Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Perinatal and Reproductive Genetics

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EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS
EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS: Perinatal and Reproductive Genetics
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CONTENTS
LIST OF CONTRIBUTORS
PREFACE TO THE SEVENTH EDITIONO F EMERY AND RIMOIN’SPRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS
PREFACE TO PERINATAL ANDRE PRODUCTIVE GENETICS
1 - Introduction to Perinatal Disorders and Reproductive Genetics
	1.1 INTRODUCTION
	1.2 IMAGING DURING PREGNANCY—A FIRST LOOK
		1.2.1 Radiography
		1.2.2 Ultrasound Imaging
		1.2.3 MR Imaging
	1.3 PRENATAL DIAGNOSTICS—CONFIRMING GENETIC DISORDERS
		1.3.1 Amniocentesis
		1.3.2 CVS
		1.3.3 Preimplantation Genetic Testing
		1.3.4 Cytogenetic and Molecular Techniques Used for Prenatal Diagnosis
	1.4 PRENATAL SCREENING FOR GENETIC DISORDERS—ANEUPLOIDY AND SINGLE GENE
		1.4.1 Fetal Aneuploidy Screening
		1.4.2 Carrier Screening for Genetic Disorders
	1.5 THE END OF THE BEGINNING AND WHAT LIES AHEAD
		1.5.1 We Can Do It, but Should We Do It?
		1.5.2 Women’s Autonomy
	1.6 CONCLUSION
2 - Prenatal Screening for Neural Tube Defects and Aneuploidy
	2.1 INTRODUCTION
	2.2 PRENATAL SCREENING FOR BIRTH DEFECTS
		2.2.1 Neural Tube Defects
		2.2.2 Down Syndrome and Aneuploidies in Pregnancy
			2.2.2.1 Down Syndrome
			2.2.2.2 Trisomy 18
			2.2.2.3 Other Chromosome Abnormalities
			2.2.2.4 Aneuploidy and Spontaneous Fetal Loss
		2.2.3 Maternal Age as a Marker for Aneuploidy
		2.2.4 AFP as a Biomarker of Fetal Development in Maternal Circulation
			2.2.4.1 AFP in Unaffected Pregnancies
			2.2.4.2 AFP in Pregnancies Affected with Neural Tube Defects
			2.2.4.3 AFP in Pregnancies Affected with Down Syndrome
		2.2.5 Prenatal Screening—Primary Focus on NTD and Down Syndrome
		2.2.6 Biochemical Markers for Down Syndrome and Other Conditions
			2.2.6.1 In Serum
			2.2.6.2 Blood Spots
			2.2.6.3 Urine
		2.2.7 Reagents and Platforms in Clinical Perspective
		2.2.8 Nonbiochemical Markers from Ultrasound
			2.2.8.1 Nuchal Translucency
			2.2.8.2 Nasal Bone
			2.2.8.3 Other Ultrasound Markers for Aneuploidy
	2.3 RISK DETERMINATION AND THRESHOLDS
		2.3.1 Computation of Risk
		2.3.2 A Priori Risks and Distribution Limits
	2.4 MODALITIES OF TESTING FOR NTD AND DOWN SYNDROME
		2.4.1 Second Trimester Biochemical Screening for Down Syndrome and Trisomy 18
		2.4.2 First Trimester Biochemical Screening with or Without Ultrasound for Aneuploidy
		2.4.3 Integrated First and Second Trimester Screening
		2.4.4 Contingent Testing
	2.5 FOLLOW-UP TO POSITIVE SCREENS—NTD
		2.5.1 Biochemical Analysis from Amniotic Fluid
		2.5.2 Prenatal Ultrasound in NTD Screening
		2.5.3 Follow-up to Positive Screens—Down Syndrome and Other Aneuploidies
			2.5.3.1 Diagnostic Testing
			2.5.3.2 Reflex Screening via Cell-free DNA
	2.6 MAINTAINING AND MONITORING SCREENING PERFORMANCE
		2.6.1 Measures of Screening Performance
		2.6.2 Detection Rate and Specificity Tradeoff in Multiple Marker Screening Comparisons
	2.7 KEEPING SCREENING IN PERSPECTIVE
	2.8 SUMMARY
3 - Techniques for Prenatal Diagnosis
	3.1 INTRODUCTION
	3.2 AMNIOCENTESIS
		3.2.1 Traditional Amniocentesis: 15Weeks Gestation and Greater
			3.2.1.1 Technique
			3.2.1.2 Multiple Gestations
			3.2.1.3 Safety
				3.2.1.3.1 Transmission of maternal infection. There is a paucity of data on vertical transmission of chronic viral infections to...
