Principles of Genetic Counseling in Prenatal and Perinatal Medicine



Principles of Genetic Counseling in Prenatal and Perinatal Medicine


Laura Igarzábal

Jeffrey A. Kuller



Introduction

Normal body structure and function are direct consequences of multiple gene actions that are frequently conditioned by environmental interaction. Not unexpectedly, genetics has a role in virtually every illness: in causation, susceptibility, immune response, modulation, or reaction to medical treatment. Approximately 2% to 3% of all newborns have a major congenital anomaly, 25% of which have an underlying identifiable genetic etiology.1,2,3 Some of these defects will be detected in the prenatal period, another percentage at birth or during childhood, and less frequently later in adulthood. In recent decades, there has been an increase in prenatal diagnosis of congenital malformations due to the regular use of ultrasound in pregnancy and improvements of ultrasound equipment. On the other hand, advances in invasive and noninvasive diagnostic tests in pregnancy and molecular studies have contributed to the understanding of the origin of congenital defects and the possibility of carrying out genetic studies. Obstetricians, neonatologists, and other healthcare providers will increasingly encounter fetuses and children with suspected genetic disorders and be asked to order and interpret complex genetic tests.

The revolutionary breakthrough in molecular diagnostic techniques and the understanding of genetic diseases of the fetus and newborn have resulted in a new genomic era with an increase in the number of genetic tests available, diagnostic yield, and information provided to patients. While in the past, routine genetic testing was reduced to a small number of genetic diseases, with the advent of chromosomal microarray analysis (CMA) and next-generation sequencing (NGS), significant improvement to evaluate a more extensive range of genetic and genomic disorders, both before and during pregnancy, has come. New screening and diagnostic tests are being introduced regularly in clinical practice. This expanded menu creates a challenge for healthcare providers to keep pace with technologic advances and to effectively provide patients with accurate information related to advantages, disadvantages, limitations, and risks for all testing options.4 In this scenario, genetic counseling has become increasingly important and an integral part of health care, to provide a framework to patients for informed decision-making and support.5 This complex task needs expertise and knowledge, as well as time and resources for adequate counseling.6,7


The Genetic and Genomic Basis for Counseling

The word genome refers to the genetic information contained in the cell. This information is encoded in the double strand of DNA, which is compactly wrapped to form the 46 chromosomes (23 matching pairs) located in the nucleus, and a small amount in the mitochondria. One of each pair came from the mother, and one from the father. There are 22 pairs with the same morphology in each sex, the autosomes (1-22 homologous chromosomes), and a pair of sex chromosomes (females have a pair of X chromosomes; males have one X chromosome and one Y chromosome). The gametes have a single set of homologous (haploid complement: [n] 23), whereas the rest of somatic cells have a double set (diploid complement: [2n] 46). The chromosomes can be distinguished from each other based on size, location of the centromere (which divides a chromosome into long and short arms), and the unique banding pattern.3 The karyotype is the paired-up presentation of all of the chromosomes, cut out from a photograph or captured from an electronic image, but is generally used to define chromosomal constitution (Figure 11.1).







Human genes also present in pairs; each copy or allele is located in a homologous chromosome. A locus is the location of a gene on the genome. Genes are DNA segments that specify an amino acid sequence of a protein or function. There are approximately 22,000 to 25,000 genes (although this number is subject to continuing revision), and even with the completion of the Human Genome Project, the function of only a small percentage of genes is known. Each gene contains one or more encoding exons (DNA sequences that encode proteins, expressed sequences), introns (noncoding regions, intervening sequences), and regulatory sequences that are important for proper gene expression. Approximately 1.5% of the genome is composed of exons, collectively called the exome. In addition to the exons and introns, there are long DNA stretches that are not part of protein-coding genes, with roles in DNA replication, chromosome pairing, and recombination. Some of these genetic sequences code for classes of noncoding RNAs (eg, micro-RNAs involved in gene regulation at a posttranscriptional level). Another type of sequences interspersed throughout the noncoding DNA stretches is repeated sequences.3,8,9

An allele is the variant form of a given gene. They are normal variants within the population. The occurrence in the same population of more than one allele is called polymorphism. The least common allele shall occur with a “frequency” of at least 1%.3

On the other hand, a pathogenic variant is an alteration in the DNA sequence that produces a change in protein structure or function, which may have an adverse impact on the phenotype (eg, base substitutions, microdeletions, microduplications, chromosome deletions, and duplications). The American College of Medical Genetics and Genomics (ACMG) has released a new classification for variants (pathogenic, likely pathogenic, benign, likely benign, uncertain significance) that is used in most publications.10 Some DNA changes cannot be characterized reliably as benign or pathogenic and are, therefore, classified as a variant of uncertain significance (VUS).

