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N Marle,
D Martinet,
A Aboura,
G Joly-Helas,
J Andrieux,
E Flori,
J Puechberty,
F Vialard,
D Sanlaville,
S Fert Ferrer, [......],
A Liquier,
T Rousseau,
Al Mosca,
V Kremer,
M Payet,
C Rangon, F Mugneret,
S Aho,
L Faivre,
P Callier
[show abstract]
[hide abstract]
ABSTRACT: Small supernumerary marker chromosomes (sSMC) are structurally abnormal chromosomes that cannot be characterized by karyotype. In many prenatal cases of de novo sSMC, the outcome of pregnancy is difficult to predict because the euchromatin content is unclear. The present study aimed to determine the presence or absence of euchromatin material of 39 de novo prenatally ascertained sSMC by array-CGH or SNP array. Cases were prospectively ascertained from the study of 65,000 prenatal samples (0.060%; 95% CI, 0.042-0.082). Array-CGH showed that 22 markers were derived from non-acrocentric markers (56.4%), seven from acrocentic markers (18%). The 10 additional cases remained unidentified (25.6%), but 7/10 could be further identified using FISH. Sixty-nine per cent of de novo sSMC contained euchromatin material, 95.4% of which for non-acrocentric markers. Some sSMC containing euchromatin had a normal phenotype (31% for non-acrocentric, 75% for acrocentric markers). Statistical differences between normal and abnormal phenotypes were demonstrated for the size of the euchromatin material (more or less than 1Mb, p=0.0006) and number of genes (more or less than 10, p=0.0009). This study is the largest to date and demonstrates the utility of array-CGH / SNP array in the detection and characterization of de novo sSMC in a prenatal context.
Clinical Genetics 03/2013; · 3.13 Impact Factor
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A L Mosca,
P Callier,
L Faivre,
N Laurent,
T Rousseau,
N Marle,
M Payet,
H Guy,
S Couvreur,
A Masurel-Paulet,
P Sagot,
C Thauvin-Robinet, F Mugneret
American Journal of Medical Genetics Part A 08/2011; 155A(8):2031-4. · 2.39 Impact Factor
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A L Mosca-Boidron,
S Bouquillon,
L Faivre,
P Callier,
J Andrieux,
N Marle,
C Bonnet,
C Vincent-Delorme,
M Berri,
G Plessis, [......],
E Pipiras,
A Delahaye,
M Payet,
C Ragon,
A Masurel-Paulet,
E Questiaux,
B Benzacken,
P Jonveaux, F Mugneret,
M Holder-Espinasse
[show abstract]
[hide abstract]
ABSTRACT: Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.
Clinical Genetics 07/2011; 82(1):41-7. · 3.13 Impact Factor
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A L Mosca,
L Pinson,
J Andrieux,
H Copin,
N Bigi,
J Puechberty,
P Sarda,
A Receveur,
H Sevestre,
S Pigeonnat, [......],
T Rousseau,
C Thauvin-Robinet,
A Masurel-Paulet,
A Schneider,
N Laurent,
P Sagot, F Mugneret,
G Lefort,
L Faivre,
P Callier
Prenatal Diagnosis 06/2011; · 2.11 Impact Factor
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C Bonnet,
J Andrieux,
M Béri-Dexheimer,
B Leheup,
O Boute,
S Manouvrier,
B Delobel,
H Copin,
A Receveur,
M Mathieu, [......],
C Thauvin-Robinet,
A Masurel-Paulet,
L Faivre,
M Tardieu,
N Bahi-Buisson,
P Callier, F Mugneret,
P Edery,
P Jonveaux,
D Sanlaville
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND Genome-wide screening of large patient cohorts with mental retardation using microarray-based comparative genomic hybridisation (array-CGH) has recently led to identification several novel microdeletion and microduplication syndromes. METHODS Owing to the national array-CGH network funded by the French Ministry of Health, shared information about patients with rare disease helped to define critical intervals and evaluate their gene content, and finally determine the phenotypic consequences of genomic array findings. RESULTS In this study, nine unrelated patients with overlapping de novo interstitial microdeletions involving 4q21 are reported. Several major features are common to all patients, including neonatal muscular hypotonia, severe psychomotor retardation, marked progressive growth restriction, distinctive facial features and absent or severely delayed speech. The boundaries and the sizes of the nine deletions are different, but an overlapping region of 1.37 Mb is defined; this region contains five RefSeq genes: PRKG2, RASGEF1B, HNRNPD, HNRPDL and ENOPH1. DISCUSSION Adding new individuals with similar clinical features and 4q21 deletion allowed us to reduce the critical genomic region encompassing two genes, PRKG2 and RASGEF1B. PRKG2 encodes cGMP-dependent protein kinase type II, which is expressed in brain and in cartilage. Information from genetically modified animal models is pertinent to the clinical phenotype. RASGEF1B is a guanine nucleotide exchange factor for Ras family proteins, and several members have been reported as key regulators of actin and microtubule dynamics during both dendrite and spine structural plasticity. CONCLUSION Clinical and molecular delineation of 4q21 deletion supports a novel microdeletion syndrome and suggests a major contribution of PRKG2 and RASGEF1B haploinsufficiency to the core phenotype.