				3.2.1.3.2 Diagnostic testing in multiple gestations. With regard to twin pregnancies, Cahill and colleagues [50] reported a 16-y...
		3.2.2 Early Amniocentesis: 14Weeks Gestation or Less
	3.3 CHORIONIC VILLUS SAMPLING
		3.3.1 Techniques for CVS
			3.3.1.1 Transcervical CVS
			3.3.1.2 Transabdominal CVS
			3.3.1.3 Transvaginal CVS
		3.3.2 Safety of CVS
			3.3.2.1 Pregnancy Loss After CVS
			3.3.2.2 CVS in Multifetal Pregnancy
			3.3.2.3 Limb-Reduction Deformities
	3.4 FETAL BLOOD SAMPLING
		3.4.1 Technique
		3.4.2 Safety
	3.5 FETAL SKIN AND TISSUE BIOPSY PROCEDURES
	ACKNOWLEDGMENTS
4 - Neonatal Screening
	4.1 INTRODUCTION
	4.2 HISTORICAL ASPECTS
	4.3 COMPONENTS OF SCREENING PROGRAMS
		4.3.1 Collection of Specimens
		4.3.2 Organization of Screening
		4.3.3 Analysis of Specimens
		4.3.4 Interpretation of the Screening Results
		4.3.5 Confirmatory Tests
	4.4 POTENTIAL PROBLEMS IN NEWBORN SCREENING
		4.4.1 False-Positive Results
		4.4.2 Early Newborn Screening
		4.4.3 Sick and Transfused Infants
		4.4.4 Missed and Uncovered Disorders
		4.5.1 Amino Acid Disorders
		4.5.2 Organic Acid Disorders
		4.5.3 Fatty Acid Oxidation Disorders
		4.5.4 Galactosemia
		4.5.5 Biotinidase Deficiency
		4.5.6 Lysosomal Storage Disorders
		4.5.7 X-Linked Adrenoleukodystrophy
	4.6 OTHER CONGENITAL DISORDERS AND CONDITIONS DETECTED BY NEWBORN BLOOD SCREENING
		4.6.1 Congenital Adrenal Hyperplasia
		4.6.2 Congenital Hypothyroidism
		4.6.3 Cystic Fibrosis
		4.6.4 Hemoglobinopathies and Thalassemias
		4.6.5 Severe Combined Immunodeficiency
		4.6.6 Spinal Muscular Atrophy
		4.6.7 Other Disorders
	4.7 ISSUES AND CONCERNS IN SCREENING
5 - Hypogonadotropic and Hypergonadotropic Hypogonadism in Females: Disorders of Reproductive Ducts
	5.1 KALLMANN SYNDROME AND IDIOPATHIC (CONGENITAL) HYPOGONADOTROPIC HYPOGONADISM
		5.1.1 Nomenclature and Categorization
		5.1.2 Kallmann Syndrome and KAL1 Mutations
		5.1.3 Hypogonadotropic Hypogonadism and Anosmia Caused by Genes Other than ANOS1
		5.1.4 Failure of Neuroendocrine Secretion
		5.1.5 Disorders Associated with Cerebellar Ataxias and Neurodegenerative Conditions
		5.1.6 Pituitary Causes of IHH
		5.1.7 Dysmorphic Features Identifying a Specific Mutant Gene
		5.1.8 Oligogenic and Digenic Causations of Hypogonadotropic Hypogonadism
		5.2.1 Chromosomal Abnormalities
		5.2.2 Localization of X-Chromosome Regions
		5.2.3 Cytogenomic Variants
		5.2.4 Candidate Gene Approaches
		5.2.5 Genome-Wide Association Studies
		5.2.6 Whole Exome Sequencing and Whole Genome Sequencing
		5.2.7 POF/POI Gene Identification in the Future
	5.3 MECHANISM OF ACTION FOR GENES CAUSING HYPERGONADOTROPIC HYPOGONADISM
		5.3.1 Genes on the X Chromosome
			5.3.1.1 BMP15
				5.3.1.1.1 AR. The androgen receptor (AR) gene is located at Xq12, a region that phenotypic/karyotypic correlations indicated was...