A gene is in a homozygous state when it has the same sequence in both copies (or alleles) of the gene. On the other hand, if the alleles differ in their sequence, the gene is said to be in a heterozygous state. When a gene is in a heterozygous state and only one of the copies determines the phenotype (over the other), this gene and the trait or disease it manifests are considered dominant. On the contrary, they are called recessive genes if both copies of the gene are necessary to determine the phenotype.3,8,9


Congenital Anomalies: Definition and Causes

Congenital anomalies are important causes of infant and childhood deaths, chronic illness, and disability. They are also known as birth defects, congenital disorders, or congenital malformations. Congenital
anomalies are structural or functional anomalies that occur during gestation and can be identified prenatally, at birth, or sometimes later in life.11 The word congenital means presence at or before birth, but it does not refer to the genetic origin of the defect, nor a hereditary origin.12

Some 2% to 3% of all births are associated with a major congenital defect, a rate that doubles by 7 to 8 years of age, given late-appearing and late-diagnosed genetic disorders.11 Congenital anomalies are classified according to etiology into three main groups: (1) genetic, (2) environmental, and (3) polygenic or multifactorial. This division facilitates the identification of risk factors and planning the diagnostic methodology, establishing the prognosis, and performing the correct genetic counseling. It has been estimated that 25% of birth defects are due to identifiable genetic causes (15%-20% single-gene disorders and 5% chromosomal abnormalities), 10% to environmental exposures, and the remaining 65% to 75% with suspected polygenic or multifactorial etiologies.2

Genetic diseases are produced by changes in DNA and range from a small pathogenic variant in single genes, to duplication or absence of entire chromosomes or set of chromosomes. Genetic diseases can be inherited from parents (hereditary) or appear for the first time in a family (de novo). These inherited diseases increase the risk of recurrence for siblings and offspring of affected individuals, while those that appear for the first time only increase the risk in their offspring.3 Multifactorial or polygenic disorders result from an interaction between multiple genes and one or more environmental factors.


Genetic Disorders

Genetic disorders are generally divided into two broad categories, chromosomal abnormalities and single-gene disorders.


Chromosome Abnormalities

Chromosome abnormalities arise as a consequence of abnormal chromosome number (numerical) or from structural rearrangements of one or more chromosomes (structural).3

The loss or gain of large chromosomal segments alters significant amounts of genetic material and often results in pregnancy loss or offspring that may not survive after birth. In the case of a surviving newborn, birth defects, intellectual disability, infertility, and shortened lifespan are common. The frequency of chromosomal abnormalities varies from 60% to 80% in first trimester abortions; 5% to 7% in infant and childhood deaths; 4% to 8% in structural congenital malformations; and almost 10% in neurodevelopmental disorders in infancy.13,14,15

Numerical chromosome abnormalities involve the gain or loss of a whole chromosome (full aneuploidy); part of a chromosome (partial aneuploidy); or an extra set of chromosomes (polyploidy) (triploidy: 69 chromosomes; tetraploidy: 94 chromosomes).

In trisomy, there is three of a particular chromosome. The most common numerical chromosome disorder in newborns is trisomy 21, observed in 1 every 800 live births. Trisomy 18 and trisomy 13 occur in 1 in 8000 and 1 in 20,000 live births, respectively11,13,14 (Table 11.1). Trisomy of other autosomes usually ends in spontaneous abortion.

In monosomy, only one member of the pair is present. Among first-trimester abortuses, 45,X (monosomy of X chromosome) is the most common numerical disorder. About half of individuals with Turner syndrome have monosomy X. The most common features of girls with Turner syndrome are short stature and primary ovarian insufficiency. There is also a high rate of heart defects, renal and skeletal abnormalities, and webbed neck.3

The prevalence of trisomy increases with maternal age and decreases with gestational age (because of an increase in pregnancy loss). The prevalence of trisomy 21 at 12 weeks is 30% higher than the prevalence at 40 weeks.16 In contrast, 45,X has no relationship with maternal age.