Journal of Medical Genetics 06/2010; 47(6):377-84. · 6.36 Impact Factor
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A L Mosca,
P Callier,
A Masurel-Paulet,
C Thauvin-Robinet,
N Marle,
M Nouchy,
F Huet,
D Dipanda,
A De Paepe,
P Coucke, F Mugneret,
L Faivre
American Journal of Medical Genetics Part A 05/2010; 152A(5):1314-7. · 2.39 Impact Factor
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A.L. Mosca,
P. Callier,
A. Masurel-Paulet,
C. Thauvin-Robinet,
N. Marle,
M. Nouchy,
F. Huet,
D. Dipanda,
A. De Paepe,
P. Coucke, F. Mugneret,
L. Faivre
American Journal of Medical Genetics Part A 04/2010; 152A(5):1314 - 1317. · 2.39 Impact Factor
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A Masurel-Paulet,
J Andrieux,
P Callier,
J M Cuisset,
C Le Caignec,
M Holder,
C Thauvin-Robinet,
B Doray,
E Flori,
M P Alex-Cordier, [......],
C Bidon,
A Gautier,
P Pernes,
J M Pinoit,
F Huet, F Mugneret,
B Aral,
P Jonveaux,
D Sanlaville,
L Faivre
[show abstract]
[hide abstract]
ABSTRACT: 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.
Clinical Genetics 02/2010; 78(2):149-61. · 3.13 Impact Factor
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American Journal of Medical Genetics Part A 11/2009; 149A(12):2865-6. · 2.39 Impact Factor
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P Callier,
L Faivre,
S Pigeonnat,
B Quilichini,
N Marle,
C Thauvin-Robinet,
A L Mosca,
A Masurel-Paulet,
T Rousseau,
P Sagot,
N Laurent, F Mugneret
Prenatal Diagnosis 09/2009; 29(10):1002-5. · 2.11 Impact Factor
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L Couronné,
E Lippert,
J Andrieux,
O Kosmider,
I Radford-Weiss,
D Penther,
N Dastugue, F Mugneret,
M Lafage,
N Gachard,
N Nadal,
O A Bernard,
F Nguyen-Khac
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 09/2009; 24(1):201-3. · 8.30 Impact Factor
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P Callier,
L Faivre,
N Marle,
C Thauvin-Robinet,
J Guy,
A L Mosca,
P D'Athis,
A Masurel-Paulet,
D Assous,
J R Teyssier,
F Huet, F Mugneret
American Journal of Medical Genetics Part A 06/2009; 149A(6):1323-6. · 2.39 Impact Factor
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P. Callier,
L. Faivre,
N. Marle,
C. Thauvin-Robinet,
J. Guy,
A.L. Mosca,
P. D'Athis,
A. Masurel-Paulet,
D. Assous,
J.R. Teyssier,
F. Huet, F. Mugneret
American Journal of Medical Genetics Part A 05/2009; 149A(6):1323 - 1326. · 2.39 Impact Factor
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A L Mosca,
P Callier,
L Faivre,
N Marle,
N Mejean,
C Thauvin-Robinet,
A Masurel-Paulet,
N Madinier,
C Durand,
G Couillaud,
S Ragot,
F Huet,
J R Teyssier, F Mugneret
[show abstract]
[hide abstract]
ABSTRACT: Polymicrogyria (PMG) is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12-year-old girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplication/deletion and bacterial artificial chromosomes (BACs)-array also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACs-array in detecting complex rearrangements.