				5.3.1.1.2 FOX04. Located at Xq13.1, Forkhead Homeobox04 (FOXO4) is expressed in granulosa cells. Its perturbation has been repor...
				5.3.1.1.3 POF, 1B. Located at Xq21.2, this gene is actually a region, but named as one of the 15 OMIM-designated POF genes (Tabl...
				5.3.1.1.4 DACH2. DACH2 (Dachsund family transcription factor 2) is located at Xq21.3, initially identified in an X-autosome tran...
				5.3.1.1.5 PGRMC1. Located at Xq22-24, progesterone receptor membrane component 1 (PGRMC1) is a progesterone-binding receptor inv...
				5.3.1.1.6 FMR1. Perturbation in FMR1 (Xq27) results in the clinically well-known Fragile X syndrome. Localized to Xq27.3, Famili...
		5.3.2 Autosomal Genes Involved in Embryonic Ovarian Development
		5.3.3 Genes Involved in Chromosomal Segregation
		5.3.4 Autosomal Genes Involving DNA Repair
		5.3.5 Autosomal Genes Involved in Oocyte Maturation and Follicular Development
		5.3.6 Pleiotropic Genes and Multiple Malformation Syndrome with POF/POI
		5.3.7 Mitochondrial Dysfunction with POF/POI Caused by Mitochondrial and Nuclear DNA Mutations
			5.3.7.1 Nuclear DNA Mutations
			5.3.7.2 Mitochondrial DNA Mutations
		5.3.8 Autosomal Genes Involving G-Protein Gonadotropin Receptor Defects
			5.3.8.1 FSHR
			5.3.8.2 LH-coupled–G protein receptor mutations
				5.3.8.2.1 G-Protein–Coupled Receptor 3. This G-protein receptor helps maintain meiotic arrest until time for the LH surge. Absen...
		5.3.9 Micro RNA and POF/POI
	5.4 RELATED GYNECOLOGICAL DISORDERS CAUSING INFERTILITY
		5.4.1 Polycystic Ovary Syndrome
		5.4.2 Ovarian Hyperstimulation due to Activating FSHR Mutations
		5.4.3 17α Hydroxylase/17,20–Lyase (CYP17)
		5.4.4 Aromatase Deficiency (CYP19)
		5.4.5 46,XY Agonadia and 46,XX Agonadia
		5.4.6 Zona Pellucida Defects
		5.4.7 Fertilization Failure due to Oocyte Maturation Defects
		5.4.8 Failure of Embryogenesis due to Zygote/Embryonic Arrest
		5.4.9 Leiomyomata
		5.4.10 Endometriosis
	5.5 STRUCTURAL ANOMALIES OF THE UTERUS AND VAGINA
		5.5.1 Müllerian Aplasia
		5.5.2 Incomplete Müllerian Fusion (IMF)
		5.5.3 Hand–Foot–Genital Syndrome
		5.5.4 Transverse Vaginal Septa and the McKusick–Kaufman Syndrome
		5.5.5 Vaginal Atresia
		5.5.6 Longitudinal Vaginal Septa
		5.5.7 Imperforate Hymen
6 - Genetics of Male Infertility
	6.1 MALE INFERTILITY—INTRODUCTION
	6.2 CHROMOSOME ANOMALIES
		6.2.1 Karyotype Anomalies
			6.2.1.1 Numerical Alterations of the Chromosomes
			6.2.1.2 Structural Alterations of the Chromosomes Detectable with Karyotyping
		6.2.2 Submicroscopic Deletions of the Y Chromosome: AZF Deletions
		6.2.3 Chromosomal Alterations Detectable with Array-Comparative Genomic Hybridization/Chromosomal Microarray
	6.3 GENE DEFECTS INVOLVED IN ENDOCRINE FORMS OF INFERTILITY
		6.3.1 Mutations and Polymorphisms Affecting the Androgen Receptor
		6.3.2 Congenital Hypogonadotropic Hypogonadism
		6.3.3 Persistent Müllerian Duct Syndrome
		6.3.4 Luteinizing Hormone, Luteinizing Hormone Receptor, and FSH and FSH Receptor
	6.4 MONOGENIC DEFECTS OF MALE INFERTILITY
		6.4.1 Monogenic Defects Causing Quantitative Spermatogenic Disturbances
		6.4.2 Monogenic Defects Causing Qualitative Spermatogenic Disturbances