A single cell division, soon after fertilization, may go awry resulting in a numerical chromosome abnormality in the daughter cells of that division and, consequently, in chromosomally abnormal cells from that original stem cell. These abnormal cells continue to divide and multiply alongside the subjacent chromosomally normal cells and eventually result in an individual who has two or more different cell lines—a chromosomal mosaic (Figure 11.2). Chromosome mosaicism detected prenatally may also reflect confined placental mosaicism (CPM). CPM refers to the discrepancy between the chromosomal complement of the fetus and its placenta, due to postzygotic mitotic errors during embryonic development. CPM can be detected prenatally in about 2% of viable human pregnancies at 10 to 12 weeks of gestation. CPM may also be caused by the trisomic zygote rescue, a genetic phenomenon in which a fertilized ovum containing three copies
of a chromosome loses one of these chromosomes to form a normal diploid chromosome complement. The most common placental-fetal dichotomy involves placental trisomy for chromosome 16.17








Structural chromosomal abnormalities may result from the breakage and loss or addition of a variable-sized piece of a long or short arm (deletion, duplication), or the breakage and change in the order of segments within the same chromosome or between different chromosomes (translocation, inversion, insertion) (Figure 11.3). The abnormality can be balanced (without loss or gain of material) or unbalanced (with loss or gain of chromosomal material, usually with abnormal phenotype). Parents with balanced structural chromosomal abnormalities are at risk of unbalanced offspring, the level of risk depending on the specific anomaly, chromosomes involved, size of the abnormal segments, and type of ascertainment.9

There are two types of translocations, Robertsonian and reciprocal. Robertsonian translocations involve the acrocentric (a chromosome in which the centromere is located quite near one end of the chromosome) chromosomes (chromosomes 13, 14, 15, 21, and 22). Carrier parents are associated with risks of offspring with unbalanced translocation ranging mostly from 4% to 20%, with higher risks for maternal carriers. Reciprocal translocations occur when there is exchange of genetic material between autosomes are associated, almost invariably, with much lower risks for unbalanced karyotypes, mostly below 3% and frequently around 1%.3

Chromosome inversions occur following breakage at two sites along a chromosome length, followed by inversion and reattachment. Inversions may involve the centromere (called pericentric inversions) or not (called paracentric inversions). Estimates of frequency range from about 0.12% to 0.7% (pericentric inversions) and about 0.1% to 0.5% (paracentric inversions).3 The risk to have a liveborn abnormal child due to recombination is between 1% and 5% when a parent has a pericentric inversion and much lower for paracentric inversions carriers. There are some inversions with a breakpoint within the heterochromatic regions of chromosomes 1, 9, 16, and Y, which are frequently seen, and they are considered normal variants.

All these chromosomal abnormalities can be diagnosed using classical cytogenetic techniques (conventional karyotype) or by molecular cytogenetics (fluorescence in situ hybridization [FISH], quantitative fluorescence polymerase chain reaction [QF-PCR], multiplex ligation-dependent probe amplification [MLPA], CMA).8







Some deletions and duplications in the genome involve a segment of a chromosome that is too small (from less than 1 kilobase [kb] to a few megabases [Mb]) to be readily seen through classical cytogenetic methods. These microdeletions or microduplications (CNV: copy number variant) involve multiple disease genes, each potentially contributing to a phenotype independently. There are more than 200 microdeletion syndromes described to date (Table 11.2). The most common microdeletion involves chromosome region 22q11.2 and has been associated with several distinct genetic disorders that are known to have overlapping clinical features (22qDS—deletion syndrome). These disorders include DiGeorge syndrome, velocardiofacial syndrome, isolated conotruncal cardiac defects, Cayler syndrome, and Opitz syndrome. The expanding, variable phenotype of individuals with 22q11 DS is now recognized.18 The genetic changes of microdeletions can be studied by molecular cytogenetic techniques (FISH, MLPA, QF-PCR, CMA) or NGS (CNV-seq).19