American Journal of Medical Genetics Part A 03/2009; 149A(3):475-81. · 2.39 Impact Factor
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A.L. Mosca,
P. Callier,
L. Faivre,
N. Marle,
N. Mejean,
C. Thauvin-Robinet,
A. Masurel-Paulet,
N. Madinier,
C. Durand,
G. Couillaud,
S. Ragot,
F. Huet,
J.R. Teyssier, F. Mugneret
[show abstract]
[hide abstract]
ABSTRACT: Polymicrogyria (PMG) is a relatively common malformation of the cortex for which the pathogenesis remains poorly understood. Both acquired and genetic causes are known, and to date more than 70 cases of PMG have been associated with chromosomal abnormalities. Here we report on a 12-year-old girl presenting with asymmetrical PMG predominantly affecting the right occipital lobe. She was the only child of consanguineous parents. At 7 years of age she was referred for mental retardation with speech delay and seizures. Cytogenetic studies of the patient revealed an inverted 9p duplication/deletion and bacterial artificial chromosomes (BACs)-array also showed a 22q11.2 microduplication confirmed by quantitative PCR. This case is of interest in the search for candidate genes and emphasizes the importance of the 22q11 region in PMG. It also highlights the efficiency of BACs-array in detecting complex rearrangements. © 2009 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 02/2009; 149A(3):475 - 481. · 2.39 Impact Factor
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C Graux,
M Stevens-Kroef,
M Lafage,
N Dastugue,
C J Harrison, F Mugneret,
K Bahloula,
S Struski,
M J Grégoire,
N Nadal, [......],
K Barber,
A Bosly,
L Michaux,
P Vandenberghe,
I Lahortiga,
K De Keersmaecker,
I Wlodarska,
J Cools,
A Hagemeijer,
H A Poirel
[show abstract]
[hide abstract]
ABSTRACT: Episomes with the NUP214-ABL1 fusion gene have been observed in 6% of T-ALL. In this multicentric study we collected 27 cases of NUP214-ABL1-positive T-ALL. Median age was 15 years with male predominance. Outcome was poor in 12 patients. An associated abnormality involving TLX1 or TLX3 was found in all investigated cases. Fluorescent in situ hybridization revealed a heterogeneous pattern of NUP214-ABL1 amplification. Multiple episomes carrying the fusion were detected in 24 patients. Episomes were observed in a significant number of nuclei in 18 cases, but in only 1-5% of nuclei in 6. In addition, intrachromosomal amplification (small hsr) was identified either as the only change or in association with episomes in four cases and two T-ALL cell lines (PEER and ALL-SIL). One case showed insertion of apparently non-amplified NUP214-ABL1 sequences at 14q12. The amplified sequences were analyzed using array-based CGH.These findings confirm that the NUP214-ABL1 gene requires amplification for oncogenicity; it is part of a multistep process of leukemogenesis; and it can be a late event present only in subpopulations. Data also provide in vivo evidence for a model of episome formation, amplification and optional reintegration into the genome. Implications for the use of kinase inhibitors are discussed.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 11/2008; 23(1):125-33. · 8.30 Impact Factor
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A Murati,
C Gervais,
N Carbuccia,
P Finetti,
N Cervera,
J Adélaïde,
S Struski,
E Lippert, F Mugneret,
I Tigaud, [......],
P Cornillet-Lefebvre,
N Nadal,
F Nguyen-Khac,
C Pérot,
S Olschwang,
F Bertucci,
M Chaffanet,
M Lessard,
M-J Mozziconacci,
D Birnbaum
[show abstract]
[hide abstract]
ABSTRACT: The t(8;16)(p11;p13) is a rare translocation involved in de novo and therapy-related myelomonocytic and monocytic acute leukemia. It fuses two genes encoding histone acetyltransferases (HATs), MYST3 located at 8p11 to CREBBP located at 16p13. Variant translocations involve other HAT-encoding genes such as EP300, MYST4, NCOA2 or NCOA3. MYST3-linked acute myeloid leukemias (AMLs) share specific clinical and biological features and a poor prognosis. Because of its rarity, the molecular biology of MYST3-linked AMLs remains poorly understood. We have established the genome and gene expression profiles of a multicentric series of 61 M4/M5 AMLs including 18 MYST3-linked AMLs by using array comparative genome hybridization (aCGH) (n=52) and DNA microarrays (n=44), respectively. We show that M4/5 AMLs have a variety of rare genomic alterations. One alteration, a gain of the MYB locus, was found recurrently and only in the MYST3-linked AMLs (7/18 vs 0/34). MYST3-AMLs have also a specific a gene expression profile, which includes overexpression of MYB, CD4 and HOXA genes. These features, reminiscent of T-cell acute lymphoid leukemia (ALL), suggest the targeting of a common T-myeloid progenitor.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 10/2008; 23(1):85-94. · 8.30 Impact Factor
