Genomic imprinting is important to understand many clinical disorders and diseases. Imprinted genes are involved in various aspects of growth (intrauterine, postnatal, and cancers), behavior, and placental development. Genomic imprinting effects are observed as clinical disorders when there is a lack of expression of a gene because of deletion, mutation, or deficiency, or when there is overexpression of a gene because of biallelic expression due to duplication, relaxation of imprinting, or loss of imprinting control.
Observations that genomic imprinting may be important in humans have come from (a) hydatidiform moles and ovarian teratomas, which are naturally occurring equivalents of artificially constructed androgenetic and gynegenetic mouse embryos (see the section “How Errors in the Imprinting Process Contribute to Human Disease” earlier in this chapter); (b) triploid phenotypes in which the phenotype differs depending on whether the extra set of chromosomes is contributed by the mother or the father; (c) human chromosomal deletion syndromes (Prader-Willi syndrome and Angelman syndrome), the phenotypes of which differ depending on whether the deletion involves the mother's or the father's chromosome; (d) uniparental disomy in which the phenotype differs depending on which parent has contributed both of the chromosomes; (e) “imprinting center” mutations in Prader-Willi, Angelman, and, perhaps, Beckwith-Wiedemann syndromes; (f) a number of different cancers; (g) X chromosome inactivation; (h) disorders of growth, and; (i) parental origin effects on behavior.
Chromosomal Deletion Syndromes
Prader-Willi Syndrome and Angelman Syndrome.
Prader-Willi syndrome (PWS) and Angelman syndrome (AS) have been studied extensively in relation to genomic imprinting. Although the two syndromes are phenotypically distinct neurobehavioral syndromes, it has become clear that both involve imprinted genes on the long arm of chromosome 15. Both syndromes may be associated with deletions of the same region of chromosome 15 (15q11-q13). In PWS, the deletion is exclusively of the paternally derived chromosome 15, whereas in AS, the deletion is of the maternally derived chromosome 15. This observation suggests that there is a critical region on the paternal chromosome 15 that is required to prevent the Prader-Willi phenotype. Likewise, there is a critical region on the maternal chromosome 15 that must be present in order to prevent Angelman syndrome.60,70,78
Prader-Willi syndrome is characterized by hypotonia in the newborn. Failure to thrive may occur without special feeding efforts. However, hyperphagia and obesity develop early in childhood. Affected individuals usually develop small hands and feet; almond-shaped eyes; narrow bitemporal diameter; somewhat long face; mild to moderate developmental delay; hypothalamic hypogonadotrophic hypogonadism; small genitalia; and delayed puberty. Although PWS was recognized more than 40 years ago its relationship to a parent of origin effect was not recognized until the late 1980s.79 In the early 1980s, a deletion of chromosome 15q11-q13 was recognized in 60 percent of individuals with PWS.80 Later it was discovered that these deletions were always on the paternally inherited chromosome 15, 59,81 suggesting that there is a critical region on paternal chromosome 15 that must be inherited from the father in order to prevent PWS. Another group of individuals with PWS was recognized as having maternal uniparental disomy of chromosome 15 (two copies of maternal chromosome 15 and no contribution from the father (paternal deficiency)), suggesting that an imprinted gene or genes may be lacking because the paternal chromosome was not inherited.79 Twenty-five to 30 percent of individuals with PWS have now been recognized to have maternal uniparental disomy of chromosome 15. A small percentage of individuals with PWS have mutations or microdeletions in a region known as the imprinting control region.82 Molecular studies have revealed that the Prader-Willi critical region has several genes that are expressed only from the paternally inherited chromosome. Among these are SNRPN (a developmentally regulated protein component of spliceosome expressed predominantly in neuronal tissue), ZNF127 and FZN 127 (zinc finger proteins), IPW (an RNA functional unit83), NDN (the necdin gene, expressed in differentiating neurons of the brain), 84-87 and two expressed sequence tags (PAR 1 and PAR 5). The distance between these imprinted genes is 1 to 1.5 Mb, which suggests that additional imprinted genes may exist in this critical region. Gunay-Aygun et al. have suggested that there may be phenotypic differences in PWS associated with deletion and PWS associated with uniparental disomy.88 However, more studies are required to distinguish these subtle variations in these two groups. The paternally deleted region usually contains a gene for pigmentation; as a result, individuals with PWS due to deletions may have fair complexions and blond hair.89
Angelman syndrome, also known as “happy puppet syndrome,” was first described in 1965. The phenotype is characterized by severe mental retardation; ataxia; seizures; abnormal EEG; very happy disposition; midfacial hypoplasia; and inappropriate outbursts of laughter. Sixty to 70 percent of individuals with AS have been recognized to have a deletion involving maternal chromosome 15q11-q13; about 5 percent have been recognized to have paternal uniparental disomy; and most of the remaining individuals with AS have been found to have mutations within the imprinting control region90 or the UBE3A gene.
