly Bladder exstrophy and cloacal exstrophy Gastrointestinal anomalies Esophageal atresia Duodenal atresia Small bowel obstruction Meconium peritonitis Abdominal cysts Kidneys and urinary tract anomalies Renal development and CAKUT Dilatation of the renal pelvis Structural kidney malformations Renal agenesis Abnormalities of pelvic migration Skeletal anomalies Nuchal translucency Phenotypic expression in chromosome anomalies Trisomy 21 – Down syndrome Trisomy 18 – Edwards syndrome Trisomy 13 – Patau syndrome Triploidy Turner syndrome References Chapter 18 Prenatal Diagnosis and Management of Abnormal Fetal Development in the Third Trimester of Pregnancy Cardiac anomalies Value of the four‐chamber view in screening for congenital heart disease Abnormalities in four‐chamber view screening Hypoplastic left heart Functional assessment of the fetal heart Echogenic lung lesions Bronchopulmonary sequestration Congenital cystic adenomatoid malformation Congenital high airway obstruction sequence Hydrothorax Congenital diaphragmatic hernia Anomalies of gastrointestinal tract and abdominal wall Gastrointestinal obstruction Abdominal wall defects Urinary tract anomalies Incidence and etiology Diagnosis Fetal treatment Prognosis Central nervous system malformations Fetal ventriculomegaly Spina bifida Absence of cavum septum pellucidum and abnormalities in the midline Holoprosencephaly Agenesis of the corpus callosum Schizencephaly Absent cavum septum pellucidum Abnormalities of the posterior cranial fossa and cerebellar anomalies Parental counseling after diagnosis of fetal brain abnormalities References Chapter 19 Prenatal Diagnosis by Fetal Magnetic Resonance Imaging Introduction MRI of the fetal central nervous system Technical issues Fetal brain MRI: when and why? Developing brain Developmental abnormalities CNS malformations Ventriculomegaly and genetic disorders Inborn errors of metabolism Subependymal cysts Brain injury MRI of non‐CNS fetal systems Technical issues Fetal neck Fetal chest Fetal abdomen and pelvis Urinary tract pathologies, kidney diseases, and genital malformations Skeletal malformations Conclusion References Chapter 20 Prenatal Diagnosis of Skeletal Dysplasias and Connective Tissue Disorders Prenatal sonographic diagnosis of skeletal dysplasias Abnormal fetal morphology as an unexpected finding Molecular testing during pregnancy Estimating the probability of recurrence Achondroplasia, thanatophoric dysplasia, and hypochondroplasia (FGFR3 disorders) Prenatal diagnosis Osteogenesis imperfecta Prenatal diagnosis Disorders due to defects in type II collagen (achondrogenesis type 2, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita) Prenatal diagnosis Disorders due to defects in the diastrophic dysplasia sulfate transporter gene (achondrogenesis 1B, atelosteogenesis type 2, and diastrophic dysplasia) Prenatal diagnosis Joint dislocations: Larsen syndrome and connective tissue disorders Prenatal diagnosis Marfan syndrome and Marfan overlap disorders Pregnancy‐related aspects and prenatal diagnosis Acknowledgments References Chapter 21 Prenatal Diagnosis of Disorders of Carbohydrate Metabolism Introduction Glycogen storage diseases Type I GSD (glucose‐6‐phosphatase and glucose‐6‐phosphate translocase deficiency, von Gierke disease) Type II GSD (acid α‐glucosidase deficiency, Pompe disease) Type III GSD (debrancher deficiency, limit dextrinosis, Cori or Forbes disease) Type IV GSD (branching enzyme deficiency, amylopectinosis, or Andersen disease) Type V GSD (muscle phosphorylase deficiency, McArdle disease, myophosphorylase deficiency) Type VI GSD (liver phosphorylase, Hers disease) Type VII GSD (phosphofructokinase deficiency, Tarui disease) Type IX GSD (phosphorylase b kinase deficiency) Glycogen synthase deficiency Hepatic glycogenosis with renal Fanconi–Bickel syndrome Disorders of galactose metabolism Galactosemia with transferase deficiency Galactokinase deficiency Uridine diphosphate galactose‐4‐epimerase (UDPgal‐4‐epimerase) deficiency Disorders of fructose metabolism Essential fructosuria