Aurélie Coussement

Prenatal diagnosis of 24 cases of microduplication 22q11.2: an investigation of phenotype‐genotype correlations

Microduplication 22q11.2 is primarily characterized by a highly variable clinical phenotype, which ranges from apparently normal or slightly dysmorphic features (in the presence or absence of learning disorders) to severe malformations with profound mental retardation. Hence, genetic counseling is particularly challenging when microduplication 22q11.2 is identified in a prenatal diagnosis. Here, we report on 24 prenatal cases of microduplication 22q11.2.

Pregnancy outcomes of prenatally diagnosed Turner syndrome: a French multicenter retrospective study including a series of 975 cases

The objectives of this study were to report pregnancy outcomes after prenatal diagnosis of Turner syndrome (TS) and to compare and assess termination of pregnancy rates during two periods. The intervals selected were before and after 1997 when multidisciplinary centers for prenatal diagnosis (MCPDs) were established in France.

Inherited interstitial 16q21 deletion of 5.8 Mb without apparent phenotypic effect in three generations of a family: An array-CGH study†

An interstitial deletion of a euchromatic chromosomal segment, diagnosed by classical cytogenetic analysis, is usually associated with an abnormal phenotype. However, a few cases involving several different chromosomes have been reported where an inherited deletion did not appear to have any phenotypic consequences [Barber, 2005; Kowalczyk et al., 2007]. Deletions of 16q are rare and usually lead to an abnormal phenotype [Yamamoto et al., 2008]. Witt et al. [1988] described a deletion of the band 16q21 in individuals with a normal phenotype in two generations of a family. The breakpoints of this deletion were later mapped by Callen et al. [1993]. A deletion 16q21 with the same breakpoints was found in a mother and her children, also without apparent phenotypic effect [Hand et al., 2000].Here, we report on a case of a 5.8Mbdeletion in 16q21 without an abnormal phenotype in three generations of a family. The exact localization and size of the deleted segment was defined with array-CGH. The patient a 41-year-old womanG1P1, was referred for amniocentesis at 18 weeks of gestation because of a positive Down syndrome maternal serum screening test (1/54). She had no personal, obstetrical or familial history of abnormalities. Chromosome analysis was performed on in situ cultured amniocytes with GTGbanding (400–500 bands) using standard methods. The karyotype was 46,XX,del(16)(q13q22) (Fig. 1A). The same interstitial deletion was identified in the blood lymphocytes of the patient. A normal healthy girl was born at term after an uneventful pregnancy. Subsequently, the same deletion was found also in the healthy 68-year-old mother of the patient. Fluorescence in situ hybridization (FISH) was performed on metaphase spreads with a commercial whole chromosome paint 16 probe (WCP 16, QBiogen , Illkirch France), and the CBFB dual color probe (QBiogen , Illkirch France) according to the manufacturer’s instructions. We also used a bacterial artificial chromosome (BAC) probe, localized on 16q21, which was selected from the human RPCI-11 library (RP11-229O3, kindly provided byWellcome Trust Sanger Institute). The array-CGH was performed with Roche Nimbelgen 385k arrays (Meylan, France) according to the manufacturer’s protocol and analyzed with Signal Map software. FISHstudies showed thatnoother chromosomewas labeledwith WCP 16. Labeling with BAC confirmed the deletion of 16q21 on chromosome16and that this locuswasnot inserted elsewhere in the genome (Fig. 1B). Use of the CBFB probe confirmed that the 16q22.1 band is not involved in the deletion (Fig. 1C). ArrayCGHshowed that the deleted fragment had a size of 5.8Mb, ranging from nucleotide 58,491,600 to 64,259,873 (hg18) (Fig. 2); the definitive karyotype is therefore 46,XX,del(16)(q13q22).arr 16q21(58,491,600–64,259,873) 1. The length of the deletion is the same in all three generations and do not correspond to any previously reported CNV in the Toronto database. The deleted region contains only two genes of the cadherine family: cadherine 8 (cerebral expression) and cadherine 11 (osteoclastic expression). Barber [2005] has divided inherited cytogenetically visible euchromatic chromosomal abnormalities, mostly without a phenotypic effect, into two categories: euchromatic variants (EVs) and unbalanced chromosomal abnormalities (UBCAs) which are deletions or duplications involving several Mb of DNA without any effect on the phenotype or fertility. These abnormalities are reported on the ‘‘Chromosomal Anomaly Collection’’ web site (http://www.ngrl.co/Wessex/collection.html).