UBE3A (a protein that functions in ubiquitination of other proteins) has been localized in the Angelman critical region and been shown to be differentially expressed90 depending on the parent of origin and the tissue. UBE3A has biparental expression in most tissues, but only maternal expression in the brain.91-93 Therefore, maternal deletion, deficiency, or lack of expression of the maternal allele in the brain is expected to result in the Angelman phenotype. Consistent with this expectation, several patients have been identified who carry mutations in the maternal UBE3A allele.93
Genes in the PWS/AS critical region have been shown to have parent-specific methylation patterns, parent-specific replication timing patterns, and several control regions that may be involved in differential gene expression.94 The exact mechanisms of control are not yet understood, but maternal chromosomal abnormalities seem to more often involve improper control of gene expression, whereas the paternal chromosome abnormalities seem to more often involve deficiencies. A specific PCR test based on DNA methylation can be used to identify the parental origin of a particular chromosome.36,37 Determining the mechanisms leading to Angelman and Prader-Willi syndromes (deletion, chromosomal rearrangements such as translocation, uniparental disomy, or gene control) alterations in a specific case has implications for estimating recurrence risks, for genetic counseling, and for prenatal diagnosis. Higher recurrence risk is associated with mutations involving the imprinting control center or mutations of specific genes, while lowest recurrence risk is associated with uniparental disomy.95 A recent study suggests that parent of origin-specific DNA methylation analysis at the SNRPN locus in amniotic fluid cells and of chorionic villi samples may be useful for prenatal diagnosis when trying to detect imprinting defects.96
Individuals with PWS and AS have been noted to have two- to threefold higher levels of plasma γ-aminobutyric acid (GABA) compared to nonretarded moderately obese or retarded nonobese controls.97 It is speculated that this may be due to an alteration of a subset of postsynaptic GABA receptors leading to reduced sensitivity, with the result that there is a compensatory increase in presynaptic GABA release.97 The GABRB3 gene has been localized to the 15q11-q13 region and appears to be imprinted.96
That uniparental disomy could occur was first proposed by Eric Engel in 1980.98 Uniparental disomy is a situation in which both members of a chromosome pair have been inherited from one parent (maternal deficiency/paternal duplication or vice versa). When two different chromosomes are inherited from one parent, the uniparental disomy is heterodisomy. If identical copies of the same chromosome are inherited, it is called isodisomy. Whole chromosomes or parts of a chromosome can be involved, and an individual may be mosaic for the event; for example, some cells may be trisomic and some may have uniparental disomy. New molecular diagnostic techniques allow us to distinguish between almost any of these possibilities.
Uniparental disomy is surprisingly common and is now known to occur in a number of disorders. The primary mechanism producing uniparental disomy appears to be a “trisomy rescue” after meiotic nondisjunction. Nondisjunction in the first meiotic division results in heterodisomy, whereas nondisjunction in the second meiotic division results in isodisomy. Because of crossing-over during meiosis, there may be isodisomy for only part of a chromosome. Isodisomy may also occur as a result of nondisjunction in a somatic cell; however, this appears to be a relatively rare event.
Ten to 15 percent of all recognized human conceptions might begin as trisomies. However, most trisomic conceptuses are lethal and are miscarried early in pregnancy. The only way that most trisomy conceptions can survive is by loss of one of the three chromosomes, resulting in a disomic cell line. If the parental origin of the loss of a chromosome is random, then this event is expected to lead to uniparental disomy in one-third of surviving cases.
Uniparental disomy has been reported for chromosomes 1, 99 2, 100 4, 101 5, 102 6, 103-105 7, 106-110 8, 111 9, 112,113 10, 114 11, 62,115,116 13, 117 14, 118-121 15, 79,122,123 16, 124-126 21, 127 and 22, 128 and the sex chromosomes.129-131
Three types of complications and sequelae are seen with uniparental disomy (a) uncovering imprinted genes; (b) producing autosomal recessive disorders; and (c) producing abnormalities related to residual aneuploidy.
