Publications by authors named "Celine Pebrel-Richard"

24 Publications

  • Page 1 of 1

Further refining the critical region of 10q26 microdeletion syndrome: A possible involvement of INSYN2 and NPS in the cognitive phenotype.

Eur J Med Genet 2021 Sep 9;64(9):104287. Epub 2021 Jul 9.

Cytogénétique Médicale, CHU Clermont-Ferrand, CHU Estaing, F-63000, France; Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000, Clermont Ferrand, France. Electronic address:

Background: The 10q26 subtelomeric microdeletion syndrome is a rare and clinically heterogeneous disorder. The precise relationships between the causative genes and the phenotype are unclear.

Case Presentation: We report two new cases of 860 kb deletion of 10q26.2 identified by array CGH in a fetus with intrauterine growth retardation and his mother. The deleted region encompassed only four coding genes, DOCK1, INSYN2, NPS and FOX12. The proband had dysmorphic facies characterized by a high forehead, malformed ears, a prominent nose, and retrognathia. He had bilateral club feet, clinodactily and mild psychomotor retardation. His mother had a short stature, microcephaly, a long face with a high forehead and bitemporal narrowing, arched and sparse eyebrows, strabismus, prominent nose and chin, a thin upper lip and large protruding ears, and mild intellectual disability.

Conclusions: This study presents the smallest 10q26.2 deletion so far identified, which further refines the minimal critical region associated with the 10q26 microdeletion syndrome. It focuses on three genes potentially responsible for the phenotype: DOCK1, which is the major candidate gene, and INSYN2 and NPS, which could be involved in cognitive functions.
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http://dx.doi.org/10.1016/j.ejmg.2021.104287DOI Listing
September 2021

Optical genome mapping enables constitutional chromosomal aberration detection.

Am J Hum Genet 2021 08 7;108(8):1409-1422. Epub 2021 Jul 7.

Department of Cytogenetics, APHP.centre - Université de Paris, Hôpital Cochin, 75014 Paris, France; Université de Paris, Cochin Institute U1016, INSERM, 75014 Paris, France. Electronic address:

Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."
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http://dx.doi.org/10.1016/j.ajhg.2021.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387289PMC
August 2021

Idiopathic central precocious puberty in a Klinefelter patient: highlights on gonadotropin levels and pathophysiology.

Basic Clin Androl 2020 Dec 9;30(1):19. Epub 2020 Dec 9.

CHU Clermont-Ferrand, Service d'endocrinologie, diabétologie et maladies métaboliques, 58, rue Montalembert, F-63003, Clermont-Ferrand, France.

Background: Idiopathic central precocious puberty (ICPP) is supposed to be non-existent in a context of testicular destruction that is typically present in Klinefelter syndrome (KS). Herein, we describe a rare case of ICPP in a Klinefelter patient (47,XXY) with 2 maternal X chromosomes. Moreover, we highlight the differences in gonadotropin levels in comparison to males with ICPP and a normal karyotype.

Case Presentation: An 8 years old boy with a history of cryptorchidism was evaluated for precocious puberty (Tanner staging: P2/G3). Both testes measured 25x35mm. His hormonal profile confirmed a central origin of precocious puberty with high serum testosterone (4.3 ng/ml), luteinizing hormone [LH (3.5 UI/l)] and follicle stimulating hormone [FSH (7.7 UI/l)] levels. Luteinizing hormone-releasing hormone (LHRH) test amplified LH and FSH secretion to 24 and 14 UI/l respectively. Brain magnetic resonance imaging (MRI) was normal. No MKRN3 mutation was detected. He was treated for ICPP for two years. During puberty, he suffered from hypergonadotropic hypogonadism leading to the diagnosis of KS (47,XXY karyotype). Chromosomal analysis by fluorescent multiplex polymerase chain reaction (PCR) using X chromosome microsatellite markers identified 2 maternal X chromosomes. Analysing 8 cases of KS developing ICPP (our reported case and 7 other published cases) revealed that these KS patients with ICPP have higher LH and FSH levels during ICPP episode than in ICPP patients with a normal karyotype (ICPP with KS vs ICPP with a normal karyotype: LH levels 9.4 ± 12 vs 1.1 ± 0.6 UI/l; FSH levels 23.1 ± 38.5 vs 2.7 ± 1.5 UI/l). Furthermore, their response to gonadotropin-releasing hormone (GnRH) stimulation is characterized by excessive LH and FSH secretion (LH levels post-GnRH: 58 ± 48 vs 15.5 ± 0.8 UI/l; FSH levels post-GnRH: 49.1 ± 62.1 vs 5.7 ± 3.9 UI/l).