Hereditary fructose intolerance (fructose‐1‐phosphate aldolase B deficiency) Disorders of gluconeogenesis Fructose‐1,6‐bisphosphatase deficiency Phosphoenolpyruvate carboxykinase deficiency Pentosuria Acknowledgments References Chapter 22 Disorders of Metabolism of Amino Acids and Related Compounds Introduction Inborn errors of metabolism Amino acid disorders Methods of prenatal screening of amino acid disorders The placenta as a filter Maternal nutrition and amino acid disorders: potential impact on the fetus Intoxication disorders Urea cycle disorders Other disorders presenting with hyperammonemia or involving urea cycle intermediates Disorders of ornithine metabolism Sulfite oxidase deficiency Nonketotic hyperglycinemia Mevalonic aciduria 4‐Hydroxybutyric aciduria (succinic semialdehyde dehydrogenase deficiency) Disorders of organic acids Other disorders of catabolism of branched‐chain amino acids Disorders of sulfur amino acid metabolism Disorders of energy production l‐2‐Hydroxyglutaric aciduria d‐2‐Hydroxyglutaric aciduria Glutaric aciduria type II (multiple acyl‐CoA dehydrogenase disorder) Very rare amino acid disorders Hypervalinemia (a disorder of valine metabolism) Hypermethioninemia due to methionine adenosyltransferase deficiency Combined d‐2‐ and l‐2‐hydroxyglutaric aciduria Methylenetetrahydrofolate reductase deficiency Prolidase deficiency Disorders of proline metabolism Disorders of renal amino acid transport In conclusion References Chapter 23 The Mucopolysaccharidoses: Prenatal Diagnosis, Neonatal Screening and Emerging Therapies Introduction Disease and biochemical characteristics Clinical and biochemical fundamentals Structure and function of glycosaminoglycans Prenatal diagnosis Clinical characteristics and disease pathogenesis Clinical heterogeneity Genetic heterogeneity Genotype–phenotype correlations Mucopolysaccharidose disease pathogenesis Pathophysiology of disease Pathogenesis of MPS skeletal disease Pathogenesis of MPS nervous system disease Postnatal MPS therapeutics Newborn screening Fetal considerations Future directions References Chapter 24 Prenatal Diagnosis of the Peroxisomal and Mitochondrial Fatty Acid Oxidation Deficiencies Introduction Mitochondrial versus peroxisomal fatty acid β‐oxidation Mitochondrial fatty acid β‐oxidation disorders Primary carnitine deficiency (OCTN2 deficiency) (OMIM 212140) Carnitine palmitoyl transferase‐1 A deficiency (OMIM 600528) Carnitine–acylcarnitine translocase deficiency (OMIM 212138) Carnitine palmitoyl transferase 2 deficiency (OMIM 600649, 600650, 255110, 608836) Very long‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201475) Medium‐chain acyl‐CoA dehydrogenase deficiency (OMIM 201450) Mitochondrial trifunctional protein deficiency (OMIM 600890) Secondary disorders of mitochondrial fatty acid oxidation Peroxisomal fatty acid β‐oxidation disorders Primary peroxisomal fatty acid oxidation disorders X‐linked adrenoleukodystrophy (OMIM 300100) Acyl‐CoA oxidase 1 deficiency (OMIM 264470) Acyl‐CoA oxidase 2 deficiency (OMIM 601641) D‐bifunctional protein deficiency (OMIM 261515) Sterol carrier protein X deficiency (OMIM 613724) 2‐Methylacyl‐CoA racemase deficiency (OMIM 604489) PMP70 deficiency (OMIM 170995) and ACBD5 deficiency (OMIM 616618) Secondary disorders of peroxisomal fatty acid oxidation References Chapter 25 Prenatal Diagnosis of Disorders of Lipid Metabolism Introduction Lipoprotein‐associated disorders Defects in the metabolism of glycosphingolipids Structure of glycosphingolipids Function and distribution of glycosphingolipids Biosynthesis of glycosphingolipids Defects in the biosynthesis of glycosphingolipids The lysosomal catabolism of glycosphingolipids GM1‐gangliosidosis/mucopolysaccharidosis IVB (Morquio B) GM2‐gangliosidoses Tay–Sachs disease: mutations in HEXA gene (α‐subunit) (OMIM: 272800) B1 variant Pseudodeficiency Hexosaminidase S Sandhoff disease: mutations in HEXB (β‐subunit) (GM2‐gangliosidosis 0 variant) (OMIM: 268800) Variant AB Fabry disease Gaucher disease Metachromatic leukodystrophy Multiple