Uncovering Imprinted Genes.
Genomic imprinting results in the expression of a gene from only one parent's allele. When uniparental disomy occurs (situation in which both chromosomes come from one parent), if a critical gene is normally expressed from only the missing allele of the other parent, the effects of that imprinted gene may be uncovered. The pioneering work of Cattanach132 using translocation disomies in mice defined multiple chromosome regions associated with gross phenotypic effects of uniparental disomy. This level of phenotypic screen yielded effects predominantly on growth, behavior, and survival.
Some of the phenotypes observed in the mouse suggested the existence of homologous loci in humans. Thus when two chromosomes 15 are inherited from the mother, the paternally derived Prader-Willi critical region (essential to prevent PWS) are missing, resulting in the PWS phenotype. Conversely, when two chromosomes 15 are inherited from the father, the maternally derived Angelman critical region (essential to prevent AS) are missing, resulting in the AS phenotype. Uniparental disomy for the homologous loci in the mouse produce morphological effects similar to those observed in humans. Thus far, six human chromosome regions that carry imprinted genes and that are homologous to the mouse chromosome regions demonstrated to carry imprinted genes, have been identified; paternal chromosome 6q, maternal chromosome 7q, paternal and maternal chromosome 11p, maternal chromosome 14q, and both maternal and paternal chromosome 15q (Table 15-1).
Table 15-1: Imprinted Genes Associated with Human Disease Phenotypes |Favorite Table|Download (.pdf) Table 15-1: Imprinted Genes Associated with Human Disease Phenotypes
|Gene Symbol ||Normally Inactivated Allele ||Human Chromosome ||Phenotype |
| IGF2R ||Paternal* ||6q25-q27 ||Transient neonatal diabetes mellitus |
| PEG1/MEST ||Maternal ||7q32 ||Russel-Silver syndrome |
| IGF2 ||Maternal ||11p15 ||BWS/Wilms |
| H19 ||Paternal ||11p15 ||Wilms |
| P57KIP2 ||Maternal ||11p15 ||BWS |
| KVLQT ||Maternal ||11p15 ||BWS |
|? ||? Maternal ||14q ||Precocious puberty/short stature |
| ZNF127 ||Paternal ||15q11-q13 ||PWS |
| FZN127 ||Paternal ||15q11-q13 ||PWS |
| IPW ||Paternal ||15q11-q13 ||PWS |
| NDN ||Paternal ||15q11-q13 ||PWS |
| PAR1 ||Paternal ||15q11-q13 ||PWS |
| PAR5 ||Paternal ||15q11-q13 ||PWS |
| UBE3A ||Maternal ||15q11-q13 ||Angelman syndrome |
Such studies have given rise to “imprinting maps” of the mouse and human genomes. While such maps are very useful, they should be interpreted with caution because they are not exclusionary. By this we mean that those regions identified as having some measurable phenotypic effect undoubtedly harbor imprinted genes. However, one cannot draw the opposite conclusion from the negative result. Failure to observe an effect of uniparental disomy on survival, gross morphology, or behavior does not imply that no imprinted genes exist in these regions; it implies only that their absence does not result in any of the phenotypes detectable by the screening procedure. For example, the neuronatin gene on mouse chromosome 2 has been shown to be imprinted, but lies outside the region delimited as imprinted by studies using translocation chromosomes.133 In addition, the recent description of cognitive differences in Turner syndrome individuals carrying a maternal versus a paternal X chromosome (see below) points out the importance of this precaution. In the absence of such tests, one could have concluded that because individuals with Turner syndrome may carry either maternal or paternal X chromosomes, and that females with exclusively maternal X chromosomes have been identified, 130,131 no genes on the X chromosome are imprinted. We now know that at least two genes on the X chromosome, in addition to the cognitive function locus, 65 are imprinted (Xist 64 and the choroideremia locus134).
Producing Autosomal Recessive Disorders.
According to the rules of Mendelian inheritance, a mutant phenotype is expected in one quarter of the offspring when both parents are carriers of a recessive allele at an autosomal locus. When uniparental disomy occurs, it is possible for the offspring to receive both copies of the identical chromosome or chromosomal region (isodisomy) from only one parent. If that chromosome carries the abnormal allele, the autosomal recessive disorder will be manifested in the offspring, even though only one parent is a carrier of the abnormal gene. An autosomal recessive disorder due to uniparental isodisomy was first reported in a female affected with cystic fibrosis.106 Subsequent to this report, many individuals with recessive disorders as a result of uniparental disomy have been reported (see Table 15-2).