		6.4.3 Monogenic Defects Causing Posttesticular Infertility: Congenital Absence of the Vas Deferens
	6.5 SYNDROMIC MONOGENIC DEFECTS
		6.5.1 Bardet–Biedl Syndrome
		6.5.2 Prader–Willi Syndrome
		6.5.3 Primary Ciliary Dyskinesia
		6.5.4 Noonan Syndrome
		6.5.5 Myotonic Dystrophy
	6.6 CONCLUSION
7 - The Genetics of Disorders Affecting the Premature Newborn
	7.1 INTRODUCTION
	7.2 RESPIRATORY DISTRESS SYNDROME
		7.2.1 Twin Studies
		7.2.2 Heritability of RDS
		7.2.3 Candidate Genes
		7.2.4 SP-A and SP-B Studies from Finland
		7.2.5 SP-A and SP-B in Preterm Infants from Germany
		7.2.6 SP-A and SP-B in Preterm Infants from Greece
		7.2.7 SP-A and SP-B in Preterm Infants from Egypt
		7.2.8 SP-A in Preterm Infants from Korea
		7.2.9 SP-B and SP-C in Preterm Infants from Iran
		7.2.10 SP-B in Infants from Turkey
		7.2.11 SP-B in Preterm Infants from China
		7.2.12 Racial Differences
		7.2.13 SP-C and RDS
		7.2.14 SP-D and RDS
		7.2.15 Genes Related to Inflammation and RDS
		7.2.16 Metaanalysis
		7.2.17 Miscellaneous Genes and RDS
		7.2.18 Summary of RDS
	7.3 BRONCHOPULMONARY DYSPLASIA
		7.3.1 Heritability of BPD
		7.3.2 Candidate Genes
		7.3.3 Surfactant Genes and BPD
		7.3.4 Vascular Genes and BPD
		7.3.5 Genes Related to Inflammation and BPD
		7.3.6 Antioxidant Genes and BPD
		7.3.7 Growth Factors and BPD
		7.3.8 Miscellaneous Genes and BPD
		7.3.9 Summary of BPD
	7.4 PATENT DUCTUS ARTERIOSUS
		7.4.1 Heritability of PDA
		7.4.2 Candidate Genes
		7.4.3 Metaanalysis
		7.4.4 Genes and Response to Intervention for PDA
		7.4.5 Summary of PDA
	7.5 INTRAVENTRICULAR HEMORRHAGE
		7.5.1 Heritability of IVH
		7.5.2 Candidate Genes
		7.5.3 Hemostasis Genes and IVH
		7.5.4 Genes Related to Inflammation and IVH
		7.5.5 Additional Genes and IVH
		7.5.6 Summary of IVH
	7.6 RETINOPATHY OF PREMATURITY
		7.6.1 Twin Studies
		7.6.2 Heritability of ROP
		7.6.3 Candidate Genes
		7.6.4 Genetic Heterogeneity
		7.6.5 Vascular Genes and ROP
		7.6.6 Antioxidant Genes and ROP
		7.6.7 Metaanalysis
		7.6.8 Summary of ROP
	7.7 NECROTIZING ENTEROCOLITIS
		7.7.1 Heritability of NEC
		7.7.2 Candidate Genes and NEC
		7.7.3 Vascular Genes and NEC
		7.7.4 Immune System Genes and NEC
		7.7.5 Metaanalysis
		7.7.6 Summary of NEC
8 - Fetal Loss
	8.1 BACKGROUND
	8.2 DEFINITION OF TERMS
	8.3 EARLY PREGNANCY LOSS
		8.3.1 Cytogenetic Abnormalities in Human Conception
			8.3.1.1 Early Embryos
		8.3.2 Pattern of Chromosome Abnormalities Seen in Aborted Pregnancies
		8.3.3 Association of Advanced Maternal Age and Chromosome Abnormalities in Miscarriage
		8.3.4 Relative Incidence of Chromosome Abnormalities in Sporadic Versus Recurrent Pregnancy Loss
		8.3.5 Parental Chromosome Abnormalities
			8.3.5.1 Structural Rearrangements
			8.3.5.2 Gonadal Mosaicism
		8.3.6 Other Causes of Pregnancy Loss
		8.3.7 Other Genetic Factors
			8.3.7.1 Single Gene Disorders
			8.3.7.2 Thrombophilias
			8.3.7.3 Autoimmune Disorders
			8.3.7.4 Antiphospholipid Syndrome
				8.3.7.4.1 Fetal–Maternal alloimmunization and
			8.3.7.5 Endocrine Disorders
				8.3.7.5.1 Diabetes mellitus. In nonpregnant women of child-bearing age, the term type I diabetes is used to include all insulin-...
