paraplegia
Autosomal dominant polycystic kidney disease (PKD1)
Autosomal dominant rolandic epilepsy
Behçet syndrome
Bipolar affective disorder
Crohn disease
Facioscapulohumeral muscular dystrophy
Familial adenomatous polyposis
Familial breast cancer
Familial chronic myeloproliferative disorders
Familial Hodgkin lymphoma
Familial intracranial aneurysms
Familial pancreatic cancer
Familial paraganglioma
Familial Parkinson disease
Familial primary pulmonary hypertension
Familial rheumatoid arthritis
Graves disease
Hodgkin and non‐Hodgkin lymphoma
Holt–Oram syndrome
Idiopathic pulmonary fibrosis
Lattice corneal dystrophy type I (LCD1)
Li–Fraumeni syndrome
Ménière disease
Obsessive–compulsive spectrum disorders
Oculodentodigital syndrome
Paroxysmal kinesigenic dyskinesia (PKD)
Restless legs syndrome
Schizophrenia
Total anomalous pulmonary venous return
Unipolar affective disorder
Recognition in the last decade of hexanucleotide repeat expansions in the C9orf72 gene reveal additional challenges that have raised consideration of prenatal diagnosis, as discussed under “Accurate diagnosis.” Mutations in C9orf72 have been reported in 40–50 percent of cases with familial amyotrophic lateral sclerosis, between 3.5 percent and 8 percent of sporadic ALS cases,792–795 and in 25 percent of familial frontotemporal lobar degeneration, with about 7 percent in sporadic cases.793, 794 The clinical spectrum includes patients with frontotemporal dementia and ALS as well as those with a corticobasal syndrome.796 The real burden and likely involvement of prenatal diagnosis is the recognition of C9orf72 expansions noted in Western Europe as occurring in 18.52 percent of familial cases and 6.26 percent in sporadic cases of frontotemporal lobar degeneration.797 Overall frequencies of these expansions in Finland, Sweden, and Spain were much higher, being 29.33 percent, 20.73 percent, and 25.49 percent, respectively.797 A further distressing aspect of the C9orf72 expansion is the symptomatology that extends to family members who do not have the expansion. In a study of 1,414 first‐ and second‐degree relatives, a statistically significant number had an increased risk of schizophrenia (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,