Conclusions: ICPP in boys is extremely rare. The pathophysiology of ICPP in KS is unknown. However, maternal X supplementary chromosome and early testicular destruction may play a significant role in the initiation of ICPP, in part explaining the relative "overrepresentation of ICPP in KS. Thus, karyotype analysis could be considered for boys suffering from ICPP, especially if testicular size is smaller or gonadotropins are significantly elevated.
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http://dx.doi.org/10.1186/s12610-020-00117-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724694PMC
December 2020

Analysis of the cost effectiveness of different strategies for the antenatal diagnosis of chromosomal aberrations in cases of ultrasound-identified fetal abnormalities.

Ann Biol Clin (Paris) 2020 Oct;78(5):483-491

Service de cytogénétique médicale, CHU Clermont-Ferrand, France ; Université Clermont Auvergne, UFR de médecine, Inserm U1240 Imagerie moléculaire et stratégies théranostiques, Clermont-Ferrand, France.

Objective: Principal objective of this work was to analyse the cost effectiveness of different sequences of cytogenetic techniques from the hospital's point of view, after prenatal ultrasound has identified fetal malformations.

Methods: Cytogenetic tests were performed for each case in 3 strategies, and their results are reported and compared to one reference strategy. Two new simulated strategies were considered: chromosomal microarrays alone and a direct test + CMA.

Main Outcomes Measures: cost-effectiveness ratio.

Results: A single test result was positive in 234 of the 835 pregnancies studied (28%). CMA alone would have identified 239 abnormalities. In the simulated direct test + CMA sequence, the direct test alone would have been positive for 66.1% of the abnormalities identified. When testing was indicated for NT, reference strategy (Direct + karyotyping) costs 1 084.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively 992.7 and 550.0 euros by positive test results. For OUM indications, reference strategy costs 2 937.8 euros by positive test results. Strategies Direct + CMA and CMA alone cost respectively, 2 118.4 and 1 304.7 euros by positive test results.

Conclusions: CMA appears to be the most effective test for prenatal cytogenetic diagnosis of fetal abnormalities identified by ultrasound.
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http://dx.doi.org/10.1684/abc.2020.1580DOI Listing
October 2020

Is BRCA2 involved in early onset colorectal cancer risk?

Clin Genet 2020 04 26;97(4):668-669. Epub 2019 Dec 26.

Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, Clermont Ferrand, France.

A, Closed symbols indicate patients affected with cancer. Open symbols indicate healthy individuals. The type of cancer and age at presentation are given in brackets. Blue circle represents c.4471_4474del variant and red circle represents the c.9648 + 1G > A. B, RNA was extracted from blood of patient III-3 and his sisters III-1 and III-4. RT-PCR analysis was performed with primers mapping to exons 25 and 27, and PCR products were separated by Bioanalyzer electrophoresis. The sizes of the DNA marker (M) are indicated to the left. LM, lower marker; UM, upper marker. C, Each RT-PCR product from patient III-3 was gel-purified and analyzed by Sanger sequencing. The 297-bp band corresponds to the reference BRCA2 transcript and the 150-bp band corresponds to a BRCA2 transcript lacking exon 26.
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http://dx.doi.org/10.1111/cge.13679DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078894PMC
April 2020

Whole genome paired-end sequencing elucidates functional and phenotypic consequences of balanced chromosomal rearrangement in patients with developmental disorders.

J Med Genet 2019 08 28;56(8):526-535. Epub 2019 Mar 28.

Laboratoire de Cytogénétique, CHU Strasbourg, Strasbourg, France.

Background: Balanced chromosomal rearrangements associated with abnormal phenotype are rare events, but may be challenging for genetic counselling, since molecular characterisation of breakpoints is not performed routinely. We used next-generation sequencing to characterise breakpoints of balanced chromosomal rearrangements at the molecular level in patients with intellectual disability and/or congenital anomalies.

Methods: Breakpoints were characterised by a paired-end low depth whole genome sequencing (WGS) strategy and validated by Sanger sequencing. Expression study of disrupted and neighbouring genes was performed by RT-qPCR from blood or lymphoblastoid cell line RNA.

