SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication.

Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed.

Prenatal ultrasound diagnosis of a 48,XXYY syndrome.

The 48,XXYY syndrome is a rare uncommon gonosome aneuploidy and its incidence is estimated to be 1:18,000-1:40,000. The phenotype associated with this syndrome, classically described as Klinefelter variant, is extremely variable but developmental abnormalities are always present. Ultrasound signs during pregnancy are inconsistent, and only three prenatal cases have been described in the literature. Here, we report a case of 48,XXYY syndrome identified in prenatal period because of the presence of polyhydramnios and bilateral clubfeet on second trimester ultrasound. This observation shows the importance of chromosomal prenatal diagnosis in cases with bilateral clubfeet on morphologic ultrasound. This diagnosis is essential for further characterization of the prenatal phenotype and to improving genetic counselling.

Prenatal diagnosis of a rare de novo centromeric chromosome 6 variant.

Cytogenetic heteromorphisms are described as heritable variations at specific chromosomal regions without phenotypic effect. Polymorphisms of the size of heterochromatic centromeric regions of chromosomes 1, 9 and 16 have been well documented in humans but only four previous reports described centromeric polymorphism of chromosome 6. We present a prenatal diagnosis of a rare de novo centromeric chromosome 6 variant. Cytogenetic and molecular techniques were used to characterize this variant and confirm the de novo nature of this event. This case illustrates the importance of reporting unusual variant chromosomes for genetic counseling and for determination of the frequency of variant chromosomes in the general population.

De novo unbalanced translocation 2;4 characterized by metaphase CGH and array CGH in a child with mental retardation and dysmorphic features.

BACKGROUND: It is known from postnatal diagnosis that imbalances of the subtelomeric regions contribute significantly to idiopathic mental retardation. PATIENT AND METHODS: We report a case of a 4-year-old child with growth retardation, minor physical abnormalities, hypotonia and developmental delay associated with a derivative chromosome 4. Molecular cytogenetic investigations were performed to characterize the chromosomal rearrangement. RESULTS: Multi fluorescence in situ hybridization revealed the presence of chromosome 2 material on the derivative chromosome 4. Metaphase comparative genomic hybridization detected a terminal 4q34 deletion. Array CGH analysis could precise breakpoints with duplication 2q36 → qter. The clinical phenotype was similar to those described in cases with a trisomy 2qter. CONCLUSION: This study emphasizes the value of array CGH to detect or characterize chromosome rearrangements in mentally retarded patients. Unlike metaphase CGH, the high resolution of array CGH in subtelomeric regions allows an accurate description of chromosomal aberrations.

Familial deletion 11q14.3-q22.1 without apparent phenotypic consequences: a haplosufficient 8.5 Mb region.

We present the prenatal diagnosis of a chromosome 11q14.3-q22.1 deletion identified in three generations without apparent phenotypic consequences. A 25-year-old G2, P1 woman underwent amniocentesis at 15 weeks' gestation because of a positive result for Down syndrome maternal serum-screening test (1/70). The fetal karyotype revealed an interstitial deletion of the long arm of chromosome 11 confirmed by CGH and FISH: 46,XX,del(11)(q14.3q22.1). The mother and grandfather of the fetus presented the same interstitial deletion with a little if any phenotype effect. The pregnancy was carried to term and resulted in the birth of a normal girl. To our knowledge, only one case of a chromosome 11q14.3-q21 deletion without phenotypic anomalies has been reported. Our study allows the initially described haplosufficient region to be extended from 3.6 Mb to at least 8.5 Mb. This large deletion was compatible with fertility and apparently normal phenotype. Identification of such chromosomal regions is important for prenatal diagnosis and genetic counseling.

[Prognosis of chronic lymphocytic leukemia: focus on recent biomarkers]. / Pronostic de la leucémie lymphoïde chronique : mise au point sur les facteurs biologiques récents.

Early stages of chronic lymphocytic leukemia (CLL), which are the most frequent at diagnosis, have an extremely variable individual prognosis, as some patients remain stable for years whereas others develop aggressive forms of the disease less or more rapidly. Individual prognosis evaluation of early stages of CLL is then a challenge for physicians; also clinico-hematological stages are still the evaluation basis, numerous biological markers are helpful in providing independent information on patient prognosis. It is useful to distinguish the classical prognosis factors, described in the 1980s, and the recent markers described from the end of the 1990s, which are widely validated for certain, whereas for others further investigations are needed to confirm their prognostic impact. We propose to detail in this review these new prognostic factors of CLL, especially the different serum markers, cytogenetical abnormalities of pathologic lymphocytes, mutational status of the immunoglobulin genes (IgVH) and CD38 and ZAP-70 expression.

Gene dosage methods as diagnostic tools for the identification of chromosome abnormalities.