Single-Gene Disorders

Single-gene disorders (monogenic disorders), also referred to as Mendelian disorders, are those in which the phenotype is produced mainly by pathogenic variants in a specific gene, with little contribution from other genes or environmental influences. These disorders can be classified according to the patterns of inheritance dictated by Mendelian laws as being autosomal dominant (AD), autosomal recessive (AR), or X-linked. Single-gene disorders may also display other non-Mendelian forms of inheritance such as mitochondrial or imprinting forms. It has been
estimated that approximately 1% of people in the general population have a single-gene disorder.9






Autosomal dominant (AD) disorders are those in which the phenotype is caused by a pathogenic variant in a single copy of a gene on one of the 22 autosomes (the patient is heterozygous for the variant). An individual who carries a dominant gene pathogenic variant usually manifests the disorder. Examples of AD disorders are tuberous sclerosis, neurofibromatosis, and achondroplasia.

The following general principles characterize inheritance of AD disorders (Figure 11.4):



  • An individual who is affected has a 50% risk of transmitting the gene to each of his or her offspring.


  • Both males and females may be affected in equal proportions.


  • Both males and females are likely to transmit the disorder to male and female children.


  • An individual who is affected has one affected parent, or the disorder has appeared for the first time as a “de novo” variant in that individual (eg, approximately seven out of eight individuals with achondroplasia are due to a dominant de novo gene pathogenic variant).


  • The phenotype of a dominant gene pathogenic variant is determined by penetrance, which indicates whether or not that variant is expressed. Complete penetrance means that the dominant gene pathogenic variant expresses in all individuals who carry that variant (eg, neurofibromatosis 1 [NF 1] has complete penetrance after childhood, which means that all individuals who carry a pathogenic variant in the NF1 gene will manifest the disorder). Incomplete penetrance is expressed as a percentage, which means the number of individuals who carry the variant that expresses the phenotype. For example, 70% penetrance means that 70% of individuals with the pathogenic dominant gene variant expresses the phenotype. Incomplete penetrance may account for some AD disorders that seem to “skip” generations and may be a manifestation of the interaction of other genes.















  • The phenotype of a dominant gene is also determined by expressivity or the variability in clinical expression (the range of phenotypic features). Variable expressivity means that the dominant gene produces a range of phenotypic features from mild to severe; therefore, not all individuals will show identical phenotypes (eg, the phenotype of individuals with dominant pathogenic variants in genes associated with nonsyndromic holoprosencephaly is extremely variable, ranging from alobar holoprosencephaly to microforms with single central maxillary incisor).20

In examining the pedigree of a family with possible AD disorders, attention is usually given to whether the disease has a vertical pattern of inheritance.21

Autosomal recessive (AR) disorders are those in which the phenotype is due to pathogenic variants present in both copies of a gene on one of the 22 autosomes (the patient is homozygous [two
identical pathogenic variants] or compound heterozygous [two different pathogenic variants in both alleles of a gene]). Examples of AR disorders are cystic fibrosis, Tay-Sachs disease, and spinal muscular atrophy.

Inheritance of AR disorders is characterized by the following general principles (Figure 11.5):



  • Two unaffected individuals who are heterozygous or carriers of one pathogenic recessive gene variant have a 25% risk of having an affected offspring in each pregnancy (one of four children will be affected; three of four will be phenotypically normal with two of these being carriers).


  • Carriers of pathogenic recessive gene variants are at risk of affected offspring only if their partners are also carriers of pathogenic variants in the same gene.


  • Both males and females may be affected in equal proportions.


  • Carriers of single recessive pathogenic variants do not manifest the disease, are healthy (in some cases they may have changes at the biochemical or cellular level).







  • Carriers of recessive pathogenic variants may be recognized after the birth of an affected child, after the diagnosis of an affected family member, or as the result of a genetic screening program.

In examining the pedigree of a family with possible AR disorder, attention is usually given to whether the disease has a horizontal pattern of inheritance.

Every person is a carrier of some AR pathogenic variants, but, as recessive diseases have a low prevalence in the general population, the chance that both partners are carriers of variants in the same gene is low (1%-2%) unless there is consanguinity or they belong to specific ethnic groups. Hence, couples who share the Mediterranean, Ashkenazi Jewish, Black, or Asian extraction are at risk for beta-thalassemia, Tay-Sachs and Canavan disease, sickle cell disease, and alpha-thalassemia, respectively.22,23

X-linked disorders are those in which the phenotype is due to a pathogenic variant in a gene on the X chromosome, and they are usually recessive. Given that the male has only one X chromosome and the female has two, both the risk and severity of X-linked disease will vary between the sexes. Examples of X-linked recessive disorders are hemophilia A and Duchenne muscular dystrophy (DMD), and of an X-linked dominant disorder is incontinentia pigmenti.