Results: Among the 55 patients included (41 reciprocal translocations, 4 inversions, 2 insertions and 8 complex chromosomal rearrangements), we were able to detect 89% of chromosomal rearrangements (49/55). Molecular signatures at the breakpoints suggested that DNA breaks arose randomly and that there was no major influence of repeated elements. Non-homologous end-joining appeared as the main mechanism of repair (55% of rearrangements). A diagnosis could be established in 22/49 patients (44.8%), 15 by gene disruption (, , , , , , , , , , , ) and 7 by position effect (, , , ). In addition, 16 new candidate genes were identified. Systematic gene expression studies further supported these results. We also showed the contribution of topologically associated domain maps to WGS data interpretation.

Conclusion: Paired-end WGS is a valid strategy and may be used for structural variation characterisation in a clinical setting.
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http://dx.doi.org/10.1136/jmedgenet-2018-105778DOI Listing
August 2019

Sperm meiotic segregation of a balanced interchromosomal reciprocal insertion resulting in recurrent spontaneous miscarriage.

Reprod Biomed Online 2018 Jul 9;37(1):100-106. Epub 2018 Apr 9.

Medical Cytogenetics Department, CHU Estaing, F-63003 Clermont-Ferrand, France; Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont-Ferrand, France. Electronic address:

Research Question: Is sperm fluorescence in-situ hybridization (FISH) useful to evaluate the risk of chromosomally unbalanced gametes in interchromosomal reciprocal insertion (IRI) carriers? How do these imbalances lead to recurrent miscarriages?

Design: This study reports a clinical and molecular study of a rare familial balanced IRI resulting in recurrent spontaneous miscarriage. Sperm FISH was performed to estimate the number of unbalanced gametes.

Results: A 31-year-old healthy male (proband) and his 28-year-old female partner were referred to the Genetics Department for three spontaneous miscarriages occurring during the first trimester of pregnancy. FISH analysis of the proband with the LSI TRA/D (14q11.2) and DiGeorge N25 (22q11.2) break-apart probes showed the presence of a balanced IRI between 14q11.2 and 22q11.2 chromosomal regions. This IRI was also identified in the proband's father. Sperm FISH with the same probes showed that more than 40% of gametes of the proband were unbalanced for either 14q11.2 or 22q11.2, despite normal sperm parameters. FISH analysis of a product of conception indicated that unbalanced gametes result in a non-viable fetus.

Conclusions: This study shows the value of sperm FISH analysis in improving genetic reproductive advice for IRI carriers. Disruption of critical genes through this rearrangement and their consequent functional impairment could result in recurrent miscarriages. In this case, several genes located in the 14q11.2 region, particularly RNase 3, would be good candidates to explain the lethality of the imbalances.
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http://dx.doi.org/10.1016/j.rbmo.2018.03.019DOI Listing
July 2018

Spatial organization of chromosome territories in the interphase nucleus of trisomy 21 cells.

Chromosoma 2018 06 14;127(2):247-259. Epub 2017 Dec 14.

ERTICA EA 4677, Université Clermont Auvergne, 63000, Clermont-Ferrand, France.

In the interphase cell nucleus, chromosomes adopt a conserved and non-random arrangement in subnuclear domains called chromosome territories (CTs). Whereas chromosome translocation can affect CT organization in tumor cell nuclei, little is known about how aneuploidies can impact CT organization. Here, we performed 3D-FISH on control and trisomic 21 nuclei to track the patterning of chromosome territories, focusing on the radial distribution of trisomic HSA21 as well as 11 disomic chromosomes. We have established an experimental design based on cultured chorionic villus cells which keep their original mesenchymal features including a characteristic ellipsoid nuclear morphology and a radial CT distribution that correlates with chromosome size. Our study suggests that in trisomy 21 nuclei, the extra HSA21 induces a shift of HSA1 and HSA3 CTs out toward a more peripheral position in nuclear space and a higher compaction of HSA1 and HSA17 CTs. We posit that the presence of a supernumerary chromosome 21 alters chromosome compaction and results in displacement of other chromosome territories from their usual nuclear position.
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http://dx.doi.org/10.1007/s00412-017-0653-6DOI Listing
June 2018

ACTB Loss-of-Function Mutations Result in a Pleiotropic Developmental Disorder.

Am J Hum Genet 2017 Dec;101(6):1021-1033

Service de Cytogénétique Médicale, Centre Hospitalier Régional Clermont-Ferrand, 63000 Clermont-Ferrand, France.

