ASPP2 deficiency causes features of 1q41q42 microdeletion syndrome.

Chromosomal abnormalities are implicated in a substantial number of human developmental syndromes, but for many such disorders little is known about the causative genes. The recently described 1q41q42 microdeletion syndrome is characterized by characteristic dysmorphic features, intellectual disability and brain morphological abnormalities, but the precise genetic basis for these abnormalities remains unknown. Here, our detailed analysis of the genetic abnormalities of 1q41q42 microdeletion cases identified TP53BP2, which encodes apoptosis-stimulating protein of p53 2 (ASPP2), as a candidate gene for brain abnormalities. Consistent with this, Trp53bp2-deficient mice show dilation of lateral ventricles resembling the phenotype of 1q41q42 microdeletion patients. Trp53bp2 deficiency causes 100% neonatal lethality in the C57BL/6 background associated with a high incidence of neural tube defects and a range of developmental abnormalities such as congenital heart defects, coloboma, microphthalmia, urogenital and craniofacial abnormalities. Interestingly, abnormalities show a high degree of overlap with 1q41q42 microdeletion-associated abnormalities. These findings identify TP53BP2 as a strong candidate causative gene for central nervous system (CNS) defects in 1q41q42 microdeletion syndrome, and open new avenues for investigation of the mechanisms underlying CNS abnormalities.

A novel mutation in the RPS6KA3 gene in a patient with Coffin-Lowry syndrome.

Coffin-Lowry syndrome is an X-linked disorder characterized by mental retardation, characteristic facial features, skeletal abnormalities, and tapering fingers. Herein we report a novel missense mutation in exon 7 at codon 180 in the RPS6KA3 gene in a boy with Coffin-Lowry syndrome.

Fluorescence in situ hybridization characterization of ider(20q) in myelodysplastic syndrome.

Isochromosome of the long arm of chromosome 20 with loss of interstitial material [ider(20q)] is a variant of deletion of chromosome 20q and a rare abnormality in myelodysplastic syndrome (MDS). We studied seven cases with an ider(20q) in MDS. Fluorescence in situ hybridization (FISH) studies showed all proximal breakpoints to be consistently located in 20q11.21 band whereas distal breakpoints were variable. Amplification of HCK, TNFRSF6B and DIDO1 genes included in retained regions associated with loss of tumour suppressor genes in deleted regions could explain cell tumour progression and possibly the less favourable prognosis of ider(20q) compared with del(20q).

[Array-CGH for routine diagnosis of cryptic chromosomal imbalances]. / Puces à ADN (CGH-array) : application pour le diagnostic de déséquilibres cytogénétiques cryptiques.

Cytogenetics allows detection of genomic anomalies between 10 and 15 Mb (classical cytogenetics) and between 3 and 5 Mb (high-resolution cytogenetics). These pangenomic techniques are associated with more accurate analyses, single probe interstitial FISH and subtelomeric studies. Array-CGH (aCGH) allows high resolution pangenomic analyses. BAC/PAC and oligonucleotides array-CGH have transformed the field of genetics and are useful for constitutional, hematological and solid tumors cytogenetics. Array-based comparative pangenomic hybridization resolutions vary in size (range, several kilobases to 1 Mb). With the more recent improvements, aCGH is becoming the "missing link" between cytogenetics and molecular diagnostics. Despite copy number variations (CNV) and without replacing karyotype, aCGH detects cryptic quantitative anomalies anywhere in the genome and becomes day after day more useful.

[Cytogenetics and molecular genetics in myelofibrosis with myeloid metaplasia and polycythemia vera]. / Cytogénétique et génétique moléculaire dans la myélofibrose avec métaplasie myéloïde et dans la polyglobulie de Vaquez.

