Nussbaum Thompson Genetics in Medicine 8th ed 2015 PDF

C H A P T E R 6 The Chromosomal and Genomic Basis of Disease: Disorders of the Autosomes and Sex Chromosomes In this chapter, we present several of the most common and best understood chromosomal and...

C H A P T E R 6 The Chromosomal and Genomic Basis of Disease: Disorders of the Autosomes and Sex Chromosomes In this chapter, we present several of the most common and best understood chromosomal and genomic disor- ANEUPLOIDY ders encountered in clinical practice, building on the The most common mutation in our species involves general principles of clinical cytogenetics and genome errors in chromosome segregation, typically leading to analysis introduced in the previous chapter. Each of the production of an abnormal gamete that has two copies disorders presented here illustrates the principles of or no copies of the chromosome involved in the nondis- dosage balance and imbalance at the level of chromo- junction event. Notwithstanding the high frequency of somes and subchromosomal regions of the genome. such errors in meiosis and, to a lesser extent, in mitosis, Because a wide range of phenotypes seen in clinical there are only three well-defined nonmosaic chromo- medicine involve chromosome and subchromosomal some disorders compatible with postnatal survival in mutations, we include in this chapter the spectrum of which there is an abnormal dose of an entire autosome: disorders that are characterized by intellectual disability trisomy 21 (Down syndrome), trisomy 18, and trisomy or by abnormal or ambiguous sexual development. 13. It is surely no coincidence that these chromosomes Although many such disorders can be determined by are the ones with the smallest number of genes among single genes, the clinical approach to evaluation of such all autosomes (see Fig. 2-7). Imbalance for more gene- phenotypes frequently includes detailed chromosome rich chromosomes is presumably incompatible with and genome analysis. long-term survival, and aneuploidy for some of these is frequently associated with pregnancy loss (see Table 5-2). MECHANISMS OF ABNORMALITIES Each of these autosomal trisomies is associated with In this section, we consider abnormalities that illustrate growth retardation, intellectual disability, and multiple the major chromosomal and genomic mechanisms that congenital anomalies (Table 6-2). Nevertheless, each has underlie genetic imbalance of entire chromosomes or a fairly distinctive phenotype that is immediately recog- chromosomal regions. Overall, we distinguish five dif- nizable to an astute clinician in the newborn nursery. ferent categories of such abnormalities, each of which Trisomy 18 and trisomy 13 are both less common than can lead to disorders of clinical significance: trisomy 21; survival beyond the first year is rare, in Disorders due to abnormal chromosome segregation contrast to Down syndrome, in which average life (nondisjunction) expectancy is over 50 years of age. Disorders due to recurrent chromosomal syndromes, The developmental abnormalities characteristic of involving deletions or duplications at genomic hot any one trisomic state must be determined by the extra spots dosage of the particular genes on the additional chro- Disorders due to idiopathic chromosomal abnormali- mosome. Knowledge of the specific relationship between ties, typically de novo the extra chromosome and the consequent developmen- Disorders due to unbalanced familial chromosomal tal abnormality has been limited to date. Current abnormalities research, however, is beginning to localize specific genes Disorders due to chromosomal and genomic events on the extra chromosome that are responsible for spe- that reveal regions of genomic imprinting cific aspects of the abnormal phenotype, through direct The distinguishing features of the underlying mecha- or indirect modulation of patterning events during early nisms are summarized in Table 6-1. Although the cat- development (see Chapter 14). The principles of gene egories of defects that result from these mechanisms can dosage and the likely role of imbalance for individual involve any chromosomes, we introduce them here in genes that underlie specific developmental aspects of the the context of autosomal abnormalities. phenotype apply to all aneuploid conditions; these are 75 76 THOMPSON & THOMPSON GENETICS IN MEDICINE TABLE 6-1 Mechanisms of Chromosome Abnormalities and Genomic Imbalance Category Underlying Mechanism Consequences/Examples Abnormal chromosome segregation Nondisjunction Aneuploidy (Down syndrome, Klinefelter syndrome) Uniparental disomy Recurrent chromosomal syndromes Recombination at segmental Duplication/deletion syndromes duplications Copy number variation Idiopathic chromosome abnormalities Sporadic, variable breakpoints Deletion syndromes (cri du chat syndrome, 1p36 deletion syndrome) De novo balanced translocations Gene disruption Unbalanced familial abnormalities Unbalanced segregation Offspring of balanced translocations Offspring of pericentric inversions Syndromes involving genomic imprinting Any event that reveals imprinted gene(s) Prader-Willi/Angelman syndromes TABLE 6-2 Features of Autosomal Trisomies Compatible with Postnatal Survival Feature Trisomy 21 Trisomy 18 Trisomy 13 Incidence (live births) 1 in 850 1 in 6,000-8,000 1 in 12,000-20,000 Clinical presentation Hypotonia, short stature, loose Hypertonia, prenatal growth Microcephaly, sloping forehead, skin on nape, palmar crease, deficiency, characteristic fist characteristic fist clench, clinodactyly clench, rocker-bottom feet rocker-bottom feet, polydactyly Dysmorphic facial features Flat occiput, epicanthal folds, Receding jaw, low-set ears Ocular abnormalities, cleft lip and Brushfield spots palate Intellectual disability Moderate to mild Severe Severe Other common features Congenital heart disease Severe heart malformations Severe CNS malformations Duodenal atresia Feeding difficulties Congenital heart defects Risk for leukemia Risk for premature dementia Life expectancy 55 yr Typically less than a few months; 50% die within first month, >90% almost all