Table 15-2: Recessive Disorders Associated with Uniparental Isodisomy |Favorite Table|Download (.pdf) Table 15-2: Recessive Disorders Associated with Uniparental Isodisomy
|Chromosome ||Transmission ||Recessive Disorder ||Reference |
|5 ||Paternal ||Spinal muscular atrophy ||102 |
|6 ||Paternal ||Complement deficiency ||105 |
|7 ||Maternal ||Cystic fibrosis ||106 |
| ||Maternal ||Osteogenesis imperfecta ||110 |
| ||Paternal ||Congenital chloride diarrhea ||161 |
|8 ||Paternal ||Lipoprotein lipase deficiency ||111 |
|9 ||Maternal ||Cartilage hair hypoplasia ||112 |
|11 ||Maternal || β-Thalassemia ||162 |
|13 ||Paternal ||Retinoblastoma ||163 |
|14 ||Maternal ||Rod monochromacy ||119 |
|15 ||Maternal ||Bloom syndrome ||123 |
|16 ||Paternal ||α-Thalassemia ||126 |
| ||Paternal ||Familial Mediterranean fever ||125 |
|X ||Paternal ||Hemophilia ||129 |
| ||Maternal ||Duchenne muscular dystrophy ||131 |
Effects of Residual Aneuploidy.
When trisomy occurs, the extra chromosome is derived from one or the other parent. When a trisomy converts into a disomic cell line, there is a one in three chance that this will result in uniparental disomy. This “trisomy rescue” allows the pregnancy to survive, and allows the fetus to come to term, but puts the fetus at risk both for having uniparental disomy and for having trisomic cells (residual aneuploidy in some tissues). These cells may lead to malformations or dysfunction. They may also subsequently predispose to cancer.
Uniparental disomy should be suspected when chorionic villus sampling or amniocentesis reveals mosaicism. Studies of chorionic villus sampling suggest that at least 2 to 3 percent of pregnancies have some trisomic cells, which suggests that the conception began as trisomy. One-third of trisomy conceptions are predicted to result in uniparental disomy, suggesting that as much as 1 percent of all pregnancies have converted to uniparental disomy. Because many uniparental disomies have phenotypic abnormalities, if mosaicism is detected on prenatal diagnosis, an effort must be made to exclude uniparental disomy, especially with chromosomes 6, 7, 11, 14, and 15.
Because most uniparental disomy results from trisomy rescue and because trisomies are associated with advanced maternal age, it is not surprising that uniparental disomies are associated with advanced maternal age as well. For example, PWS resulting from chromosome 15 deletions is not associated with advanced parental age, but uniparental disomy Prader-Willi is associated with advanced maternal age. Because parents who are carriers of translocations are at a risk for trisomy, they are also at a risk for uniparental disomy, and, consequently, at risk for uncovering the effects of imprinting, producing autosomal recessive disorders, and the effects of residual aneuploidy.
Specific Disorders Associated with Imprinting
Albright Hereditary Osteodystrophy.
Albright hereditary osteodystrophy is an autosomal dominant disorder occurring with a variety of phenotypes within the same family. At least two linkage groups have been described. One involves mutations in the human Gs alpha gene (GNAS1) which is mapped to chromosome 20q13.11.135 Depending on which parent transmits the abnormal allele, a different phenotype is produced (i.e., the phenotype is dependent on the parent from whom the mutation is inherited). If the abnormal allele is inherited from the father, a milder phenotype (pseudo-pseudohypoparathyroidism) occurs, in which there is hormone responsiveness. On the other hand, if the abnormal allele is inherited from the mother, a severe hormone-resistant, pseudohypoparathyroidism type 1a develops, which is characterized by seizures, mental retardation, and subcutaneous and intracranial calcification. Both phenotypes can be seen within the same family depending on which parent is transmitting the mutation.136-138 It is not yet clear whether both Albright hereditary osteodystrophy loci involve parent of origin effects.
Transient Neonatal Diabetes Mellitus.
