Genetic Disorders and the Fetus. Группа авторов

maintained that about 30 percent of all patients with a rare disease died before the age of 5 years.¹² In the United States in 2013–2014, congenital malformations, deformations, and chromosomal abnormalities accounted for the most infant deaths – 4,746 (20.4 percent) out of 23,215 – in any category of causation.¹³

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 and MRI

       Accuracy of diagnosis

       Age at diagnosis

       Case selection, bias, and ascertainment

       Congenital hypothyroidism

       Consanguinity

       Definitions of major and minor congenital anomalies

       Diagnostic DNA analysis

       Duration of follow‐up

       Economic level in developed or developing world

       Environmental toxins

       Family history

       Frequency, inclusion, and exclusion of stillbirths, fetal deaths, and elective pregnancy termination

       Frequency of certain infectious diseases

       Frequency of de novo gene mutations

       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

       Mortality rates decreasing

       Multiple pregnancy rate

       Necropsy

       Noninvasive prenatal testing using cell‐free fetal DNA for chromosomal abnormalities and monogenic disorders

       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

Incidence and prevalence of genetic disorders and congenital malformations

      Estimates of aneuploidy in oocytes and sperm reach 25 percent and 3–4 percent, respectively.^{14, 15} Estimates, especially for oocytes, vary widely (see Chapter 2). The effect of maternal age, among other factors, is important. At 25 years, early thirties, and >40 years of age, the rate of aneuploidy approximates 5 percent, 10–25 percent, and 50 percent, respectively.^15–19 Estimates of aneuploidy and structural chromosomal abnormalities in sperm vary from 7 to 14 percent.²⁰ Not surprisingly, then, about one in 13 conceptions results in a chromosomally abnormal conceptus,²¹ while about 50 percent of first‐trimester spontaneous abortions are associated with chromosomal anomalies.²² One study of blastocysts 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.²³ Similar results have been reported by others.²⁴ 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 (see Chapters 11 and 13). Between 5.6 and 11.5 percent of stillbirths and neonatal deaths have chromosomal defects.²⁵

      Congenital malformations with obvious structural defects are found in about 2 percent of all births.²⁶ This was the figure in Spain among 710,815 livebirths,²⁷ with 2.25 percent in Liberia,²⁸ 2.03 percent in India,²⁹ and 2.53 percent among newborn males in Norway.³⁰ 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.³¹ 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 (including anotia or microtia, cleft lip, trisomy 18, encephalocele, limb‐reduction defect).³² Factors that had an impact on the incidence/prevalence of congenital malformations are discussed later.

Over 25,500 entries for genetic disorders and traits have been catalogued.² 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).³³ Baseline birth prevalence of rare single‐gene disorders for multiple countries are shown in Figure 1.1, which highlights the contribution of consanguinity‐associated disorders.³⁴ Polygenic disorders occurred at a rate of 46.4 in 1,000 (Table 1.1). A key study of homozygosity in consanguineous patients with an autosomal recessive disease showed that, on average, 11 percent of their genomes were homozygous.³⁵ Each affected individual had 20 homozygous segments exceeding 3 cM.

Figure 1.1 Total baseline birth prevalence of rare single‐gene disorders by World Health Organization (WHO) region, highlighting the important contribution of consanguinity to monogenic disorders.

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