Пренатальне генетичне консультування

Some risk of genetic abnormality exists in all pregnancies. Among live births, incidence is

• 0.5% for numeric or structural chromosomal disorders

• 1% for single-gene (mendelian) disorders

• 1% for multiple-gene (polygenic) disorders

Among stillbirths, rates of abnormalities are higher.

Most malformations involving a single organ system (eg, neural tube defects, most congenital heart defects) result from polygenic or multifactorial (ie, also influenced by environmental factors) inheritance.

Risk of having a fetus with a chromosomal disorder is increased for most couples who have had a previous fetus or infant with a chromosomal disorder (recognized or missed), except for a few specific types (eg, 45,X; triploidy; de novo chromosomal rearrangements). Chromosomal disorders are more likely to be present in the following:

• Fetuses that spontaneously abort during the 1st trimester (50 to 60%)

• Fetuses with a major malformation (30%; 35 to 38% if submicroscopic abnormalities are included)

• Stillborns (5%)

Rarely, a parent has a chromosomal disorder that increases risk of a chromosomal disorder in the fetus. Asymptomatic parental chromosomal disorders (eg, balanced abnormalities such as certain translocations and inversions (no disruption of a gene and no genetic material lost or added) may not be suspected. A balanced parental chromosomal rearrangement should be suspected if couples have had recurrent spontaneous abortions, infertility, or a child with a malformation.

The chance of a fetal chromosomal disorder increases as maternal age increases because rates of nondisjunction (failure of chromosomes to separate normally) during meiosis increase. The risk of common aneuploidies by maternal age (1) is

• < 35 years: Trisomy 21 (1/591), trisomy 18 (1/2862), and trisomy 13 (1/4651)

• ≥ 35 years: Trisomy 21 (1/100), trisomy 18 (1/454), and trisomy 13 (1/1438)

Most chromosomal disorders due to older maternal age involve an extra chromosome (trisomy), particularly trisomy 21 (Down syndrome). Paternal age > 50 increases risk of some spontaneous dominant pathogenic gene variants (formerly termed mutations), such as achondroplasia, in offspring.

Some chromosomal disorders are submicroscopic and thus not identified by traditional karyotyping. The submicroscopic chromosomal abnormalities, sometimes called copy number variants, occur independently of the age-related nondisjunction mechanisms. The precise incidence of these abnormalities is unclear, but incidence is higher in fetuses with structural abnormalities. A multicenter study sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) demonstrated a 1% incidence of clinically relevant copy number variants in fetuses with normal karyotypes independent of indication for testing and a 6% incidence in fetuses with structural abnormalities (2).

An autosomal dominant disorder is suspected if there is a family history in more than one generation; autosomal disorders affect males and females equally. If one parent has an autosomal dominant disorder, risk is 50% that the disorder will be transmitted to an offspring.

For an autosomal recessive disorder to be expressed, an offspring must receive a pathogenic gene variant for that disorder from both parents. Parents may be heterozygous (carriers) and, if so, are usually clinically normal. If both parents are carriers, offspring (male or female) are at a 25% risk of being homozygous for the pathogenic gene variant and thus affected, 50% are likely to be heterozygous, and 25% are likely to be genetically normal. If only siblings and no other relatives are affected, an autosomal recessive disorder should be suspected. Likelihood that both parents carry the same autosomal recessive trait is increased if they are consanguineous.

Because females have two X chromosomes and males have only one, X-linked recessive disorders are expressed in all males who carry the pathogenic gene variant. Such disorders are usually transmitted through clinically normal, heterozygous (carrier) females. Thus, for each son of a carrier female, risk of having the disorder is 50%, and for each daughter, risk of being a carrier is 50%. Affected males do not transmit the gene to their sons, but they transmit it to all their daughters, who thus are carriers. Unaffected males do not transmit the gene.