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P Callier,
L Faivre,
C Thauvin-Robinet,
N Marle,
A L Mosca,
P D'Athis,
J Guy,
A Masurel-Paulet,
L Joly,
S Guiraud,
J R Teyssier,
F Huet, F Mugneret
[show abstract]
[hide abstract]
ABSTRACT: Genosensor Array 300 (Abbott) is a multiplex platform for array-based comparative genomic hybridization that detects unbalanced genomic aberrations including whole chromosome gains/losses, microdeletions, duplications and unbalanced subtelomeric rearrangements. A series of 30 patients with unexplained mental retardation, dysmorphic features, congenital abnormalities and normal high resolution karyotype and FISH subtelomeric studies were analyzed using Genosensor Array 300 array-CGH. We identified a chromosomal aberration in one patient with an interstitial 1p31.1 deletion. FISH analysis with BACs specific probes of the 1p region confirmed the interstitial 1p22.2-p31.1 deletion. The patient was a 20-year-old man with short stature, facial dysmorphism including asymmetry, scoliosis, severe psychomotor delay and an epibulbar dermoid cyst. The phenotype was compatible with Goldenhar syndrome despite the absence of asymmetric ears. This observation is of interest since it could be a clue in the search for the genes responsible for Goldenhar syndrome. This study demonstrates the utility of the array-CGH technology in detecting interstitial deletions.
American Journal of Medical Genetics Part A 08/2008; 146A(16):2109-15. · 2.39 Impact Factor
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C Gervais,
A Murati,
C Helias,
S Struski,
A Eischen,
E Lippert,
I Tigaud,
D Penther,
C Bastard, F Mugneret, [......],
I Luquet,
N Nadal,
F Nguyen-Khac,
O Maarek,
C Herens,
D Sainty,
G Flandrin,
D Birnbaum,
M-J Mozziconacci,
M Lessard
[show abstract]
[hide abstract]
ABSTRACT: Thirty cases of acute myeloid leukaemia (AML) with MYST histone acetyltransferase 3 (MYST3) rearrangement were collected in a retrospective study from 14 centres in France and Belgium. The mean age at diagnosis was 59.4 years and 67% of the patients were females. Most cases (77%) were secondary to solid cancer (57%), haematological malignancy (35%) or both (8%), and appeared 25 months after the primary disease. Clinically, cutaneous localization and disseminated intravascular coagulation were present in 30 and 40% of the cases, respectively. AMLs were myelomonocytic (7%) or monocytic (93%), with erythrophagocytosis (75%) and cytoplasmic vacuoles (75%). Immunophenotype showed no particularity compared with monocytic leukaemia without MYST3 abnormality. Twenty-eight cases carried t(8;16)(p11;p13) with MYST3-CREBBP fusion, one case carried a variant t(8;22)(p11;q13) and one case carried a t(8;19)(p11;q13). Type I (MYST3 exon 16-CREBBP exon 3) was the most frequent MYST3-CREBBP fusion transcript (65%). MYST3 rearrangement was associated with a poor prognosis, as 50% of patients deceased during the first 10 months. All those particular clinical, cytologic, cytogenetic, molecular and prognostic characteristics of AML with MYST3 rearrangement may have allowed an individualization into the World Health Organization classification.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 07/2008; 22(8):1567-75. · 8.30 Impact Factor
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E Chapiro,
I Radford-Weiss,
C Bastard,
I Luquet,
C Lefebvre,
E Callet-Bauchu,
D Leroux,
P Talmant,
M-J Mozziconacci, F Mugneret, [......],
S Ramond,
C Terré,
E Lippert,
F Berger,
P Felman,
H Merle-Béral,
O A Bernard,
F Davi,
R Berger,
F Nguyen-Khac
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2008; 22(11):2123-7. · 8.30 Impact Factor
