Chapter 063. Chromosome Disorders (Part 10)

Deletions involving the long arm of chromosome 22 (22q11) are the most common microdeletions identified to date, present in ~1/3000 newborns. VCF syndrome, the most commonly associated syndrome, consists of learning disabilities or mild mental retardation, palatal defects, a hypoplastic aloe nasi and long nose, and congenital heart defects (conotruncal defect). Some individuals with 22q11 deletion are more severely affected and present with DiGeorge syndrome, which involves abnormalities in the development of the third and fourth branchial arches leading to thymic hypoplasia, parathyroid hypoplasia, and conotruncal heart defects. In ~30% of these cases, a deletion at 22q11 can be...
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Chapter 063. Chromosome Disorders (Part 10) Chapter 063. Chromosome Disorders (Part 10) Deletions involving the long arm of chromosome 22 (22q11) are the mostcommon microdeletions identified to date, present in ~1/3000 newborns. VCFsyndrome, the most commonly associated syndrome, consists of learningdisabilities or mild mental retardation, palatal defects, a hypoplastic aloe nasi andlong nose, and congenital heart defects (conotruncal defect). Some individualswith 22q11 deletion are more severely affected and present with DiGeorgesyndrome, which involves abnormalities in the development of the third and fourthbranchial arches leading to thymic hypoplasia, parathyroid hypoplasia, andconotruncal heart defects. In ~30% of these cases, a deletion at 22q11 can bedetected with high-resolution banding; by combing conventional cytogenetics,FISH, and molecular detection techniques (i.e., Southern blotting or polymerasechain reaction analyses), these rates improve to >90%. Additional studies havedemonstrated a surprisingly high frequency of 22q11 deletions in individuals withnonsyndromic conotruncal defects. Approximately 10% of individuals with a22q11 deletion inherited it from a parent with a similar deletion. Smith-Magenis syndrome involves a microdeletion localized to theproximal region of the short arm of chromosome 17 (17p11.2). Affectedindividuals have mental retardation, dysmorphic facial features, delayed speech,peripheral neuropathy, and behavior abnormalities. Most of these deletions can bedetected with cytogenetic analysis, although FISH is available to confirm thesefindings. In contrast, William syndrome, a chromosome 7 (7q11.23)microdeletion, cannot be diagnosed with standard or high-resolution analysis; it isonly detectable utilizing FISH or other molecular methods. William syndromeinvolves a deletion of the elastin gene and is characterized by mental retardation,dysmorphic features, a gregarious personality, premature aging, and congenitalheart disease (usually supravalvular aortic stenosis). In addition to microdeletion syndromes, there is now at least one well-described microduplication syndrome, Charcot-Marie-Tooth type 1A (CMT1A).This is a nerve conduction disease previously thought to be transmitted as a simpleautosomal dominant disorder. Recent molecular studies have demonstrated thataffected individuals are heterozygous for duplication of a small region ofchromosome 17 (17p11.2–12). Although it is not yet clear why increased genedosage would result in CMT1A, the inheritance pattern is explained by the factthat one-half of the offspring of affected individuals inherit the duplication-carrying chromosome. Imprinting Disorders Two other microdeletion syndromes, Prader-Willi syndrome (PWS) andAngelman syndrome (AS), exhibit parent-of-origin, or imprinting, effects. Formany years, it has been known that cytogenetically detectable deletions ofchromosome 15 occur in a proportion of patients with PWS, as well as in thosewith AS. This seemed curious, as the clinical manifestations of the two syndromesare very dissimilar. PWS is characterized by obesity, hypogonadism, and mild tomoderate mental retardation, whereas AS is associated with microcephaly, ataxicgait, seizures, inappropriate laughter, and severe mental retardation. New insightinto the pathogenesis of these disorders has been provided by the recognition thatparental origin of the deletion determines which phenotype ensues: if the deletionis paternal, the result is PWS, whereas if the deletion is maternal, the result is AS(Fig. 63-2). This scenario is complicated further by the recognition that not allindividuals with PWS or AS carry the chromosome 15 deletion. For suchindividuals, the parental origin of the chromosome 15 region is again theimportant determinant. In PWS, for example, nondeletion patients invariably havetwo maternal and no paternal chromosomes 15 [maternal uniparental disomy(UPD)], whereas for some nondeletion AS patients the reverse is true (paternalUPD). This indicates that at least some genes on chromosome 15 are differentlyexpressed, depending on which parent contributed the chromosome. Additionally,this means that normal fetal development requires the presence of one maternaland one paternal copy of chromosome 15. Approximately 70% of PWS cases are due to paternal deletions of 15q11-q13, whereas 25% are due to maternal UPD, and about 5% are caused bymutations in a chromosome 15 imprinting center. In AS, 75% of cases are due tomaternal deletions, and only 2% are due to paternal UPD. The remaining cases arepresumably caused by imprinting mutations (5%), or mutations in the UBE3Agene, which is associated with AS. The UPD cases are mostly caused by mei ...