The following general principles characterize inheritance of X-linked disorders (Figure 11.6):

In X-linked recessive disorders:



  • Males will usually manifest the fullest expression of the disorder, whereas random X inactivation will largely influence expression in females.


  • Affected men will produce carrier daughters, while their sons will be healthy.


  • The male-to-male transmission does not occur because a male never contributes his X chromosome to a son.


  • Females heterozygotes have a risk of 50% of male children affected in each conception, while half of the female daughters will be carriers.


  • Females heterozygotes are generally asymptomatic but may manifest some sign(s) of the disease in question (eg, female carriers of DMD are generally asymptomatic but may manifest cardiomyopathy or cardiac conduction defects).

X-linked dominant traits are characterized by an affected male transmitting the condition to all his
daughters and none of his sons; an affected female has a 50% likelihood of transmitting the disorder to her sons or daughters. Rarely, an X-linked dominant trait may be lethal in affected males, resulting in a disorder that appears to occur, clinically, only in females and in which an affected female has a 50% likelihood of transmitting the trait to her daughters. These affected women have an increased frequency of miscarriage due to affected male fetuses.






In examining the pedigree of a family with possible X-linked disease, attention is usually given to whether the disease has occurred in maternal nephews, uncles, or first cousins and through the female line.

Pathogenic variants in single gene disorders can be diagnosed using molecular techniques (eg, Sanger sequencing, NGS, PCR, MLPA). Carrier screening tests for some disorders are also available using biochemical tests (eg, quantification of hexosaminidase A enzyme activity in plasma or leukocytes to assess in Tay-Sachs disease carrier status).8


Non-Mendelian Patterns of Inheritance

Some disorders do not follow the classic Mendelian patterns of inheritance. There are several mechanisms described below.


Mitochondrial Inheritance

Mitochondrial disorders are a heterogeneous group of diseases produced by dysfunction of mitochondria. Each cell has hundreds of mitochondria located in the cytoplasm. Each mitochondrion has its own genome. Mitochondrial disorders can be caused by genetic defects either at the nuclear or at the mitochondrial DNA (mtDNA). When pathogenic variants are located in the nuclear DNA, the disorder will be inherited in the usual autosomal recessive or dominant patterns (eg, Leigh syndrome). On the contrary, if the genetic defect is encoded in the mitochondrial genome, the pattern of inheritance of these disorders will be mitochondrial, which are described below (eg, Leber hereditary optic neuropathy).

The following general principles characterize mitochondrial inheritance24:



  • The mother transmits mitochondrial DNA because only maternal mitochondria are transmitted to the offspring (sperm mitochondria are eliminated during fertilization).


  • Males and females can be equally affected.


  • The phenotype will be affected by mitochondrial heteroplasmy, which is the coexistence of normal and abnormal mitochondrial DNA molecules within each cell (each cell contains multiple mitochondria, and each mitochondrion contains multiple copies of mitochondrial DNA). Mitochondria divide through mitosis and segregate to daughter cells during cell division. An mtDNA pathogenic variant present in one mitochondrion will generate more abnormal mitochondria that will segregate to daughter cells. The proportion of normal and abnormal mitochondria will vary in different cells and different tissues, therefore affecting the expression and severity of the disorder depending on the eventual abnormal mitochondrial load in various tissues.


  • The mother of an affected individual has the mtDNA pathogenic variant and may or may not have symptoms.


  • Males with an mtDNA pathogenic variant will not transmit the variant to offspring.


  • Females with an mtDNA will transmit the variant to all her offspring, and the phenotype will vary according to the number of abnormal mitochondria in different tissues.


  • An individual is unique in the proportion of normal and abnormal mitochondrial DNA in different organs.