				8.3.7.5.2 Luteal phase defect. During the luteal phase of the menstrual cycle, the corpus luteum produces progesterone, which in...
				8.3.7.5.3 Thyroid disorders. Clinical hypothyroidism and hyperthyroidism have both been associated with decreased fertility and ...
				8.3.7.5.4 Hyperprolactinemia. Hyperprolactinemia is associated with hypogonadotropic hypogonadism and infertility. It also has b...
				8.3.7.5.5 Polycystic ovarian syndrome.
			8.3.7.6 Nongenetic Factors
				8.3.7.6.1 Uterine anomalies. Defects caused by abnormal Müllerian fusion are a recognized cause of pregnancy loss. The anomalies...
				8.3.7.6.2 Infectious agents. Pregnancy-related infections are uncommon, but have been reported to be a cause of fetal loss. Mump...
				8.3.7.6.3 Teratogens. Exposure to teratogenic agents during pregnancy is known to produce abnormalities of form or function, inc...
				8.3.7.6.4 Maternal stress. Maternal psychological stress has been considered to be a risk factor for early pregnancy loss. Howev...
				8.3.7.6.5 Maternal trauma. Trauma during pregnancy is not an uncommon occurrence. Approximately 6%–7% of pregnancies are affecte...
	8.4 LATE PREGNANCY LOSS
		8.4.1 Chromosome Abnormalities
		8.4.2 Maternal Anatomic Abnormalities
		8.4.3 Abnormal Serum Markers
		8.4.4 Thrombophilic Disorders
		8.4.5 Infection
		8.4.6 Recurrent Loss
	8.5 EVALUATION AND MANAGEMENT OF RECURRENT ABORTION
	8.6 CONCLUSIONS
9 - Preeclampsia
	9.1 THE PREECLAMPSIA PHENOTYPE
		9.1.1 Classification Schemes
	9.2 PREECLAMPSIA IS A QUANTITATIVE TRAIT DISORDER
	9.3 PREECLAMPSIA AND THE PLACENTA
		9.3.1 Maternal–Fetal Interface
		9.3.2 Immune Regulation and HLA
		9.3.3 Immune Regulation and Fas and Fas Ligand
		9.3.4 Oxygen and the Microenvironment
		9.3.5 Toxins and the Endothelium
		9.3.6 Angiogenic Factors
	9.4 PREECLAMPSIA BIOMARKERS IN CLINICAL USE
		9.4.1 Proangiogenic Factors and Antiangiogenic Factors
	9.5 PREECLAMPSIA MANAGEMENT AND FUTURE HEALTH
		9.5.1 Management
		9.5.2 Future Health Implications
	9.6 GENETIC BASIS OF PREECLAMPSIA
		9.6.1 Family Studies
		9.6.2 Association Studies
		9.6.3 Genome-Wide Scans
		9.6.4 Parent of Origin
	9.7 PREECLAMPSIA AND ANIMAL MODELS
10 - Noninvasive Prenatal Testing and Noninvasive Prenatal Screening
	10.1 PRECISION IN SCREENING TESTS
		10.1.1 The Initial Providers
			10.1.1.1 Sequenom: Maternit21 [25]
			10.1.1.2 Verinata: Verifi [27]
			10.1.1.3 Ariosa: Harmony [29]