ACTB encodes β-actin, an abundant cytoskeletal housekeeping protein. In humans, postulated gain-of-function missense mutations cause Baraitser-Winter syndrome (BRWS), characterized by intellectual disability, cortical malformations, coloboma, sensorineural deafness, and typical facial features. To date, the consequences of loss-of-function ACTB mutations have not been proven conclusively. We describe heterozygous ACTB deletions and nonsense and frameshift mutations in 33 individuals with developmental delay, apparent intellectual disability, increased frequency of internal organ malformations (including those of the heart and the renal tract), growth retardation, and a recognizable facial gestalt (interrupted wavy eyebrows, dense eyelashes, wide nose, wide mouth, and a prominent chin) that is distinct from characteristics of individuals with BRWS. Strikingly, this spectrum overlaps with that of several chromatin-remodeling developmental disorders. In wild-type mouse embryos, β-actin expression was prominent in the kidney, heart, and brain. ACTB mRNA expression levels in lymphoblastic lines and fibroblasts derived from affected individuals were decreased in comparison to those in control cells. Fibroblasts derived from an affected individual and ACTB siRNA knockdown in wild-type fibroblasts showed altered cell shape and migration, consistent with known roles of cytoplasmic β-actin. We also demonstrate that ACTB haploinsufficiency leads to reduced cell proliferation, altered expression of cell-cycle genes, and decreased amounts of nuclear, but not cytoplasmic, β-actin. In conclusion, we show that heterozygous loss-of-function ACTB mutations cause a distinct pleiotropic malformation syndrome with intellectual disability. Our biological studies suggest that a critically reduced amount of this protein alters cell shape, migration, proliferation, and gene expression to the detriment of brain, heart, and kidney development.
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http://dx.doi.org/10.1016/j.ajhg.2017.11.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812896PMC
December 2017

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea.

Am J Hum Genet 2016 09 25;99(3):753-761. Epub 2016 Aug 25.

Neuropédiatrie et Unité d'électrophysiologie clinique, Centre de Référence des Maladies Neuromusculaires de l'EST parisien et DHU I2B, Hôpital d'Enfants Armand Trousseau, 75012 Paris, France.

The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011057PMC
September 2016

A novel 2q14.1q14.3 deletion involving GLI2 and RNU4ATAC genes associated with partial corpus callosum agenesis and severe intrauterine growth retardation.

Birth Defects Res A Clin Mol Teratol 2016 Sep 27;106(9):793-7. Epub 2016 Jun 27.

Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Clermont-Ferrand, CHU Estaing, France.

Background: Microdeletions encompassing chromosome bands 2q14.1q14.3 are rare. To date, eight reports of relatively large deletions of this region (∼20 Mb) but only two small deletions (<6 Mb) have been reported. These deletions can cause a variable phenotype depending on the size and location of the deletion. Cognitive disability, facial dysmorphism, and postnatal growth retardation are the most common phenotypic features.

Case: We report on a novel 5.8 Mb deletion of 2q14.1q14.3 identified by array comparative genomic hybridization in a fetus with severe intrauterine growth retardation and partial agenesis of the corpus callosum. The deletion contained 24 coding genes including STEAP3, GLI2, and RNU4ATAC and was inherited from the mild affected mother. A sibling developmental delay and similar dysmorphic facial features was found to have inherited the same deletion.

Conclusion: This case emphasizes the variable expressivity of the 2q14 microdeletion and reinforces the hypothesis that agenesis of corpus callosum, microcephaly, developmental delay, and distinctive craniofacial features may be part of the phenotypic spectrum characterizing the affected patients. We suggest that GLI2 is a dosage-sensitive gene that may be responsible for the agenesis of corpus callosum observed in the proband. Birth Defects Research (Part A) 106:793-797, 2016. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdra.23535DOI Listing
September 2016

A case which further refines the critical region for 15q25.2 microduplication phenotypes.

Acta Neurol Belg 2016 Dec 29;116(4):683-685. Epub 2016 Feb 29.

Génétique médicale, Université d'Auvergne, Centre hospitalo-universitaire de Clermont-Ferrand, Clermont-Ferrand, France.

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http://dx.doi.org/10.1007/s13760-016-0620-7DOI Listing
December 2016

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Am J Hum Genet 2016 Feb 28;98(2):363-72. Epub 2016 Jan 28.

Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre (MAHSC), Manchester M13 9WL, UK. Electronic address:

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ∼350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.
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http://dx.doi.org/10.1016/j.ajhg.2015.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746363PMC
February 2016

A French multicenter study of over 700 patients with 22q11 deletions diagnosed using FISH or aCGH.

Eur J Hum Genet 2016 06 28;24(6):844-51. Epub 2015 Oct 28.

Service de Génétique, CHU de Poitiers, Poitiers, France.

Although 22q11.2 deletion syndrome (22q11.2DS) is the most recurrent human microdeletion syndrome associated with a highly variable phenotype, little is known about the condition's true incidence and the phenotype at diagnosis. We performed a multicenter, retrospective analysis of postnatally diagnosed patients recruited by members of the Association des Cytogénéticiens de Langue Française (the French-Speaking Cytogeneticists Association). Clinical and cytogenetic data on 749 cases diagnosed between 1995 and 2013 were collected by 31 French cytogenetics laboratories. The most frequent reasons for referral of postnatally diagnosed cases were a congenital heart defect (CHD, 48.6%), facial dysmorphism (49.7%) and developmental delay (40.7%). Since 2007 (the year in which array comparative genomic hybridization (aCGH) was introduced for the routine screening of patients with intellectual disability), almost all cases have been diagnosed using FISH (96.1%). Only 15 cases (all with an atypical phenotype) were diagnosed with aCGH; the deletion size ranged from 745 to 2904 kb. The deletion was inherited in 15.0% of cases and was of maternal origin in 85.5% of the latter. This is the largest yet documented cohort of patients with 22q11.2DS (the most commonly diagnosed microdeletion) from the same population. French cytogenetics laboratories diagnosed at least 108 affected patients (including fetuses) per year from among a national population of ∼66 million. As observed for prenatal diagnoses, CHDs were the most frequently detected malformation in postnatal diagnoses. The most common CHD in postnatal diagnoses was an isolated septal defect.
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http://dx.doi.org/10.1038/ejhg.2015.219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867458PMC
June 2016

Prenatal Screening of 21 Microdeletion/Microduplication Syndromes and Subtelomeric Imbalances by MLPA in Fetuses with Increased Nuchal Translucency and Normal Karyotype.

Cytogenet Genome Res 2015 21;146(1):28-32. Epub 2015 Jul 21.

Service de Cytogx00E9;nx00E9;tique Mx00E9;dicale, Unitx00E9; de Mx00E9;decine Fx0153;tale, CHU Clermont-Ferrand, Clermont-Ferrand, France.

Fetuses with increased nuchal translucency thickness (NT) are at increased risk for chromosomal abnormalities. In case of a normal karyotype, a minority of them may present with structural abnormalities or genetic syndromes, which may be related to submicroscopic chromosomal imbalances. The objective of this study was to evaluate whether MLPA screening of 21 syndromic and subtelomeric regions could improve the detection rate of small chromosomal aberrations in fetuses with increased NT and a normal karyotype. A total of 106 prenatal samples from fetuses with NT ≥ 99th centile and normal R- and G-banding were analyzed by MLPA for subtelomeric imbalances (SALSA P036 and P070) and 21 syndromic regions (SALSA P245). One sample showed a benign CNV (dup(8)pter, FBXO25 gene), and 1 patient was found to have a loss of 18 qter and a gain of 5 pter as a result of an unbalanced translocation. The incidence of cryptic pathogenic variants was <1% or 2.7% when only fetuses with other ultrasound abnormalities were taken into account. Submicroscopic imbalances in fetuses with increased NT may be individually rare, and genome-wide screening seems more likely to improve the diagnostic yield in these fetuses.
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http://dx.doi.org/10.1159/000435865DOI Listing
March 2016

Congenital diaphragmatic hernia may be associated with 17q12 microdeletion syndrome.

Am J Med Genet A 2015 Jan 25;167A(1):250-3. Epub 2014 Nov 25.

Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Clermont-Ferrand, CHU Estaing, France; EA 4677, ERTICa, Université d'Auvergne, Clermont-Ferrand, France.

