Genetic Aspects of Perinatal Disease and Prenatal Diagnosis

Maternal Age Considerations

Epidemiologic studies suggest that women are having fewer children, often later in life. The National Center for Health Statistics (NCHS) reported that from 2000 to 2014, the proportion of first births to women aged 30-34 rose 28% (from 16.5% to 21.1%), and first births to women aged 35 and over rose 23% (from 7.4% to 9.1%). With the advent of assisted reproductive technology (ART), women in their 50s and 60s can achieve pregnancy. Although it cannot be emphasized enough that the effects of increasing age occur as a continuum, the term advanced maternal age has historically referred to pregnant women who will be 35 or older on their expected date of confinement.

Chromosomal analysis of samples from spontaneous abortions, prenatal diagnosis, and live births reveals that there is a steady increase in aneuploidy as a woman ages ( Fig. 10.2 ). The basis for this increase is unknown, although it may be related to a decrease in the number of normal oocytes available or cumulative oxidative stress on the finite number of oocytes with which females are born. Along with chromosomal abnormalities, it has been observed that congenital anomalies increase with increased maternal age. The FASTER trial reported rates of congenital anomalies for women younger than 35 years old as 1.7%; women 35 to 39 years old and 40 years old or older had rates of 2.8% and 2.9%, respectively.

Abnormalities of Chromosome Number

The mere presence of additional genetic material, albeit of normal makeup, can result in clinically significant phenotypes. Following is a discussion of the various types of numerical abnormalities.

Aneuploidy

In humans, the term aneuploid is used to describe any genotype in which the total chromosome number is not a multiple of 23. Most aneuploid patients have either a monosomy (only one representative of a particular chromosome) or a trisomy (three copies of a particular chromosome). As a rule, monosomies tend to be more deleterious than trisomies. Complete monosomies are generally not viable except for monosomy X (Turner syndrome). Trisomies for chromosomes 13, 18, 21, X, and Y are compatible with life, with trisomy 21 (Down syndrome) being the most common trisomy in live-born infants.

The most common mechanism for aneuploidy is meiotic nondisjunction, in which a pair of chromosomes fails to separate during either of the meiotic divisions ( Fig. 10.3 ). Nondisjunction can rarely occur during a mitotic division after the formation of the zygote. If this happens early in cleavage, mosaicism may occur. In this situation, two or more different chromosome complements are present in one individual. The clinical significance of mosaicism is difficult to evaluate and depends on the developmental timing when the mosaicism occurred, the tissues affected, and the proportion of tissue affected.

Abnormalities of Chromosome Structure

Chromosomal structural abnormalities are the result of chromosome breakage followed by anomalous reconstitution. Rearrangements result spontaneously or are due to inducing agents, such as ionizing radiation. Structural abnormalities can be divided into two categories—balanced and unbalanced. Balanced rearrangements have the normal complement of chromosomal material. Also, a balanced rearranged chromosome must have a functional centromere and two functional telomeres. Unbalanced rearrangements are either missing or have additional genetic information.

Structural rearrangements include deletions, insertions, ring chromosomes, isochromosomes, and translocations ( Fig. 10.4 ). One unique type of translocation is the Robertsonian translocation, in which two acrocentric chromosomes lose their short arms and fuse near the centromeric region. Because the short arms of acrocentric chromosomes contain only genes for ribosomal RNAs, loss of the short arm is rarely deleterious. The result is a balanced karyotype with only 45 chromosomes, including the translocated chromosome, which comprises the long arms of two chromosomes. Carriers of Robertsonian translocations are phenotypically normal but have the risk of producing unbalanced gametes. The main clinical relevance of a Robertsonian translocation is that one involving chromosome 21 could result in a child with Down syndrome. About 4% of cases of Down syndrome have 46 chromosomes, one of which is a Robertsonian translocation between chromosome 21 and another chromosome.

Autosomal Dominant Disorders

Approximately half of Mendelian disorders are inherited in an autosomal dominant fashion. Inheritance usually exhibits a vertical pattern of transmission, meaning that the phenotype appears in every generation, with each affected person having an affected parent ( Fig. 10.5 ). For each offspring of an affected parent, the risk of inheriting the mutated allele is 50%. An example of a disorder inherited in an autosomal dominant fashion is osteogenesis imperfecta. Biochemical defects in either the amount or the structure of collagen result in various clinical phenotypes depending on the mutation.

Autosomal Recessive Disorders

An autosomal recessive condition occurs when an individual possesses two mutant alleles that were inherited from heterozygous parents. For autosomal recessive diseases, an individual with one normal allele does not manifest the disease, because the normal gene copy is able to compensate. Autosomal recessive disorders exhibit horizontal transmission, meaning that if the phenotype appears in more than one family member, it is typically in the siblings of the proband, not in parents, offspring, or other relatives ( Fig. 10.6 ). If both parents are carriers of a mutated allele, 25% of offspring have the autosomal recessive disease. Consanguineous unions (mating between individuals who are second cousins or closer) are at increased risk for an autosomal recessive disorder, because there is a higher likelihood that both individuals carry the same recessive mutation. A common autosomal recessive disease is cystic fibrosis. Carrier screening and prenatal implications are discussed in a later section.

