(hazard ratio of 4.9), late‐onset psychosis, and suicide.798 There is also evidence of anticipation.799
Preimplantation genetic testing (see Chapter 2) has been successful for many repeat expansion disorders including fragile X syndrome (see Chapter 16), Huntington disease, myotonic muscular dystrophy, and spinocerebellar ataxias types 2 and 12.800–802
Imprinting and uniparental disomy
All that is genetic is not necessarily Mendelian. Developing gametes or early embryonic cells may have genes deleted or silenced, with such primal events being of a single parent origin and lifelong. Moreover, these occurrences may be a consequence of an environmental (epigenetic) factor or influence. Notwithstanding this epigenetic phenomenon, the genomic change, termed “imprinting,” is heritable with potentially serious clinical implications. Epigenetics does not alter DNA sequence, but it does alter its expression.
The expectation is that each pair of autosomes have an equal matched allele from each parent. Infrequently, a pair may be constituted by alleles from one parent, termed uniparental disomy (UPD). If those two are chromosome 7 alleles from one parent and harbor a mutation in the CFTR gene, and the chromosome 7 from the other parent is lost during meiosis, the offspring will have autosomal recessive cystic fibrosis.803, 804 Multiple different disorders are known to be a consequence of UPD and influenced by parent of origin (see Chapter 14).
Relatively rarely, with biparental alleles, one gene (or a cluster) on one allele may be silenced (imprinted). If it is the paternally only expressed region on chromosome 15q, the consequence would be Prader–Willi syndrome, and if it is the maternally expressed UBE3A gene, Angelman syndrome would be the consequence. Silencing occurs through a process of DNA methylation. The repressed allele is methylated; the functional allele is unmethylated. Various assays are available to determine methylation status.805, 806 Multilocus imprinting may also occur, and result in a phenotypic spectrum.807 Accurate detection of UPD can also be determined by whole‐exome sequencing.808 Imprinted gene clusters are primarily found on chromosomes 6, 7, 11, 14, 15, and 20.809
Recommendations made by the ACMG810 for prenatal UPD testing include the following:
Multiple‐cell pseudomosaicism or true mosaicism for trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 from amniocentesis or CVS.
Multiple‐cell pseudomosaicism or true mosaicism for trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 in CVS followed by normal karyotype in amniocentesis.
In the context of preimplantation genetic screening (PGS), a transfer of mosaic embryos with trisomy or monosomy of chromosomes 6, 7, 11, 14, 15, or 20 should be followed by prenatal studies including UPD testing.
Prenatal imaging anomalies consistent with a UPD phenotype. The classic example is the pathognomonic coat‐hanger sign in paternal UPD14.
Familial or de novo balanced Robertsonian translocation or isochromosome involving chromosome 14 or 15 based on CVS or amniocentesis. Both familial and de novo translocations are associated with an increased risk for UPD.
De novo small supernumerary marker chromosome with no apparent euchromatic material in the fetus.
Non‐Robertsonian translocation between an imprinted chromosome with possible 3:1 disjunction that can lead to trisomy or monosomy rescue or gamete complementation. Although every chromosome abnormality that increases the occurrence of nondisjunction in theory would increase the risk of UPD of the chromosomes involved, there are only very few cases reported.
Imprinting disorders are the results of abnormal expression of imprinted genes at seven imprinted domains on the six chromosomes noted above. These disorders are due to different molecular changes that include copy number variation (loss or gain), UPD, point mutation in the active allele, an epimutation resulting in gain or loss of DNA methylation at the imprinting control region, a microdeletion or microduplication at an imprinting control region interfering with DNA methylation, and structural chromosome rearrangements.811 Recurrence risks for imprinting disorders vary according to the molecular alteration. For example, copy number variations or point mutations may occur de novo or come from one parent, who may or may not be affected, depending upon which grandparent transmitted the mutant allele.811 For Angelman syndrome and the Prader–Willi syndrome genetic alterations are almost invariably de novo, resulting in extremely low risks of recurrence. The expectation, however, is a point mutation in the culprit UBE3A gene that causes Angelman syndrome, with a recurrence rate of 50 percent when inherited from an unaffected mother. Fortunately, only about 1 percent of our genes find expression from one or other parent.812
Multilocus imprinting disorders with maternal effect genes (including NLRP2, NLRP7, and PADI6) can affect oocytes and resulting offspring, who may manifest with atypical imprinting disorders.813, 814 Multilocus imprinting disturbance in methylation may affect growth and development. Epigenetic effects are evident in sperm, oocyte, and zygote genomes.815, 816 It is no surprise then, that mutations in NLRP genes may result in early miscarriages, hydatidiform moles, and apparent infertility.813 Most imprinted genes express in the placenta, and loss of imprinting can affect placental weight, fetal growth, and development,817–821 and the regulation of placental hormones.821
Potential imprinting disturbances at the sperm, oocyte, or zygote stages are associated with ART and preimplantation procedures. Cogent evidence exists of an increased incidence of imprinting disorders following ART.822–828 In the most extensive report to date, Hattori et al.822 in a nationwide study in Japan, reported on 931 patients with imprinting disorders. These included 117 cases of Beckwith–Weidemann syndrome, 67 with Silver–Russel syndrome, 520 with Prader–Willi syndrome, and 227 with Angelman syndrome. Most were conceived through ART including intracytoplasmic sperm injection. They noted a 4.46‐ and 8.91‐fold increased frequency of Beckwith–Weidemann syndrome and Silver–Russel syndrome respectively. Cortessis et al.,828 in a meta‐analysis of 23 studies on ART and the occurrence of imprinting disorders, reported significant odds ratios of 4.7 for Angelman syndrome, 5.8 for Beckwith–Weidemann syndrome, 2.2 for Prader–Willi syndrome, and 11.3 for Silver–Russel syndrome.
Mutations in imprinted genes that occur after fertilization can result in somatic mosaicism.829 An interesting example is represented by discordant monozygotic twins in which only one has the disorder (Beckwith–Weidemann syndrome)830–832 or Silver–Russel syndrome,829, 833 pointing to epigenetic disturbances in early development.829
About 1.7 percent of births in the United States result from ART.834 Although the frequency of imprinting disorders is increased, the actual risks are very low, but should be discussed.
Genotype–phenotype associations
DNA mutation analysis has slowly clarified genotype–phenotype associations requiring extensive databases and definitive phenotyping835, 836 (see Chapter 14). Notwithstanding this limitation, mutation analysis does provide precise prenatal diagnosis opportunities and