Transient neonatal diabetes mellitus is a rare type of diabetes mellitus that presents in the neonatal period with intrauterine growth retardation. These babies lack insulin in the neonatal period. However, insulin production may start within a few months, and often becomes normal by about age 3 years. This type of transient neonatal diabetes mellitus has been associated with paternal uniparental isodisomy of chromosome 6.104,139 The gene involved in transient neonatal diabetes mellitus has been localized to chromosome 6q22-q23.103 Duplications of paternal chromosome 6q have also been associated with transient neonatal diabetes mellitus.140 The gene for insulin is on chromosome 11 and must have different types of control at different times in development and in different tissues (i.e., in utero, in the neonatal period, and in later period). In mice during the embryonic period, only the paternal insulin allele is expressed in the yolk sac, suggesting tissue-specific, time-specific, and parental origin-specific control of alleles at the insulin locus.141
Absence of paternal chromosome 7 (maternal uniparental disomy for chromosome 7) has been associated with intrauterine, as well as postnatal, growth retardation, suggesting that a gene on paternal chromosome 7 is necessary for normal intrauterine and postnatal growth. Maternal uniparental disomy for chromosome 7 has been associated with growth retardation (intrauterine as well as postnatal).106,107,110 Maternal uniparental disomy for chromosome 7 has also been associated with Russell-Silver syndrome.109 Russell-Silver syndrome is a growth-retardation syndrome that is characterized by intrauterine and postnatal growth retardation; short stature; normal head size for age; frontal bossing; triangular face; incurved fifth finger; and hemihypertrophy. Hemihypertrophy (one side larger than the other) may reflect mosaicism for uniparental disomy. Ten to 15 percent of individuals with Russell-Silver syndrome may have uniparental disomy for chromosome 7.109
In humans, one imprinted gene, PEG1/MEST, that is expressed from the paternal allele has been located on chromosome 7 (7q31-q34).142
In addition to maternal uniparental disomy for chromosome 7, maternal uniparental disomy for chromosome 2100 and maternal uniparental disomy for chromosome 16124 have also been associated with intrauterine growth retardation. However, these reports are associated with residual trisomy mosaicism, which may be responsible for the intrauterine growth retardation.
As mentioned earlier, paternal uniparental disomy for chromosome 6 produces transient neonatal diabetes mellitus as well as intrauterine growth retardation.
The Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth syndrome associated with excessive insulin production (secondary to an enlarged pancreas) and hypoglycemia in the neonatal period. These babies are large for gestational age, have macroglossia and visceromegaly. Omphalocele is often present secondary to visceromegaly. Occasionally, mental retardation is seen and thought to be related to hypoglycemia in the neonatal period. In some patients, visceromegaly may develop postnatally. Recently several genes have been implicated in the Beckwith-Wiedemann phenotype, including IGF2, H19, p57KIP2, and KVLQT1. 143-145 KVLQT1 shows tissue-specific imprinting with only paternal expression in most tissues, but biparental expression in the heart.146
In individuals with a family history of BWS, the phenotype appears to only occur with maternal transmission.147 Paternally inherited duplications of 11p15.5 associated with BWS148 have suggested that a double-dose of paternal alleles, or maternal relaxation of imprinting of these genes, is responsible for BWS in a number of patients, indicating that these genes are imprinted. Comparison of phenotypes of individuals with BWS associated with paternal uniparental disomy p11.5 and of individuals with BWS with normal chromosomes, has revealed that individuals with BWS associated with uniparental disomy tend to have a lower incidence of hypoglycemia, a lower incidence of hemihypertrophy, a lower incidence of facial nevus flammeus, and an increased incidence of learning difficulties compared to BWS with normal chromosomes.148 Maternally derived inversions and balanced translocations have also been associated with BWS, 149 suggesting that maternal loss of imprinting control (i.e., relaxation and maternal expression) can also be responsible for BWS.
Individuals with BWS have a higher incidence of cancers.150 Relaxation of imprinting of IGF2 resulting in biparental expression of IGF2 is seen in a number of tumors.151 The risk of recurrence for BWS depends on the genetic rearrangements that produce the disorder. The risk can be as high as 50 percent in complex rearrangements. Hemihypertrophy suggests somatic mosaicism. Discordance of monozygotic female twins suggests somatic loss of control (relaxation) during monozygotic twinning process.