Sex-Linked Disorders

X chromosome inactivation is a normal process in females in which one X chromosome is randomly inactivated early in development. Females are normally mosaic with respect to X-linked gene expression. Disorders of genes located on the X chromosome have a characteristic pattern of inheritance that is affected by gender. Males with an X-linked mutant allele are described as being hemizygous for that allele. Males have a 50% chance of inheriting a mutant allele if the mother is a carrier. Females can be homozygous wild-type allele, homozygous mutant allele, or a heterozygote.

An X-linked recessive mutation is phenotypically expressed in all males but is expressed only in females who are homozygous for the mutation. As a result, X-linked recessive disorders are generally seen in males and rarely seen in females. An example of such a condition is hemophilia A. X-linked dominant disorders may manifest differently among heterozygous females in the same family because of different patterns of X chromosome inactivation. X-linked inheritance is classically characterized by the lack of male-to-male transmission, because males transmit their Y chromosome to their sons, not their X chromosome ( Fig. 10.7 ).

Mitochondrial Inheritance

Mitochondrial DNA (mtDNA) is organized as a 16.5-kb circular chromosome located in the mitochondrial organelles of a cell, not the cell nucleus. mtDNA contains 37 genes that encode for important proteins, including proteins involved in oxidative phosphorylation.

Mitochondrial inheritance has a few distinct features that differ from Mendelian inheritance: maternal inheritance, replicative segregation, and heteroplasmy. Because sperm mitochondria are eliminated from the forming embryo, mtDNA is inherited entirely from the maternal side, with very rare exception. At cell division, the mitochondria sort randomly between two daughter cells, a process known as replicative segregation . A cell containing a mix of mutant and wild-type mtDNA can distribute variable proportions of mutant or wild-type DNA to daughter cells. By chance, a daughter cell may receive all wild-type or all mutant mtDNA, a state known as homoplasmy . Heteroplasmic daughter cells can result in variable penetrance and expression depending on the amount of mutant mtDNA present.

More than 100 different mutations in mtDNA have been identified to cause disease in humans and with new technologies, that number is growing. Most of these involve the central nervous system or musculoskeletal system ( Table 10.2 ).

Mitochondrial disease typically manifests as dysfunction in high energy-consuming organs such as the brain, muscle, heart, and kidneys. Poor growth, muscle weakness, loss of coordination, or developmental delay not explained by more common causes should alert a neonatologist or pediatrician to the possibility of a mitochondrial disease. When a mitochondrial disease is suspected, the child should be referred to a specialized medical center wherein comprehensive evaluation, including genetic studies, can be performed.

Epigenetics and Uniparental Disomy

Epigenetics refers to modification of genes that determines whether a gene is expressed or not (see Chapter 16 ). These modifications, an example of which is methylation, affect the expression of a gene, but not the primary DNA sequence itself. Imprinting refers to a phenomenon in which genetic material is differentially expressed depending on whether it was inherited from the father or the mother. A different phenotype can result depending on the parent of origin, because for certain genes, only the allele from one parent is transcriptionally active.

Uniparental disomy is the inheritance of a pair of homologous chromosomes from one parent rather than the normal scenario in which one chromosome is inherited from each parent. This situation is thought to arise most commonly by a process called trisomy rescue, during which a trisomic cell is converted into a disomic cell. It is a matter of chance as to which chromosome drops out. When trisomy rescue occurs, both chromosomes are from one parent a third of the time.

Classic examples of disorders related to genomic imprinting are Prader-Willi and Angelman syndromes. Both these syndromes involve the long arm of chromosome 15 (15q11-15q13). At birth, Prader-Willi syndrome is characterized by hypotonia, low birth weight, and almond-shaped eyes. During childhood, other features such as short stature, obesity, indiscriminate eating habits, small hands and feet, mental retardation, and hypogonadism develop. In most of these cases, there is paternally derived deletion, which means that all the genetic information in the region is maternal in origin. Angelman syndrome, characterized by mental retardation, short stature, abnormal facies, and seizures, is the opposite situation, in which the deletion is maternally derived, and the genetic information in the region is paternal only in origin. Approximately 30% of Prader-Willi cases and 5% of Angelman cases are the result of uniparental disomy. In this scenario, there is no cytogenetically detectable deletion. Because of imprinting, Prader-Willi syndrome results from uniparental disomy in which both chromosomes derive from the mother. The loss of the paternal contribution results in Prader-Willi syndrome. Paternal uniparental disomy in the same region results in Angelman syndrome because of the loss of maternal contribution of genes in the 15q11-q13 region.

Another aspect of epigenetics that has become an exciting avenue for research is the fetal origin of adult disease hypothesis. This is also known as the Barker Hypothesis, named after British epidemiologist David Barker, who proposed that intrauterine stress in the form of growth restriction and prematurity can predispose the individual to hypertension, cardiac disease, and diabetes. The initial evidence was provided by epidemiologic data that correlated low birth weight with poor health outcomes in adulthood. Since then, several animal and human studies have shown that a harsh intrauterine environment can lead to a host of changes in DNA methylation and ultimately influence gene expression and metabolic dysregulation in adulthood.