sulfatase deficiency Krabbe disease (globoid cell leukodystrophy) Niemann–Pick disease Niemann–Pick disease types A and B (acid sphingomyelinase deficiency) Niemann–Pick type C Farber disease Lysosomal acid lipase deficiency: Wolman disease and cholesteryl ester storage disease The neuronal ceroid lipofuscinoses Acknowledgments References Chapter 26 Prenatal Diagnosis of Primary Immunodeficiency Diseases Family history Specific immune defects Lymphocyte deficiencies T‐cell and combined deficiencies Antibody deficiencies Phagocyte deficiencies Defects with autoimmunity or immune dysregulation Complement deficiencies Additional syndromic immune defects References Chapter 27 Prenatal Diagnosis of the Hemoglobinopathies Introduction Clinical types α‐Thalassemia Hb Bart's hydrops fetalis syndrome Hb H disease β‐Thalassemia β‐Thalassemia major β‐Thalassemia intermedia Hb E disorders Hb E/β‐thalassemia Hb AE Bart's disease Hb EF Bart's disease Hb E/E plus αCSα/αCSα Sickle cell disorders Sickle cell anemia Hb S/β‐thalassemia Hb S/fδβ‐thalassemia Hb S/Hb C Hb S/Hb E Hb S/Hb D‐Punjab Hb S/Hb O‐Arab Hb S/Hb C‐Harlem Hb S/Hb S‐Southend Hb S‐Antilles Hb S‐Oman Other sickling variants Hb S/other rare β‐chain variants Carrier screening Reduced red cell indices with a raised Hb A2 value Reduced red cell indices with a normal Hb A2 value Strategy for fetal diagnosis Approaches to prenatal diagnosis Amniotic fluid DNA Chorionic villus DNA Noninvasive prenatal diagnosis Preimplantation diagnosis DNA diagnosis of the hemoglobinopathies α‐Thalassemia β‐Thalassemia The δβ‐thalassemias, Hb Lepore, and hereditary persistence of fetal hemoglobin disorders Abnormal hemoglobins Hb S Hb C Hb D‐Punjab and Hb O‐Arab Hb E Diagnostic pitfalls and best practice for fetal diagnosis Maternal DNA contamination Technical errors Diagnostic error rate Guidelines for best practice Summary References Chapter 28 Prenatal Diagnosis of Inherited Disorders of Folate and Cobalamin Metabolism Inborn errors of folate metabolism Hereditary malabsorption of folate Cerebral folate deficiency Glutamate formiminotransferase deficiency Methylenetetrahydrofolate reductase deficiency Dihydrofolate reductase deficiency MTHFD1 deficiency Methenyltetrahydrofolate synthetase deficiency Inborn errors of cobalamin metabolism Disorders of cobalamin uptake Transcobalamin deficiency Transcobalamin receptor deficiency Disorders of cobalamin utilization Isolated methylmalonic aciduria Isolated methylcobalamin deficiency Combined methylmalonic aciduria and homocystinuria Prenatal diagnosis and fetal therapy References Chapter 29 Fetal Surgery Introduction Brief history of fetal surgery Ethical considerations Imaging principles for fetal intervention and surgical procedures Control of fetal pain Closed fetal therapies Conditions treated using fetoscopic procedures Placental laser photocoagulation for twin‐to‐twin transfusion syndrome Placental laser photocoagulation for twin anemia polycythemia sequence Placental laser photoco "The time is fast approaching when virtually all the culprit genes and their mutations for 7,000 rare monogenic disorders1 will be known. Thus far causal single genes and their mutations have been determined for 5,6732 genetic disorders, enabling pre-implantation genetic testing or prenatal genetic diagnosis. These advances using chromosomal microarrays, whole exome sequencing and even whole genome sequencing together with fetal imaging, and non-invasive prenatal testing, expand the era in which all couples have the option of avoiding or preventing having children with irreversible, irremediable, crippling, or lethal monogenic disorders. Primary care physicians, and those in all medical specialties, will need to inform their patients of this key option. This imperative is already partly in current practice. Missing is the requirement of physicians to request and obtain the precise name of the genetic disorder in question or an existing DNA report on a family member, for prospective parents to benefit from available options"-- Provided by publisher