The Simpson-Golabi-Behmel syndrome is an X-linked disorder characterized by overgrowth, coarse facies, and anomalies of the skeleton, heart, kidney, gastrointestinal tract, and the central nervous system. Mutations in GPC3, a glypican gene, are seen in the Simpson-Golabi-Behmel overgrowth syndrome.152 The GPC3 gene is a member of the glypican family of heparin sulfate proteoglycans.153 The gene codes for a cell-surface receptor proteoglycan that binds insulin-like growth factor 2 and is part of a new class of signaling protein.154 BWS and Simpson-Golabi-Behmel syndrome have considerable phenotypic overlap and seem to involve a complex pathway of fetal overgrowth. Individuals with Simpson-Golabi-Behmel syndrome are also at risk for developing some types of cancers.155,156 Suggestions are that fetal macrosomia, low ratio of head to abdominal circumference, and raised maternal serum α-fetoprotein may prove useful markers for prenatal diagnosis of Simpson-Golabi-Behmel syndrome. Postnatal evaluation with α-fetoproteins in Simpson-Golabi-Behmel syndrome and BWS may be an indicator of embryonal tumor.156
Hemihypertrophy is seen with BWS and Wilms tumor. This may suggest mosaicism for imprinting of genes involved in growth.
Mouse uniparental disomy studies suggest behavioral abnormalities can be part of imprinting effects. As already discussed, Prader-Willi and Angelman syndrome have distinct behaviors, which appear to be determined by parent of origin. Recent studies in Turner syndrome suggest that there may be genomically imprinted gene(s) on the X chromosome65 that may influence social functioning and related cognitive abilities. Turner syndrome occurs when there is absence or abnormality of one of the sex chromosomes. Turner syndrome is seen with 45,X karyotypes, ring X chromosomes, X isochromosomes, or terminal deletions involving the X chromosome, or remnants of the Y chromosome, and with mosaicism of any of these. Females with Turner syndrome often have an unusual behavior. They may act immaturely, have a particular spatial perceptual problem, and/or may lack ambition and social skills. Females with Turner syndrome who receive the maintained X chromosome from their father seem to have better social skills as compared to females with Turner syndrome who receive their maintained X chromosome from the mother. This suggests an association of unusual behavior and poor social skills with the loss of the X chromosome contributed by the father. This would also suggest that normal males who can only receive their X chromosome from their mothers are less socially adept because of imprinting of some gene(s) on the X chromosome.157
Imprinting is thought to occur during meiosis and involves methylation. One could speculate that if a mother is folic acid deficient between 6 and 12 weeks (the period of embryonic female meiosis), that this might interfere with the normal imprinting process.
When to Suspect Genomic Imprinting
Genomic imprinting is suspected:
When pedigree analysis reveals that the disorder is always expressed when transmitted from only the mother or only the father.158 Both males and females are equally likely to be affected, but the disorder is transmitted only from one parent (mother or father); that is, the transmission is dependent on the sex of the transmitting parent (e.g., BWS is almost always transmitted by the mother, and glomus tumor is almost always transmitted from the father).
In disorders of growth, behavior, and some endocrine disorders as mentioned earlier.
When monozygotic female twins are discordant for a particular syndrome, the possibility that an imprinted gene is being expressed must be considered.159 A number of genomically imprinted disorders have been reported where one of the monozygotic twins is affected, and the other is not affected. There have been several reports of female monozygotic twins discordant for BWS. It has been suggested that genomic imprinting, monozygous twinning, and X inactivation are all related.160 It is now clear that both genomic imprinting and X inactivation are linked to allelic differences in DNA methylation and chromatin structure. It may be possible that all three are in one way linked to time-specific folic acid deficiency during critical periods because folic acid deficiency has been associated with alteration in methylation and gene expression.
When prenatal diagnosis with chorionic villus sampling or amniocentesis reveals mosaicism, the possibility of uniparental disomy and genomic imprinting effects should be considered, and the fetus should be tested accordingly. Placental mosaicism puts the fetus at risk for uniparental disomy and for uncovering complications of uniparental disomy (imprinting, recessive disorders, residual aneuploidy).
Genomic Imprinting and Genetic Counseling
Understanding genomic imprinting is important because there are important implications for diagnosing some genetic disorders. It is also important for giving recurrence risk to families, for counseling families appropriately, and for providing prenatal diagnosis appropriately. Recurrence risks were discussed above. Individuals with specific syndromes involving some imprinted genes (e.g., BWS and Simpson-Golabi-Behmel syndrome) are at a higher risk for developing some types of cancer. These individuals should be counseled appropriately and should be followed accordingly for early detection and treatment. Prenatal diagnosis for PWS and AS is now possible using a specific PCR test.36,37