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Cardiovascular findings in duplication 17p11.2 syndrome.

ABSTRACT: Cardiovascular abnormalities are newly recognized features of duplication 17p11.2 syndrome. In a single-center study, we evaluated subjects with duplication 17p11.2 syndrome for cardiovascular abnormalities.Twenty-five subjects with 17p11.2 duplication identified by chromosome analysis and/or array-based comparative genomic hybridization were enrolled in a multidisciplinary protocol. In our clinical evaluation of these subjects, we performed physical examinations, echocardiography, and electrocardiography. Three of these subjects were followed up longitudinally at our institution.Cardiovascular anomalies, including structural and conduction abnormalities, were identified in 10 of 25 (40%) of subjects with duplication 17p11.2 syndrome. The most frequent abnormality was dilated aortic root (20% of total cohort). Bicommissural aortic valve (2/25), atrial (3/25) and ventricular (2/25) septal defects, and patent foramen ovale (4/25) were also observed.Duplication 17p11.2 syndrome is associated with structural heart disease, aortopathy, and electrocardiographic abnormalities. Individuals with duplication 17p11.2 syndrome should be evaluated by electrocardiography and echocardiography at the time of diagnosis and monitored for cardiovascular disease over time. Further clinical investigation including longitudinal analysis would likely determine the age of onset and characterize the progression (if any) of vasculopathy in subjects with duplication 17p11.2 syndrome, so that specific guidelines can be established for cardiovascular management.

SUBMITTER: Jefferies JL

PROVIDER: S-EPMC3666919 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Cardiovascular findings in duplication 17p11.2 syndrome.

Jefferies John L JL Pignatelli Ricardo H RH Martinez Hugo R HR Robbins-Furman Patricia J PJ Liu Pengfei P Gu Wenli W Lupski James R JR Potocki Lorraine L

Genetics in medicine : official journal of the American College of Medical Genetics 20111017 1

<h4>Purpose</h4>Cardiovascular abnormalities are newly recognized features of duplication 17p11.2 syndrome. In a single-center study, we evaluated subjects with duplication 17p11.2 syndrome for cardiovascular abnormalities.<h4>Methods</h4>Twenty-five subjects with 17p11.2 duplication identified by chromosome analysis and/or array-based comparative genomic hybridization were enrolled in a multidisciplinary protocol. In our clinical evaluation of these subjects, we performed physical examinations, ...[more]

PMID: 22237436

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Project description:Smith-Magenis syndrome (SMS) is caused by an approximately 4-Mb heterozygous interstitial deletion on chromosome 17p11.2 in approximately 80%-90% of affected patients. Three large ( approximately 200 kb), complex, and highly homologous ( approximately 98%) low-copy repeats (LCRs) are located inside or flanking the SMS common deletion. These repeats, also known as "SMS-REPs," are termed "distal," "middle," and "proximal." The directly oriented distal and proximal copies act as substrates for nonallelic homologous recombination resulting in both the deletion associated with SMS and the reciprocal duplication: dup(17)(p11.2p11.2). Using restriction enzyme cis-morphism analyses and direct sequencing, we mapped the regions of strand exchange in 16 somatic-cell hybrids that harbor only the recombinant SMS-REP. Our studies showed that the sites of crossovers were distributed throughout the region of homology between the distal and proximal SMS-REPs. However, despite approximately 170 kb of high homology, 50% of the recombinant junctions occurred in a 12.0-kb region within the KER gene clusters. DNA sequencing of this hotspot (positional preference for strand exchange) in seven recombinant SMS-REPs narrowed the crossovers to an approximately 8-kb interval. Four of them occurred in a 1,655-bp region rich in polymorphic nucleotides that could potentially reflect frequent gene conversion. For further evaluation of the strand exchange frequency in patients with SMS, novel junction fragments from the recombinant SMS-REPs were identified. As predicted by the reciprocal-recombination model, junction fragments were also identified from this hotspot region in patients with dup(17)(p11.2p11.2), documenting reciprocity of the positional preference for strand exchange. Several potential cis-acting recombination-promoting sequences were identified within the hotspot. It is interesting that we found 2.1-kb AT-rich inverted repeats flanking the proximal and middle KER gene clusters but not the distal one. The role of any or all of these in stimulating double-strand breaks around this positional recombination hotspot remains to be explored.

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Cardiovascular findings in duplication 17p11.2 syndrome.

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Cardiovascular findings in duplication 17p11.2 syndrome.

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