Uniparental Disomy

Uniparental disomy (UPD) is the inheritance of both members of a chromosome pair from the same parent, resulting in disomy of that chromosome (n = 2). UPD arises more frequently as a consequence of the “rescue” of a trisomic conception by loss of one chromosome and retention of the other two chromosomes from the same parent (uniparental heterodisomy: two different homologous chromosomes from the same parent). UPD may also occur as a result of duplication of the chromosome in a monosomic pregnancy (uniparental isodisomy: two identical homologous chromosomes from the same parent) (Figure 11.7). This process is uncommon but contributes to the occurrence of some well-known clinical disorders when it involves chromosomes with “imprinting” or genomic imprinting (Table 11.3).15

This derivation of a pair of homologs from one parent cannot be detected cytogenetically. Molecular cytogenetic techniques using DNA markers facilitate UPD detection (eg, MLPA, SNP-array).8,9 The indication for UPD study in most instances has been either a genetic disorder (eg, Prader-Willi syndrome) or an abnormality found on prenatal diagnosis. For example, trisomy 15 CPM (trisomy 15 is found in chorionic villi, but the amniotic fluid is euploid and further assessment should be conducted to determine UPD of chromosome 15).










Imprinting

The imprinting or genomic imprinting is an epigenetic mechanism by which the expression of specific genes depends on the sex of the parent of origin. If an “epigenetic mark” inactivates an imprinted gene (eg, DNA methylation), gene function will depend entirely on the active gene inherited from the other parent. It is a regulation process of gene expression where the function of the gene changes without changing its sequence. Under normal circumstances in the human genome, most genes are both expressed; only a minority of human genes are imprinted according to whether the chromosome has been inherited in the sperm or the ovum. Imprinting thus produces a differential activation status of the two alleles of a locus or loci. For example, if inactivation of the inherited maternal allele occurs, only the allele of paternal origin will be functionally active; and vice versa. There are disorders produced by loss or change in the “imprinting” pattern of a gene or chromosome segment, for example, in UPD of one entire chromosome or chromosome segment subject to imprinting (chromosomes 6, 7, 11, 14, 15, 20). UPD has been described most commonly in the Prader-Willi, and Angelman syndromes. About two-thirds of patients with Prader-Willi syndrome have a recognizable cytogenetic deletion in one chromosome 15q11-q13 region. Another approximately 30% of cases are due to maternal UPD.25,26


Trinucleotide-Repeat Expansion

There are specific genes with a region of triplet repeats (trinucleotide) that are susceptible to expansion when there is transmission from parent to offspring (eg, fragile X syndrome, Huntington disease). This process is termed anticipation. During meiosis, gametes can increase the number of triplet repeats, and when the gene reaches a critical number, it may alter its expression and produce phenotypic abnormalities. The reason for repeat expansion (or not) is unknown. Some regions of triplet repeats may expand only during female meiosis (eg, fragile X) and others may expand during male meiosis (eg, Huntington disease).

Fragile X syndrome is an X-linked disorder produced by CGG trinucleotide expansion in the FMR1 (fragile X mental retardation 1) gene and present in 1 out of every 4500 males. It is the most common single cause of inherited intellectual disability in males. The prevalence of females affected with the syndrome is approximately one-half the male prevalence. FMR1 alleles are classified according to the number of repeats in exon 1 into four groups (Table 11.4): normal alleles: 5 to 44 repeats; intermediate alleles (gray zone or borderline): 45 to 54 repeats; premutation alleles: 55 to 200 repeats; full-mutation alleles: more than 200 CGG repeats. It is also important to assess the methylation pattern of the repeat region.27,28

Fragile X syndrome occurs in individuals with an FMR1 gene with full mutation usually accompanied by aberrant methylation, which produces a loss-of-function of the gene. The chance of expansion of a premutation to a full mutation when transmitted to offspring depends on the sex of the parent and the number of trinucleotide CGG repeats present in the parental gene27,28,29,30:



  • Intermediate allele: offspring are not at increased risk for fragile X syndrome, although almost 14% may expand into the premutation range when transmitted by the mother.16 They are not known to expand to full mutations.


