Genetic Disorders and the Fetus

Diagnosis, Prevention, and Treatment

Aubrey Milunsky, Jeff M. Milunsky

• Publisher: Wiley-Blackwell
• Year: 2015
• ISBN:
  9781118981542
• Edition: 7
• Topic: Medizin
• Subtopic: Gynäkologie, Geburtshilfe & Hebammen

Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment, Seventh Edition is the eagerly awaited new edition of the discipline-leading text that has been at the forefront of diagnosis, prevention, and treatment of fetal genetic disorders for over 36 years.

The seventh edition continues the long-established tradition of excellence that has become synonymous with this text. The book builds on the foundations of preconception and prenatal genetic counseling and the original pillars of prenatal diagnosis while also providing authoritative coverage of exciting developments in non-invasive genetic testing and rapidly developing molecular techniques, including microarray analysis and next generation sequencing, that are revolutionizing the field. Chapters are once again authored by internationally recognized authorities in the field of prenatal diagnosis. The editors have added three entirely new chapters to this edition to complement the complete revision of existing content. The three new chapters focus on non-invasive prenatal screening, placental genetics, and the psychology of prenatal and perinatal grief. The broad-ranging coverage and international scope will ensure that the new edition maintains its role as the major repository for information on all aspects of prenatal diagnosis.

The editors have brought together an invaluable collection of evidence-based facts bolstered by knowledge and decades of experience in the field. Genetic Disorders and the Fetus: Diagnosis, Prevention and Treatment, 7th Edition is a timely update to this world-leading text.

1
Genetic Counseling: Preconception, Prenatal, and Perinatal

Aubrey Milunsky^1,2 and Jeff M. Milunsky¹

¹Center for Human Genetics, Cambridge, MA, USA

²Tufts University School of Medicine, Cambridge, MA, USA

Clinical cognizance of the veritable explosion in the knowledge of the human genome is more vital than ever. Precise identification of genes and their pathogenic mutations has injected an urgency among care providers to become aware of the rapidly escalating opportunities parents have to avoid having offspring with serious or fatal genetic disorders. For any health or life-threatening genetic disorder, prenatal diagnosis (or even preimplantation genetic diagnosis) has become a viable option, and should be offered. Even adult-onset malignant, neurodegenerative, cardiovascular and other serious systemic disorders now feature in the indications, not only for presymptomatic or predictive diagnosis, but for prenatal diagnosis.

Given the wide scope of clinical genetics in all medical specialties, the need for clinicians to confer and refer has never been greater. The coalescence of advances in molecular genetics, fetal imaging and noninvasive prenatal screening, has culminated in the provision of new opportunities for the prevention or avoidance of genetic disorders and congenital malformations.

In context, women at risk for having progeny with abnormalities expect to be informed about their odds and options, optimally during preconception counseling. Their concerns are serious, given the significant contribution of genetic disorders to morbidity and mortality in children and adults.

Incidence, prevalence and burden of genetic disorders and congenital malformations

An estimated 7.9 million infants worldwide are born each year with a major congenital malformation.¹ Over 7,000 rare genetic disorders are known,^2–7 with about 1 in 12 individuals affected, aware or unaware. More than 3,412 genes with phenotype-causing mutations have been identified.⁴ Severe intellectual disability is considered to be largely genetic in origin^{8, 9} and is estimated to occur in 0.5 percent of newborns.¹⁰ The European Organization for Rare Diseases maintained that about 30 percent of all patients with a rare disease died before the age of 5 years.¹¹ In the United States in 2010, congenital malformations, deformations and chromosomal abnormalities accounted for the most infant deaths – 5,107 (20.8 percent) out of 24,586 – in any category of causation.¹² Many factors influence efforts to accurately determine the incidence or prevalence of congenital anomalies or genetic disorders. Box 1.1 encompasses the majority of known etiologic categories, discussed below, which help explain sometimes striking differences among major studies. It is almost impossible to account for all these potentially confounding factors in a study and rarely has any one study come close.