Myelofibrosis with myeloid metaplasia (MMM) is a rare myeloproliferative disorder (MPD) characterized by clonal proliferation of hematopoietic progenitors. 40-50% of karyotypes on blood (or more rarely on bone marrow) revealed at least one abnormality: 30% at diagnosis and 90% in blastic transformation phase. A minority of patients with newly diagnosed polycythemia vera (PV) presented chromosomal abnormalities in their myeloid cells. The most frequent visible alteration in MMM and PV is a 20q deletion, also characterized in other MPDs and myeloid malignancies. Among other chromosomal changes, deletion 13q is more common in MMM than in other MPDs, trisomy 9 and 9p alterations appear more frequent in PV. Cytogenetic studies have disclosed cryptic anomalies and pointed out the high frequency of 9p alterations. JAK2 (V617F) mutation was found in almost all PV patients and near half of MMM patients. This molecular abnormality takes an increased importance in the knowledge of the physiopathology of MPDs, particularly in PV and also in prognosis of MMM patients.

Disruption and aberrant expression of HMGA2 as a consequence of diverse chromosomal translocations in myeloid malignancies.

Chromosomal translocations that target HMGA2 at chromosome band 12q14 are seen in a variety of malignancies, notably lipoma, pleomorphic salivary adenoma and uterine leiomyoma. Although some HMGA2 fusion genes have been reported, several lines of evidence suggest that the critical pathogenic event is the expression of truncated HMGA2 isoforms. We report here the involvement of HMGA2 in six patients with myeloid neoplasia, dysplastic features and translocations or an inversion involving chromosome bands 12q13-15 and either 7p12, 8q22, 11q23, 12p11, 14q31 or 20q11. Breaks within or very close to HMGA2 were found in all six cases by molecular cytogenetic analysis, leading to overexpression of this gene as assessed by RT-PCR. Truncated transcripts consisting of HMGA2 exons 1-2 or exons 1-3 spliced to intron-derived sequences were identified in two patients, but were not seen in controls. These findings suggest that abnormalities of HMGA2 play an important and previously unsuspected role in myelodysplasia.

t(5;14)/HOX11L2-positive T-cell acute lymphoblastic leukemia. A collaborative study of the Groupe Français de Cytogénétique Hématologique (GFCH).

To accurately estimate the incidence of HOX11L2 expression, and determine the associated cytogenetic features, in T-cell acute lymphoblastic leukemia (T-ALL), the Groupe Français de Cytogénétique Hématologique (GFCH) carried out a retrospective study of both childhood and adult patients. In total, 364 patients were included (211 children

Quantification of CFTR splice variants in adults with disseminated bronchiectasis, using the TaqMan fluorogenic detection system.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are associated with different related disorders such as congenital bilateral absence of the vas deferens, chronic idiopathic pancreatitis, or disseminated bronchiectasis (DB). Many different disease-causing mutations are associated with DB, particularly the 5T allele (IVS 8 polyT tract), a variant of the splice acceptor site at the end of intron 8 that affects the efficiency with which the site is used. It therefore affects the accuracy of exon 9 splicing and hence expression of the functional CFTR protein. In this study we quantified transcripts from nasal biopsies of patients with DB compared to normal controls. We developed a real-time quantitative reverse transcription polymerase chain reaction assay (using the TaqMan system) to evaluate the relative amounts of accurately spliced transcript, and transcript lacking exon 9. Patients with the 5T allele had increased amounts of aberrant transcript: in genotypes 5T/7T, 7T/7T and 9T/7T, mean fractions of 38.4%, 3.5% and 0.6%, respectively, of transcripts had been spliced incorrectly. There was also some evidence that nasal biopsies can provide similar information on transcripts to bronchial biopsies. This functional test is of interest for monitoring the amount of CFTR transcript in different clinical situations or to monitor the effect of drugs on CFTR transcription.

Spontaneous, post-operative and traumatic chylothorax.

Study of the malformation of the chyliferous vessels, malformations of Pecquet's cistern or of the thoracic duct has brought out the nature of the physiopathology of spontaneous chylothorax: it is the result of a rupture of a lymphatic of the diaphragm, mediastinum, or lung. Post-operative chylothorax is due to a lesion of the thoracic duct or of one of its branches.