Cytogenetics is the part of genetics that deals with chromosomes, particularly with numerical and structural chromosome abnormalities, and their implications in congenital or acquired genetic disorders. Standard karyotyping, successfully used for the last 50 years in investigating the chromosome etiology in patients with infertility, fetal abnormalities and congenital disorders, is constrained by the limits of microscopic resolution and is not suited for the detection of subtle chromosome abnormalities. The ability to detect submicroscopic chromosomal rearrangements that lead to copy-number changes has escalated progressively in recent years with the advent of molecular cytogenetic techniques. Here, we review various gene dosage methods such as FISH, PCR-based approaches (MLPA, QF-PCR, QMPSF and real time PCR), CGH and array-CGH, that can be used for the identification and delineation of copy-number changes for diagnostic purposes. Besides comparing their relative strength and weakness, we will discuss the impact that these detection methods have on our understanding of copy number variations in the human genome and their implications in genetic counseling.

Larsen-like phenotype associated with partial trisomy 3p and monosomy 5p.

BACKGROUND: We report on a fetus with radiographic features of Larsen Syndrome (LS) and unbalanced 3;5 translocation. Recently LS was shown to be caused by mutations in FLNB gene which maps on 3p14.3. METHODS: Comparative genomic hybridization (CGH) was performed to search for genomic imbalances. Fluorescence in situ analysis (FISH) was done with BAC clone RP11-754F19 probe from the FLNB gene region (3p14.3). RESULTS: CGH showed a large loss of the chromosome 5 short arm and a gain of half of the short arm of chromosome 3 resulting from a derivative chromosome 5. FISH analysis with FLNB probe demonstrated that it was not triplicated. Thus, we excluded the role of a gene dosage effect of FLNB in abnormal craniofacial development in this fetus. CONCLUSIONS: To our knowledge, this is the first report of Larsen-like phenotype associated with unbalanced translocation resulting in partial trisomy 3p and monosomy 5p.

De novo balanced complex chromosome rearrangement (CCR) involving chromosome 8, 11 and 16 in a boy with mild developmental delay and psychotic disorder.

Congenital Complex Chromosome rearrangements (CCRs) compatible with life are rare in humans. We report a de novo CCR involving chromosomes 8, 11 and 16 with 4 breakpoints in a patient with mild dysmorphic features, acquisition delay and psychotic disorder. Conventional cytogenetic analysis revealed an apparently balanced 8;16 translocation. Further FISH analysis with WCP 8 and WCP 16 probes revealed the presence of a third chromosome involved in the translocation. The multicolour karyotype confirmed the complexity of the rearrangement and showed that the derivative chromosome 8 was composed of 3 distinct segments derived from chromosomes 8, 16 and 11. The breakpoints of this complex rearrangement were located at 8q21, 11q14, 11q23 and 16q12. Comparative genomic hybridization (CGH) and array-CGH were performed to investigate the possibility of any genomic imbalance as a result of the complex rearrangement. No imbalance was detected by these two techniques. Our study showed: i) the necessity to confirm reciprocal translocations with FISH using painting probes, particularly when the karyotype resolution is weak; ii) the usefulness of multicolour karyotype for the characterization of structural chromosomal rearrangements, particularly when they are complex; iii) the usefulness of CGH and array-CGH in cases of abnormal phenotype and apparently balanced rearrangement in order to explore the breakpoints and to detect additional imbalances.

An unusual familial chromosome 9 "variant" with variable phenotype: characterization by CGH analysis.

Heterochromatin confined to pericentromeric and secondary constriction regions plays a major role in morphological variation of chromosome 9, because of its size and affinity for pericentric inversion. We report on a 6-year-old boy with growth and language delay, minor facial anomalies and unusual chromosome 9 variant with an extra-band in the centromeric region on the conventional karyotype. Subsequent analysis by FISH and CGH identified this variant as a dicentric chromosome 9 with a duplication of the 9p12-q21 region. An identical chromosome 9 variant was found in the mild language retarded brother and in the phenotypically normal father and grandfather. The presumed mechanism accounting for the phenotypic discordance observed in this family and the usefulness of CGH in characterization of such variants are discussed. To our knowledge, this is the first investigation of an unusual chromosome 9 variant by CGH.

Prenatal detection of mosaic isochromosome 20q: a fourth report with abnormal phenotype.

We described a new case of mosaic isochromosome 20q revealed by amniocentesis. The propositus presented with craniofacial dysmorphism, clubfeet, and vertebral abnormalities. A 46,XX,i(20)(q10)[14]/46,XX[1] karyotype was confirmed by FISH on cultured cells. The pregnancy was terminated. From review of literature, fetus with mosaic isochromosome 20q identified on amniocentesis are most likely to be phenotypically and cytogenetically normal after birth. So we performed CGH and array-CGH to exclude another possible imbalance. We discuss here the possible relation between this chromosomal abnormality and the abnormal phenotype.