gynecology and obstetrics
Prenatal Genetic Counseling
Risk Factors for Genetic Disorders or Congenital Anomalies
Some risk of genetic abnormality exists in all pregnancies. Among live births, incidence is ( Risk factors for congenital disorders references ) 0.5% for numeric or structural chromosomal disorders 1% for single-gene (mendelian) disorders 1% for multiple-gene (polygenic) disorders Among spontaneous abortions or stillbirths, rates of abnormalities are higher. Most malformations involving a single organ system (eg, Overview of Congenital Neurologic Anomalies , most Risk of having a fetus with a Overview of Chromosomal Abnormalities 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). Couples with a previous child with Down syndrome may be at an increased risk of recurrence, depending on the type of chromosomal abnormality. For nondisjunction trisomy 21, which is the most common form, if the female partner is < 35 years old, the risk of having another fetus with trisomy 21 is 3.5 times higher and for age ≥ 35 years it is 1.7 times higher ( Chromosomal disorders are more likely to be present in the following: Septic Abortion during the first trimester (50 to 80%) ( Fetuses with a major malformation (30%) ( Risk factors for congenital disorders references ) Stillbirth (8 to 16%) ( A small percentage of parents may have 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 partners have had recurrent spontaneous abortions, infertility, or a child with a congenital abnormality. 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 is ( Risk factors for congenital disorders references ) < 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 (Trisomy 21) ). Paternal age 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 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 ( Risk factors for congenital disorders references ). 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 unaffected but carry the abnormal gene (phenotypically normal). On average, 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 neither affected nor carriers (genotypically normal). If only one parent is a carrier, offspring are at a 50% risk of being heterozygous and a 50% chance of being genotypically 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 are expressed in all males who carry the pathogenic gene variant. Such disorders are usually transmitted through phenotypically 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. 