The Human Genome: Detecting Chromosomal Deletions: Angelman and Prader-Willi Syndromes

Angelman syndrome and Prader-Willi syndrome are two related but clinically and genetically distinct neurogenetic syndromes, characteristically caused by deletion of the human chromosomal region 15q11-q13. Clinical features of Angelman syndrome include severe mental retardation with absence of speech, epileptic seizures, ataxia, inappropriate bursts of laughter, unusually happy disposition, hyperactivity, and micro- and brachycephaly. Patients with Prader-Willi syndrome show infantile hypotonia, mild to moderate mental retardation, hyperphagia with subsequent obesity, hypogonadism, short stature, mild facial dysmorphism, and characteristic behavior. In Angelman syndrome the chromosomal deletions are exclusively of the maternal chromosome, whereas in Prader-Willi syndrome the deletions are of paternal origin, i.e., the absence of any paternal contribution to the 15q11-q13 region. Both syndromes can result either from deletions or from uniparental disomy, in which two chromosomes 15 are inherited from a single parent, instead of one chromosome from each parent.

The detection of chromosomal deletions has become routine in both prenatal and postnatal diagnosis with the use of fluorescence in situ hybridization, a process that vividly paints chromosomes or portions of chromosomes with fluorescent molecules. In situ hybridization is a powerful and versatile tool for the detection and localization of nucleic acid sequences (the constituents of genes) in cell preparations. The technique is based on the hybridization (attraction and complexing) of a labeled and complementary DNA or RNA probe to immobilized chromosomal preparations. Although radioactively labeled DNA probes were formerly used for this purpose, commercially available fluorescent probes are now available for diagnosis. Fluorescence in situ hybridization is routinely used to detect chromosomal rearrangements and deletions, including those associated with chromosomal microdeletion syndromes, such as Angelman syndrome or Prader-Willi syndrome.