Details on the phenotypic consequences of genomic microdeletions and microduplications are rapidly emerging in the wake of increased utilization of high-resolution methods for the detection of genomic copy number variants (CNVs). Due to their recent discovery, the complete phenotypic characterization of these syndromes is still in progress. For practicing clinicians, this unprecedented molecular diagnostic capability has in many cases outpaced our ability to convey conclusive information regarding these conditions to patients and family members. In particular, genomic microduplication syndromes are frequently associated with variable phenotypes and incomplete penetrance, leading to difficulty in counseling regarding the potential future consequences of a given microduplication. In this review, we have attempted to provide an initial set of recommendations for the management of patients with recurrent microduplication syndromes. We summarize the clinical information for microduplications of 14 different genomic regions and provide a framework for clinical evaluation and anticipatory guidance in these conditions. It is our expectation that these preliminary guidelines will be revised further for each microduplication syndrome as more information becomes available.
"The main method for predicting the function of a gene product in the absence of experimental data is termed 'homology-based transfer' (Friedberg, 2006; Sleator & Walsh, 2010). This approach is based on the detection of significant amino acid sequence similarity to a protein(s) of known function using programmes such as BLAST (Altschul et al., 1997). "
"Interestingly, we detected six cases of recurrent microduplication syndromes (0.7% of our series), three inherited from a phenotypically normal parent and three de novo. We faced the difficult counseling of these genomic imbalances associated with variable phenotypes and incomplete penetrance with still scarce literature, although preliminary guidelines for clinical evaluation and anticipatory guidance have been published (Berg et al. 2010). Following a 20-week normal ultrasound evaluation, the parental decision in all cases was continuation of the pregnancy. "
[Show abstract][Hide abstract] ABSTRACT: Novel methodologies for detection of chromosomal abnormalities have been made available in the recent years but their clinical utility in prenatal settings is still unknown. We have conducted a comparative study of currently available methodologies for detection of chromosomal abnormalities after invasive prenatal sampling. A multicentric collection of a 1-year series of fetal samples with indication for prenatal invasive sampling was simultaneously evaluated using three screening methodologies: (1) karyotype and quantitative fluorescent polymerase chain reaction (QF-PCR), (2) two panels of multiplex ligation-dependent probe amplification (MLPA), and (3) chromosomal microarray-based analysis (CMA) with a targeted BAC microarray. A total of 900 pregnant women provided informed consent to participate (94% acceptance rate). Technical performance was excellent for karyotype, QF-PCR, and CMA (~1% failure rate), but relatively poor for MLPA (10% failure). Mean turn-around time (TAT) was 7 days for CMA or MLPA, 25 for karyotype, and two for QF-PCR, with similar combined costs for the different approaches. A total of 57 clinically significant chromosomal aberrations were found (6.3%), with CMA yielding the highest detection rate (32% above other methods). The identification of variants of uncertain clinical significance by CMA (17, 1.9%) tripled that of karyotype and MLPA, but most alterations could be classified as likely benign after proving they all were inherited. High acceptability, significantly higher detection rate and lower TAT, could justify the higher cost of CMA and favor targeted CMA as the best method for detection of chromosomal abnormalities in at-risk pregnancies after invasive prenatal sampling.
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The online version of this article (doi:10.1007/s00439-011-1095-5) contains supplementary material, which is available to authorized users.
Human Genetics 10/2011; 131(3):513-23. DOI:10.1007/s00439-011-1095-5 · 4.82 Impact Factor
"The main method for predicting the function of a gene product in the absence of experimental data is termed 'homologybased transfer' (Friedberg, 2006; Sleator & Walsh, 2010). This approach is based on the detection of significant amino acid sequence similarity to a protein(s) of known function using programmes such as BLAST (Altschul et al., 1997). "
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