Microdeletions of 17q12 encompassing TCF2 are associated with maturity-onset of diabetes of the young type 5, cystic renal disease, pancreatic atrophy, Mullerian aplasia in females and variable cognitive impairment. We report on a patient with a de novo 17q12 microdeletion, 1.8 Mb in size, associated with congenital diaphragmatic hernia (CDH). The 5-year-old male patient presented multicystic renal dysplasia kidneys, minor facial dysmorphic features and skeletal anomalies, but neither developmental delay nor behavioral abnormalities. CDH has been previously associated with the 17q12 microdeletion syndrome only in one prenatal case. The present study reinforces the hypothesis that CDH is part of the phenotype for 17q12 microdeletion and that 17q12 encompasses candidate(s) gene(s) involved in diaphragm development. We suggest that PIGW, a gene involved in an early step of GPI biosynthesis, could be a strong candidate gene for CDH.
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http://dx.doi.org/10.1002/ajmg.a.36840DOI Listing
January 2015

Refinement of the critical region in a new 7p22.1 microduplication syndrome including craniofacial dysmorphism and speech delay.

Am J Med Genet A 2014 Nov 14;164A(11):2964-7. Epub 2014 Aug 14.

Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Estaing, Clermont-Ferrand, France; ERTICa, EA 4677, Univ Clermont1, UFR Médecine, France.

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http://dx.doi.org/10.1002/ajmg.a.36715DOI Listing
November 2014

Clinical and molecular description of a 17q21.33 microduplication in a girl with severe kyphoscoliosis and developmental delay.

Eur J Med Genet 2014 Oct 6;57(10):552-7. Epub 2014 Aug 6.

Univ Clermont 1, UFR Médecine, Cytologie Histologie Embryologie Cytogénétique, Clermont-Ferrand, F-63001, France; CHU Estaing, Cytogénétique Médicale, Clermont-Ferrand, F-63003, France; ERTICa, Univ Clermont 1, UFR Médecine, Clermont-Ferrand, F-63001, France. Electronic address:

High proportion of disease-associated copy number variant maps to chromosome 17. Genomic studies have provided an insight into its complex genomic structure such as relative abundance of segmental duplication and intercepted repetitive elements. 17q21.31, 17q11.2 and 17q12 loci are well known on this chromosome and are associated with microdeletion and microduplication syndrome. No syndrome associated with 17q21.33 locus have been described. We report clinical, cytogenetic and molecular investigations of a 13 years-old girl admitted for evaluation of microcephaly, scoliosis, skeletal defects and learning difficulties. We carried out detailed analysis of the clinical phenotype of this patient and investigated the genetic basis using Agilent 180K Array Comparative Genomic Hybridization. We identified a ∼0.9 Mb de novo microduplication on chromosome 17q21.33. Four genes, COL1A1, SGCA, PPP1R9B and CHAD located within the duplicated region are possible candidates for clinical features present in our patients. Gene expression studies by real-time RT-PCR assay only showed an overexpression of SGCA (P < 0.01), a component of the dystrophin glycoprotein complex. Defect of SGCA was previously shown to lead to severe childhood autosomal recessive muscular dystrophy (LGMD2D) which result in progressive muscle weakness and can also be associated with hyperlordosis or scoliosis. Further cases with similar duplications are expected to be diagnosed. This will contribute to the delineation of this potential new microduplication syndrome and to improve genetic counseling.
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http://dx.doi.org/10.1016/j.ejmg.2014.07.003DOI Listing
October 2014

De novo 2q36.1q36.3 interstitial deletion involving the PAX3 and EPHA4 genes in a fetus with spina bifida and cleft palate.

Birth Defects Res A Clin Mol Teratol 2014 Jun 18;100(6):507-11. Epub 2014 Apr 18.

Cytogénétique Médicale, Université Clermont1, UFR Médecine, CHU Clermont-Ferrand, CHU Estaing, France.

Background: Interstitial 2q36 deletion is a rare event. Only two previously published cases of 2q36 deletions were characterized using array-CGH. This is the first case diagnosed prenatally.

Methods: We report on the prenatal diagnosis of a 2q36.1q36.3 interstitial deletion in a fetus with facial dysmorphism, spina bifida, and cleft palate.

Results: Array-CGH analysis revealed a 5.6 Mb interstitial deletion of the long arm of chromosome 2q36.1q36.3, including the PAX3 and EPHA4 genes.

Conclusion: The present study reinforces the hypothesis that PAX3 haploinsufficiency may be associated with neural tube defects in humans and suggests that the EPHA4 gene might be implicated during palate development. This report also illustrates the added value of array-CGH to detect cryptic chromosomal imbalances in malformed fetuses and to improve genetic counseling prenatally.
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http://dx.doi.org/10.1002/bdra.23246DOI Listing
June 2014

An unusual clinical severity of 16p11.2 deletion syndrome caused by unmasked recessive mutation of CLN3.