[Diagnosis of chyliferous blockage by the hyperlipidemia test (author's transl)]. / Diagnostic du blocage des chylifères par le test d'hyperlipidémie.

In our hyperlipidemia test, the total lipids curve, a plateau without a postprandial peak, allows an easy diagnosis of the chyliferous blockage. The malformation of chyliferous vessels produces the congenital forms: exsudative enteropathy, chyloperitoneum, spontaneous chylothorax, chylous cyst of the mediastinum, reflux of chyle in the pulmonary lymphatics, lymphoedema with chyle reflux in the lymphatics of the leg and chyluria. The acquired forms comprise the post-infectious sclerosis of the intestinal lymphatics and the neoplastic invasions of the mesenteric lymph nodes. The optical density curve brings some informations for a better understanding of lipid's absorption.

[Malformations of the lacteals]. / Les malformations des chylifères.

For the diagnosis of malformations of the lymphatics is made by the hyperlipidaemia test, which shows a flat total lipids curve without a post-prandial peak. Malformation of the lymphatics of the small intestine is responsible for exudative enteropathy, chyloperitoneum, chyluria, lymphoedema with reflux of lymph in the lymphatics of the legs and its complications (chylorrhagia, chylarthrosis), chylothorax, chylopericardium and reflux of lymph in the pulmonary lymphatics. This malformation can also be associated with other disorders : such as the syndrome of Klippel and Trenaunay, and simple lymphoedema of the limbs or genital organs. Lymphography of the intestinal lymphatics carried out during laparotomy after a fatty meal shows the state of the lymphatic vessels, a lack of injection of the cistern of Pecquet, and above all the presence of adventitious vessels allowing the lymph to reach the cervical region.

[The induced hyperlipemia test. 10 years of experience]. / Le test d'hyperlipidémie provoquée. Dix ans d'expérience.

The induced hyperlipemia test, which is easly to administer, yields very interesting information for the study of lipidic metabolism in arteriosclerosis patients. Its use, in both the pre- and post-operative phases, has brought out the valuable effect of ligature of the intestinal lymphatics in treating arteritis. It may also enable us to determine whether there is a hereditary factor or family predisposition to arteriosclerosis. Furthermore, the test makes it possible to confirm diagnosis of obstruction of the lymphatics of the gut in exsudative enteropathy and in various dysfunctious of the chyliferous vessels (sclerosis, rupture, tumoral invasion) without to resort to the use of radioactive substances.

[Chyloperitoneum causing intestinal obstruction]. / Chylopéritoine entraînant une occlusion intestinale

The two cases reported here show intestinal obstruction may occur by coagulation of lymph around the loops. They permit us to better understand the physiopathology of blockage of the lymph vessels whether congenital as in the first case or traumatic as in the second case. Traumatic rupture of the cisterns chyli is exceptional. The histological lesions observed on clamped biopsies show clearly the pathology of protein-losing enteropathy.

[Ligation of lymphatic ducts in treatment of arteriosclerosis. 550 operated cases reported over a period of 9 years]. / Ligature des chylifères dans le traitement de l'artériosclérose. 550 cas opérés en 9 ans

In all diseases where there is an important loss of lymph, e.g. chylothorax, chyloperitoneum, exsudative enteropathy chyloduodenal fistula, we observed not only a fall in the serum proteins and calcium, but also a fall in lipids and cholesterol. We first carried out ligature of the lymphatic ducts in numerous dogs. Since 1966, we have carried out this ligature in 550 arteriosclerotic patients, aged less than 52 years. The metabolic changes observed over a period of 9 years were very marked. Clinically, in 100 patients who underwent classical reconstructive arterial surgery, the association of ligature of the lymphatic ducts reduced by half, after a period of 6 years, the complications normally observed.