  • Premutation alleles: Premutation carriers do not have fragile X syndrome. Women with alleles in this range have a 50% risk of transmitting a premutation in each pregnancy. They are also at risk to repeat expansion and having children with fragile X syndrome. The risk of a maternal premutation becoming a full mutation in her offspring depends on the number of CGG trinucleotide repeats. The larger the size of the premutation repeat, the more likely the expansion to a fully expanded CGG repeat. For small premutations, AGG interrupters in the FMR1 gene may help
    evaluate the risk of expansion. The presence of AGG decreases the risk of expansion of a premutation allele to a full mutation allele during maternal transmission. Premutation carriers also have an increased risk of FMR1-related primary ovarian insufficiency (POI), and fragile X-associated tremor/ataxia syndrome (FXTAS) (both males and females). Males are considered “transmitting males” because the father does not expand to full mutations (the premutation is inherited by all of his daughters and none of his sons).28








Detection of the CGG triplet repeat with concurrent ascertainment of the methylation status is the standard diagnostic test for fragile X syndrome.30


Germline Mosaicism

Germline or gonadal mosaicism occurs in a phenotypically normal individual when a pathogenic disease variant is present only in some germ cells and, therefore, increases the risk for having multiple affected children with the disease. It may explain the recurrence of some dominant diseases in unaffected parents such as osteogenesis imperfecta type 2. Germline mosaicism is also common in DMD, an X-linked disease; therefore the empiric recurrence risk after the birth of a child with DMD disease caused by apparently de novo pathogenic variants may be higher than expected in the general population.21


Multifactorial or Polygenic Disorders

Multifactorial or polygenic disorders are relatively common (about 1% of newborns) and occur due to the interaction of genetic and environmental factors. Most malformations limited to one organ or system belong to this category (eg, anencephaly). Although they have a slight tendency to recur, they do not follow Mendelian inheritance patterns. The occurrence of a defect of multifactorial origin implies a risk of recurrence of 3% to 5% for the siblings and offspring of the affected. This risk is lower than what one would expect if a single gene was affected but higher than that observed in the general population. Recurrence increases with the number of affected relatives, the severity of the defect, and sex of the affected proband. The risk is higher if the sex of the affected person is the least prevalent for this anomaly. For example, the risk of recurrence is higher for bilateral cleft lip with cleft palate (8%) than for unilateral cleft lip (4%); and for pyloric stenosis, which occurs more frequently in men, when the defect occurs in a woman.3,8,9 Most traits inherited from parents, such as height, hair and eye color, have a multifactorial or polygenic inheritance mechanism.

The advance in the understanding of the human genome allowed the discovery of the genetic origin and reclassification of some defects thought previously to be multifactorial.


Principles of Genetic Counseling

The definition of genetic counseling describes a “process of helping people understand and adapt to the medical, psychological, and familial implications of the genetic contributions to disease.”31

Genetic counseling is a communication process concerning the occurrence and the risks of recurrence of genetic disorders within a family. Such counseling aims to provide the patient with a clear and comprehensive understanding of all the important implications of the disorder in question, as well as the possible options. The purpose is also to help families through their decision making, and emotional adjustments and adaptations, where indicated.11

Genetic counseling constitutes an essential component of preconception and prenatal care.32 All prospective parents need to be told if they have an increased risk of having children with a genetic disorder, or other defects, and what are their options. The physician’s duty is to communicate this information clearly and in simple language (with a translator, if required), to offer specific tests, to offer specific treatments, or to refer couples for expert opinion and to document the consultation and recommendations. Genetic counseling can also provide an otherwise absent opportunity for validation of patient’s experiences and concerns about genetic disorders.7,33

Prospective parents can seek genetic counseling by themselves or be referred by physicians. No single model of genetic counseling exists with wide variation within and across countries.34 Genetic counseling should be developed by appropriately trained professionals who have the skills to explain genetic concepts and technologies at an appropriate level of complexity, interpret genetic information, communicate uncertainty, and support patient’s informed choice.7,32,35,36 In general, it is best provided by a clinical geneticist or certified genetic counselor under the supervision of a clinical geneticist. In both the
United States and Canada, board-certified genetic counselors are available for referral, but this career does not exist in all countries.34 Genetic counselors are professionals who have specialized education in genetics and counseling and provide personalized help to patients so as they can make informed decisions about their genetic health. They are used to interpret genetic disease etiology and clinical consequences, to incorporate new technologic information for pretest counseling, to deal with posttest result interpretation, and to provide an assessment based on patient knowledge, values, and concerns, supporting autonomy.31,33,37,38

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Principles of Genetic Counseling in Prenatal and Perinatal Medicine
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