Genetic Disorders and the Fetus. Группа авторов

whole‐exome sequencing^{672, 673} (see Chapter 14). Over 700 genes involved in intellectual disability of monogenic origin have been recognized.^{674, 675} In a meta‐analysis of 3,350 individuals with neurodevelopmental disorders^676–678 the diagnostic yield was 36 percent using whole‐exome sequencing. More recently, whole‐exome sequencing for patients sent for a chromosomal microarray yielded diagnoses in about 27 percent of intellectual disability cases.⁶⁷⁶

      Consanguinity

A wide swath of the world's population have high rates of consanguinity (50–70 percent of births to consanguineous parents). This especially applies to India, Pakistan, Bangladesh, the Middle East, and Africa. Medical literature is replete with examples of rare severe autosomal recessive disease in these populations. Where family history does not reveal unknown or hidden consanguinity, purposeful or incidental, significant runs of homozygosity seen on a chromosomal microarray (see Chapter 13) frequently will. In those instances, recognition of a shared gene and its mutation within a shared region may unexpectedly lead to a rare diagnosis. Not as well known, perhaps, is that shared variant homozygosity markedly reduces the fertility rate of close consanguineous couples.⁶⁷⁹

      Consanguineous couples face increased risks of having children with autosomal recessive disorders; the closer the relationship, the higher the risks. A study in the United Arab Emirates of 2,200 women ≥15 years of age (with a consanguinity rate of 25–70 percent) concluded that the occurrence of malignancies, congenital abnormalities, intellectual disability, and physical handicap was significantly higher in the offspring of consanguineous couples.^{680, 681} The pooled incidence of all genetic defects, regardless of the degree of consanguinity, was 5.8 percent, in contrast with a nonconsanguineous rate of 1.2 percent, similar to an earlier study.^{681, 682} A Jordanian study also noted significantly higher rates of infant mortality, stillbirths, and congenital malformations among the offspring of consanguineous couples.⁶⁸³ A Norwegian study of first‐cousin Pakistani parents yielded a relative risk for birth defects of about twofold.⁶⁸⁴ In that study, 28 percent of all birth defects were attributed to consanguinity. An observational study of 5,776 Indian newborns noted a birth defect prevalence of 11.4 per 1,000 births with a consanguinity rate of 44.74 percent.⁶⁸⁵

      A study from Saudi Arabia, where the consanguinity rate exceeds 50 percent, focused on whole‐exome sequencing of 2,219 families who had or had lost an affected fetus or child. The study group was constituted by 1,653 individual samples, 127 twosomes, 370 trios, 58 quads, and 11 others.⁶⁸⁶ They resolved many cases by determining known causal recessive genes and their mutations, but also discovering multiple previously unknown pathogenic variants. In addition, they recognized some genes that also had a dominant rather than recessive mode of inheritance. Their prenatal diagnostic detection rate was 46.2 percent (30/65 cases), 87 percent of which were autosomal recessive.

      Whole‐exome sequencing following discovery of a fetal anomaly not resolved by karyotyping or chromosomal microarray may well provide a precise diagnosis. In a study of 102 anomalous fetuses, a definitive or probable diagnosis was made in 21 (20.6 percent).⁶⁸⁷ A similar small study of 19 families with fetal anomalies yielded candidate variants in 12 (63 percent).⁶⁸⁸ A systematic evidence‐based review of exome and genome sequencing for congenital anomalies or intellectual disability on behalf of the ACMG concluded that a change in patient management was observed in nearly all studies, including an impact on reproductive outcomes.⁶⁸⁹

      The occurrence of rare, unusual or unique syndromes invariably raises questions about potential consanguinity and common ancestral origins. Clinical geneticists will frequently be cautious in these situations, providing potential recurrence risks of 25 percent. Consanguineous couples may opt for the entire gamut of prenatal tests to diminish even their background risks, with special focus on their ethnic‐specific risks.⁶⁹⁰ Abnormal or concerning prenatal ultrasound observations in pregnancies by consanguineous couples may prompt prenatal whole‐exome sequencing.⁶⁹¹

      Environmental exposures that threaten fetal health

      Concerns about normal fetal development after exposure to medications, alcohol, illicit drugs, chemical, infectious or physical agents, and/or maternal illness are among the most common reasons for genetic counseling during pregnancy. Many of these anxieties and frequently real risks could be avoided through preconception care. Public health authorities, vested with the care of the underprivileged in particular, need to focus their scarce resources on preconception and prenatal care and on the necessary public education regarding infectious diseases, immunization, nutrition, and genetic disorders.

In preconception planning, careful attention to broadly interpreted fetal “toxins” is necessary, and avoidance should be emphasized. Alcohol, smoking, illegal drug use, certain medications, and X‐ray exposure require discussion. Estimates of the prevalence of the fetal alcohol spectrum disorder approximate 2 per 1,000 livebirths⁶⁹² in the United States but in certain regions and countries rates reach as high as 10 percent.^693–695 There is a limited list of known and proven human drug teratogens⁶⁹⁶ (see Chapter 3). Maternal use of specific teratogenic medications,⁶⁹⁷ such as isotretinoin, may be missed, unless the physician expressly inquires about them.

      Preconception advice to avoid heat exposure in early pregnancy is appropriate. Our observations showed a 2.9 relative risk for having a child with a NTD in mothers who used a hot tub during the first 6 weeks of pregnancy.⁶⁹⁸ High fever in the very early weeks of pregnancy is a potential teratogen⁶⁹⁸ and should be avoided and treated promptly. Animal studies show that commonly used drugs enter the fetal brain.⁶⁹⁹

      A report from the Spanish Collaborative Study of Congenital Malformations noted a 2.8‐fold increased risk of Down syndrome in the offspring of women ≥35 years of age and who were taking oral contraceptives when they became pregnant.⁷⁰⁰

      Identification of preconception options

      The time to deal with unwanted risks is not during the second trimester of pregnancy, as is so often the case in practice. Preconception counseling will identify specific risks and attendant options, which include the following:

       Knowledge of family history

       Attention to maternal health (e.g. diabetes control,⁷⁰¹, ⁷⁰² confirm cardiac and vascular normality)

       Decision not to have children (includes consideration of vasectomy or tubal ligation)

       Adoption

       In vitro fertilization

       Gamete intrafallopian tube transfer or allied techniques

       Artificial insemination by donor

       Ovum donation (includes surrogacy)

       Intracytoplasmic sperm injection

       Carrier detection tests

       Noninvasive prenatal screening by fetal DNA in the maternal circulation

       Naternal serum α‐fetoprotein screening for NTDs

       Prenatal diagnosis (CVS, amniocentesis, cordocentesis, ultrasound, MRI)

       Preimplantation genetic testing

       Fetal treatment or surgery for selected disorders

       Folic acid supplementation in periconceptional period (see Chapter 10)

       Noninvasive prenatal testing (aneuploidy; monogenic disorders)

       Selective