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Box 1.1 Factors that influence estimates of the incidence or prevalence in the newborn of a congenital malformation (CM) or genetic disorder

• Availability and use of expertise in prenatal diagnostic ultrasound
• Case selection, bias and ascertainment
• Consanguinity
• Definitions of major and minor congenital anomalies
• Diagnostic DNA analysis
• Economic level in developed or developing world
• Family history
• Frequency, inclusion and exclusion of stillbirths, fetal deaths and elective pregnancy termination
• Frequency of certain infectious diseases
• History of recurrent spontaneous abortion
• In vitro fertilization
• Incidence and severity of prematurity
• Infertility
• Intracytoplasmic sperm injection
• Later manifestation or onset of disorder
• Maternal age
• Maternal alcohol abuse
• Maternal diabetes and gestational diabetes
• Maternal diet
• Maternal epilepsy, lupus erythematosus and other illnesses
• Maternal fever or use of hot tub in the first 6 weeks of pregnancy
• Maternal folic acid supplementation
• Maternal grandmother's age
• Maternal obesity
• Maternal serum screening for chromosome abnormalities
• Maternal smoking
• Maternal specific susceptibility genes
• Maternal use of medication
• Multiple pregnancy rate
• Necropsy
• Noninvasive prenatal screening
• Parent with a congenital abnormality or genetic disorder
• Paternal age
• Previous affected child
• Previous maternal immunization/vaccination
• Season of the year
• Training and expertise in examination of newborns
• Use of chromosomal analysis
• Use of chromosomal microarray
• Use of whole exome sequencing
• Use of whole genome sequencing
• Use of death certificates
• Use of registry data

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Incidence and prevalence

Estimates of aneuploidy in oocytes and sperm reach 25 percent and 3–4 percent, respectively.^{13, 14} Not surprisingly, then, about one in 13 conceptions results in a chromosomally abnormal conceptus,¹⁵ while about 50 percent of first-trimester spontaneous abortions are associated with chromosomal anomalies.¹⁶ A study of blastocysts have revealed that 56.6 percent were aneuploid. Moreover, these blastocysts produced in vitro from women of advanced maternal age also revealed mosaicism in 69.2 percent.¹⁷ Similar results have been reported by others.¹⁸ Clinically significant chromosomal defects occur in 0.65 percent of all births; an additional 0.2 percent of babies are born with balanced structural chromosome rearrangements that have implications for reproduction later in life. Between 5.6 and 11.5 percent of stillbirths and neonatal deaths have chromosomal defects.¹⁹

Congenital malformations with obvious structural defects are found in about 2 percent of all births.²⁰ This was the figure in Spain among 710,815 livebirths,²¹ with 2.25 percent in Liberia,²² 2.03 percent in India,²³ and 2.53 percent among newborn males in Norway.²⁴ The Mainz Birth Defects Registry in Germany in the 1990–1998 period reported a 6.9 percent frequency of major malformations among 30,940 livebirths, stillbirths and abortions.²⁵ Pooled data from 12 US population-based birth defects surveillance systems, which included 13.5 million livebirths (1999–2007), revealed that American Indians/Alaska natives had a ≥50 percent greater prevalence for seven congenital malformations (anotia or microtia, cleft lip, trisomy 18, encephalocele, limb-reduction defect).²⁶ Factors that had an impact on the incidence/prevalence of congenital malformations are discussed below.

Over 22,700 entries for genetic disorders and traits have been catalogued.⁴ Estimates based on 1 million consecutive livebirths in Canada suggested a monogenic disease in 3.6 in 1,000, consisting of autosomal dominant (1.4 in 1,000), autosomal recessive (1.7 in 1,000) and X-linked-recessive disorders (0.5 in 1,000).²⁷ Polygenic disorders occurred at a rate of 46.4 in 1,000 (Table 1.1).

Table 1.1 The frequencies of genetic disorders in 1,169,873 births, 1952–1983²⁷

	Rate per
	million	Total
Category	livebirths	births (%)
A
Dominant	1,395.4	0.14
Recessive	1,665.3	0.17
X-linked	532.4	0.05
Chromosomal	1,845.4	0.18
Multifactorial	46,582.6	4.64
Genetic unknown	1,164.2	0.12
Total	53,175.3	5.32^a
B
All congenital anomalies 740–759^b	52,808.2	5.28
Congenital anomalies with genetic etiology (included in section A)	26,584.2	2.66
C
Disorders in section A plus those congenital anomalies not already included	79,399.3	7.94

Notes: ^aSum is not exact owing to rounding. ^bInternational Classification of Disease numbers.

At least 3–4 percent of all births are associated with a major congenital defect, intellectual disability or a genetic disorder, a rate that doubles by 7–8 years of age, given later appearing and/or later diagnosed genetic disorders.^{28, 29} If all congenital defects are considered, Baird et al.²⁷ estimated that 7.9 percent of liveborn individuals have some type of genetic disorder by about 25 years of age. These estimates are likely to be very low given, for example, the frequency of undetected defects such as bicuspid aortic valves that occur in 1–2 percent of the population.³⁰ The bicuspid aortic valve is the most common congenital cardiac malformation and in the final analysis may cause higher mortality and morbidity rates than all other congenital cardiac def...