			10.1.1.4 Natera: Panorama [21]
	10.2 FETAL FRACTION
	10.3 SEX CHROMOSOME ANEUPLOIDIES AND GENDER DETERMINATION
	10.4 SEGMENTAL ANEUPLOIDIES
	10.5 TRIPLOIDIES AND HAPLOIDIES
	10.6 MENDELIAN DISORDERS IN NIPS
	10.7 GENDER DETERMINATION
	10.8 MULTIPLE PREGNANCIES AND VANISHING TWINS
	10.9 CONFINED PLACENTAL MOSAICISM
	10.10 MATERNAL FACTORS
		10.10.1 Maternal Mosaic Turner Syndrome
		10.10.2 Maternal Microduplication
		10.10.3 Global Copy Number Abnormalities
		10.10.4 Maternal Malignancies
	10.11 INAPPROPRIATE USE OF NIPS
	10.12 NIPT PATERNITY TESTING
		10.12.1 NIPT for Mendelian Disorders
	10.13 NONINVASIVE WHOLE GENOME FETAL SEQUENCING
	10.14 CONCLUSION
11 - Preimplantation Genetic Testing
	11.1 INTRODUCTION
	11.2 MILESTONES IN PGT
	11.3 INDICATIONS FOR PREIMPLANTATION GENETIC TESTING
	11.4 TECHNICAL APPROACHES
		11.4.1 Embryonic Biopsy and Cell Processing
	11.5 TESTING AND ANALYSIS OF EMBRYONIC NUCLEAR DNA
	11.6 EMBRYO TESTING FOR MONOGENIC CONDITIONS (PGT-M)
	11.7 PGT-M FOR MITOCHONDRIAL CONDITIONS
	11.8 PREIMPLANTATION GENETIC TESTING FOR STRUCTURAL CHROMOSOME REARRANGEMENTS
	11.9 PREIMPLANTATION GENETIC TESTING FOR ANEUPLOIDY
	11.10 INTERPRETATION OF PGT RESULTS AND CLINICAL DILEMMAS
	11.11 PGT-A: MOSAICISM
	11.12 ADVANTAGES AND LIMITATIONS OF PGT
	11.13 PRENATAL FOLLOW-UP AND CONFIRMATORY TESTING
	11.14 GENETIC COUNSELING
	11.15 FUTURE TECHNOLOGICAL ADVANCES IN ART AND PGT
	11.16 REGULATORY POLICIES, ETHICAL CONSIDERATIONS, AND CHALLENGES IN PGT
12 - Expanded Carrier Screening
	12.1 INTRODUCTION
	12.2 HISTORY OF REPRODUCTIVE CARRIER SCREENING
	12.3 EXPANDING CARRIER SCREENING: ONE GENE AT A TIME
	12.4 INTRODUCTION OF EXPANDED CARRIER SCREENING PANELS
	12.6 INTRODUCTION OF EXPANDED CARRIER SCREENING INTO CLINICAL PRACTICE
	12.7 PROCESS OF CARRIER SCREENING
	12.8 PRETEST COUNSELING
	12.9 INTERPRETATION OF MOLECULAR FINDINGS
		12.9.1 Selection of Conditions for Inclusion on Expanded Carrier Screening Panels
	12.10 REPRODUCTIVE OPTIONS FOR CARRIER COUPLES IDENTIFIED DURING PREGNANCY
	12.11 REPRODUCTIVE OPTIONS FOR CARRIER COUPLES IDENTIFIED BEFORE PREGNANCY
	12.12 POSTTEST COUNSELING OF PREGNANT CARRIER COUPLES
	12.13 PREIMPLANTATION GENETIC TESTING FOR CARRIER COUPLES
	12.14 USE OF PGT-M FOR IDENTIFYING POTENTIAL HLA DONOR EMBRYOS FOR AFFECTED SIBLINGS
	12.15 CONCLUSIONS
INDEX
	A
	B
	C
	D
	E
	F
	G
	H
	I
	J
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
	Z
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