Duplications Of Proximal 15q

The region of chromosome 15q11-13 has long been known to be chromosomally unstable, being the site of deletions, duplications, triplications, translocations, inversions, and the breakpoints for supernumerary chromosomes. The resulting phenotype of such rearrangements is further complicated by the abundance of imprinted genes in the region. Thus, paternal deletions of the region result in Prader-Willi syndrome (PWS), whereas maternal duplications of the exact same region cause the pheno-typically unrelated Angelman syndrome (AS) (both syndromes are described elsewhere). A series of complex low-copy repeats exist within the region and mark breakpoint sites.[8] The two most centromeric breakpoints,

BP1 and BP2, form the proximal breakpoint of the PWS or AS deletions, and the common distal deletion breakpoint is known as BP3. Between the BP1/BP2 and BP3 breakpoints lies the PWS and AS critical region, or PWACR. The prevalence of this deletion is estimated at 1/10,000.

Duplications of this region take several forms. Interstitial duplications usually include the entire PWACR. Most paternal duplications are associated with normal phenotype, whereas maternal duplications are usually associated with developmental delay, delayed speech, autistic-like and other behavioral problems, and few or no dysmorphic features.[9] Interstitial duplications appear to share the same breakpoints with deletions, spanning the region between BP1/BP2 and BP3.[10] Both intrachromosomal and interchromosomal exchanges have been reported.

Interstitial triplications are also known to occur,[10,11] and may result in a more severe phenotype. Some triplications use some of the PWS/AS breakpoints, but they also break within and distal to the PWACR, implying that they may arise by a different mechanism than duplications. The duplication of the region distal to the PWACR may also contribute to the severity of the triplication phenotype.

Supernumerary marker chromosomes (SMC) represent a second basic type of duplication. The most common SMC is a bisatellited, isodicentric chromosome (Fig. 1) derived from proximal 15q and usually referred to as an inverted duplication 15 or inv dup(15). Because one centromere is usually inactivated, these chromosomes are more properly termed pseudodicentric. The inv dup(15) chromosomes are thought to arise through a U-type exchange between low-copy repeats present in opposite orientation. The inv dup(15)s exist in two basic sizes, although specific breakpoints may vary.[12] ''Small'' inv dup(15)s do not include the PWACR, break at BP1 or BP2, and are usually associated with normal phenotype, although some male carriers have been found to be infertile with azoospermia.[13] Such chromosomes are often familial and detected during routine prenatal diagnosis. ''Large'' inv dup(15)s include the PWACR, break at BP3 or more distally, and are associated with mild to severe mental retardation, autistic-like behavior, seizures, hypotonia, poor motor coordination, abnormal dermatoglyphics, and dysmorphic features such as strabismus. They are usually symmetrical (Fig. 1a), resulting in the presence of four copies of the PWACR [two on normal chromosome 15s, two on the inv dup(15)], and thus are more like the interstitial triplications. However, rare asymmetrical inv dup(15)s (Fig. 1b) have been reported,1-12-1 resulting in only three copies of the PWACR.

It should be noted that there have been difficulties in the interpretation of some patients' karyotypes in the past, as a b

Fig. 1 Supernumerary bisatellited chromosomes, representing either inv dup(15) or inv dup(22). Such chromosomes can be symmetrical with the same breakpoint for each half (a) or asymmetrical with different breakpoints for each half (b). (Modified from Mears: Molecular Characterization of Duplications Associated with Cat Eye Syndrome. Ph.D. thesis; University of Alberta, 1995.)

Fig. 1 Supernumerary bisatellited chromosomes, representing either inv dup(15) or inv dup(22). Such chromosomes can be symmetrical with the same breakpoint for each half (a) or asymmetrical with different breakpoints for each half (b). (Modified from Mears: Molecular Characterization of Duplications Associated with Cat Eye Syndrome. Ph.D. thesis; University of Alberta, 1995.)

duplications and triplications can be difficult to distinguish using microsatellite markers. Some patients with supernumerary chromosomes have also been found to have uniparental disomy of the normal 15s, leading to a PWS or AS phenotype. Many genes in the region have been well characterized, but while many duplication studies have determined the duplication size, few have determined whether these genes are actually overexpressed.

The clinical features of the proximal 15q duplications are highly variable. Some of this variability may result from the form the duplication takes. It is possible that an interstitial duplication and duplication through a supernumerary chromosome of a similar region may not give the same phenotype. This could be due to possible differences in position effect (for instance, distance from a centromere) or changes in global imprinting of the region.

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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