Molecular and clinical delineation of 2p15p16.1 microdeletion syndrome

Interstitial 2p15p16.1 microdeletion is a rare chromosomal syndrome previously reported in 33 patients. It is characterized by intellectual disability, developmental delay, autism spectrum disorders, microcephaly, short stature, dysmorphic features, and multiple congenital organ defects. It is defined as a contiguous gene syndrome and two critical regions have been proposed at 2p15 and 2p16.1 loci. Nevertheless, patients with deletion of both critical regions shared similar features of the phenotype and the correlation genotype–phenotype is still unclear. We review all published cases and describe three additional patients, to define the phenotype–genotype correlation more precisely. We reported on two patients including the first prenatal case described so far, carrying a 2p15 deletion affecting two genes: XPO1 and part of USP34. Both patients shared similar features including facial dysmorphism and cerebral abnormalities. We considered the genes involved in the deleted segment to further understand the abnormal phenotype. The third case we described here was a 4‐year‐old boy with a heterozygous de novo 427 kb deletion encompassing BCL11A and PAPOLG at 2p16.1. He displayed speech delay, autistic traits, and motor stereotypies associated with brain structure abnormalities. We discuss the contribution of the genes included in the deletion to the abnormal phenotype. Our three new patients compared to previous cases, highlighted that despite two critical regions, both distal deletion at 2p16.1 and proximal deletion at 2p15 are associated with phenotypes that are very close to each other. Finally, we also discuss the genetic counseling of this microdeletion syndrome particularly in the course of prenatal diagnosis.

Aneuploidy: the impact of chromosome imbalance on nuclear organization and overall genome expression

The organization and dynamics of chromatin within the interphase nucleus as chromosome territories (CTs) and the relationship with transcriptional regulation are not fully understood. We studied a natural example of chromosomal disorganization: aneuploidy due to trisomies 13, 18 and 21. We hypothesized that the presence of an extra copy of one chromosome alters the CT distribution, which perturbs transcriptional activity. We used 3D‐FISH to study the position of the chromosomes of interest (18 and 21) in cultured amniocytes and chorionic villus cells from pregnancies with a normal or aneuploid karyotype. We studied the volumes of nuclei and CTs in both conditions and performed a compared transcriptome analysis. We did not observe any differences between euploid and aneuploid cells in terms of the radial and relative CT positions, suggesting that the same rules govern nuclear organization in cases of trisomy. We observed lower volumes for CTs 18 and 21. Overall genome expression profiles highlighted changes in the expression of a subset of genes in trisomic chromosomes, while the majority of transcriptional changes concerned genes located on euploid chromosomes. Our results suggest that a dosage imbalance of the genes on trisomic chromosomes is associated with a disturbance of overall genomic expression.

Inverted duplication with deletion: first interstitial case suggesting a novel undescribed mechanism of formation.

Inverted duplications with terminal deletions are a well‐defined family of complex rearrangements already observed for most of chromosome extremities. Several mechanisms have been suggested which could lead to their occurrence, either through non‐homologous end joining, non‐allelic homologous recombination, or more recently through an intrastrand fold‐back mechanism. We describe here a patient with intellectual disability and pharmacoresistant epilepsy, for which array CGH analysis showed the first interstitial case of inverted duplication with deletion on chromosome 1p. Furthermore, SNP array analysis revealed an associated segmental isodisomy for the distal part of 1p, which led us to consider a replicative mechanism to explain this abnormality. This observation extends the range of this once telomeric rearrangement.

Pregnancy outcomes in prenatally diagnosed 47, XXX and 47, XYY syndromes: a 30-year French, retrospective, multicentre study.

Sex chromosome aneuploidies are frequently detected fortuitously in a prenatal diagnosis. Most cases of 47, XXX and 47, XYY syndromes are diagnosed in this context, and parents are thus faced with an unexpected situation. The objective of the present study was to characterize a French cohort of prenatally diagnosed cases of 47, XXX and 47, XYY and to evaluate the termination of pregnancy (TOP) rate before and after Frances implementation of multidisciplinary centres for prenatal diagnosis in 1997.

The diagnostic yield of chromosomal microarray analysis in fetuses with increased nuchal translucency: a French multicentre retrospective study

To determine the frequency and nature of copy number variants (CNVs) identified by chromosomal microarray analysis (CMA) in a large cohort of fetuses with isolated increased nuchal translucency thickness (NT) ≥ 3.5 mm.