Delineation of 15q13.3 microdeletions.

The increasing use of array-comparative genomic hybridization (array-CGH) to identify copy number variations (CNVs) in patients with developmental delay (DD), mental retardation and/or dysmorphic features has allowed the recent recognition of numerous genomic imbalances, including the 15q13.3 microdeletion. Patients with this microdeletion generally present with relatively consistent breakpoints at BP4 and BP5, which include the CHRNA7 gene. About 100 index cases have been reported since the first publication in 2008. This large number of patients ascertained through highly variable samples has been necessary to describe the full phenotypic spectrum of this microdeletion, ranging from mental retardation with dysmorphic features, epilepsy, neuropsychiatric disturbances with or without cognitive impairment to complete absence of anomalies. Here, we describe a collaborative study reporting a new cohort of 12 index patients and 13 relatives carrying a heterozygous BP4-BP5 microdeletion out of a series of 4625 patients screened by array-CGH for DD. We confirm the clinical expressivity of the disease as well as the incomplete penetrance in seven families. We showed through a review of the literature that males are more likely to be symptomatic. Sequence analysis of CHRNA7 yielded no data to support the unmasking of recessive variants as a cause of phenotypic variability. We also report the first patient carrying a 15q13.3 homozygous microdeletion inherited from both parents. He had severe epileptic encephalopathy with retinopathy, autistic features and choreoathetosis. Besides the classical approximately 1.5 Mb BP4-BP5 microdeletion, we also describe three index patients and two relatives with a smaller 500 kb microdeletion, including the CHRNA7 gene.

[Molecular biology usefulness for rapid diagnosis of Down's syndrome and common aneuploidies]. / Intérêt de la biologie moléculaire dans le diagnostic rapide de la trisomie 21 et des aneuploïdies les plus fréquentes.

OBJECTIVE: Trisomy of chromosome 13, 18, 21 and sex chromosome aneuploidies are the most common chromosomal abnormalities encountered in prenatal screening and are responsible for polymaformative syndrome associated with severe mental retardation. This high degree of morbidity justifies the prenatal diagnosis of these aneuploidies. Fetal nuchal translucency measurement and maternal serum biochemical marker assessment are the method of choice used for antenatal screening of aneuploidies. This prenatal screening leads to numerous maternal samplings followed by karyotyping which is cost-effective, time consuming, while results are generally returned between 2 and 3 weeks. Our study describes the research of common aneuploidies by molecular biology. We have used on one hand the MLPA kit (MRC Holland) based on amplification of specific DNA probes that hybridize with chromosomes 13, 18, 21, X, Y. On the other hand we have developed multiplex fluorescent PCR, amplifying microsatellite DNA sequences. PATIENTS AND METHODS: We have evaluated the efficiency of these two techniques to detect chromosomal abnormalities by screening 400 amniotic fluids or chorionic villi samples obtained from pregnant women presenting a high risk of chromosomal aneuploidy. RESULTS: We have found four trisomies 21, one trisomy 13, one monosomy 13, one trisomy 18, two triploidies, one trisomy X and one Klinefelter syndrome. DISCUSSION AND CONCLUSION: In our study we have detected by molecular biology, in less than 48 h, 100% of common chromosomal aneuploidies without false positive or false negative results which could lead molecular biology as a method of choice for the rapid detection of common aneuploidies in addition to fetal karyotyping.