Eur J Hum Genet 2014 Mar 17;22(3):369-73. Epub 2013 Jul 17.

Génétique Médicale, CHU Estaing, Clermont-Ferrand, France.

With the introduction of array comparative genomic hybridization (aCGH) techniques in the diagnostic setting of patients with developmental delay and congenital malformations, many new microdeletion syndromes have been recognized. One of these recently recognized microdeletion syndromes is the 16p11.2 deletion syndrome, associated with variable clinical outcomes including developmental delay, autism spectrum disorder, epilepsy, and obesity, but also apparently normal phenotype. We report on a 16-year-old patient with developmental delay, exhibiting retinis pigmentosa with progressive visual failure from the age of 9 years, ataxia, and peripheral neuropathy. Chromosomal microarray analysis identified a 1.7-Mb 16p11.2 deletion encompassing the 593-kb common deletion (∼29.5 to ∼30.1 Mb; Hg18) and the 220-kb distal deletion (∼28.74 to ∼28.95 Mb; Hg18) that partially included the CLN3 gene. As the patient's clinical findings were different from usual 16p11.2 microdeletion phenotypes and showed some features reminiscent of juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, OMIM 204200), we suspected and confirmed a mutation of the remaining CLN3 allele. This case further illustrates that unmasking of hemizygous recessive mutations by chromosomal deletion represents one explanation for the phenotypic variability observed in chromosomal deletion disorders.
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http://dx.doi.org/10.1038/ejhg.2013.141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3925269PMC
March 2014

A new case of 8q22.1 microdeletion restricts the critical region for Nablus mask-like facial syndrome.

Am J Med Genet A 2013 Jan 13;161A(1):162-5. Epub 2012 Dec 13.

Génétique Médicale, Univ Clermont1, UFR Médecine, CHU Clermont-Ferrand, CHU Estaing, France.

Microdeletions of 8q21.3-8q22.1 have been identified in all patients with Nablus mask-like facial syndrome (NMLFS). A recent report of a patient without this specific phenotype presented a 1.6 Mb deletion in this region that partially overlapped with previously reported 8q21.3 microdeletions, thus restricting critical region for this syndrome. We report on another case of an 8q21.3 deletion revealed by array comparative genome hybridization (aCGH) in a 4-year-old child with global developmental delay, autism, microcephaly, but without Nablus phenotype. The size of the interstitial deletion was estimated to span 5.2 Mb. By combining the data from previous reports on 8q21.3-8q22.1 deletions and our case, we were able to narrow the critical region of Nablus syndrome to 0.5 Mb. The deleted region includes FAM92A1, which seems to be a potential candidate gene in NMLFS.
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http://dx.doi.org/10.1002/ajmg.a.35614DOI Listing
January 2013

An atypical 0.8 Mb inherited duplication of 22q11.2 associated with psychomotor impairment.

Eur J Med Genet 2012 Nov 14;55(11):650-5. Epub 2012 Jul 14.

Cytogénétique Médicale, Univ Clermont1, UFR Médecine, CHU Clermont-Ferrand, CHU Estaing, 1 place Lucie Aubrac, 63003 Clermont-Ferrand Cedex1, France.

Microduplications 22q11.2 have been recently characterized as a new genomic duplication syndrome showing an extremely variable phenotype ranging from normal or mild learning disability to multiple congenital defects and sharing some overlapping features with DiGeorge/velocardiofacial syndrome (DGS/VCFS), including heart defects, urogenital abnormalities and velopharyngeal insufficiency. We present an atypical and inherited 0.8-Mb duplication at 22q11.2, in the distal segment of the DGS/VCFS syndrome typically deleted region (TDR), in a 3-year-old boy with motor delay, language disorders and mild facial phenotype. This 22q11.2 microduplication was identified by MLPA, designed to detect recurrent microdeletions and microduplications of chromosomal regions frequently involved in mental retardation syndromes and was further characterized by aCGH. The duplicated region encompasses 14 genes, excluding TBX1 but including CRKL, ZNF74, PIK4CA, SNAP29 and PCQAP known to contribute to several aspects of the DGS/VCFS phenotype. To the best of our knowledge, only one case of an isolated duplication in the distal segment of the TDR between chromosome 22-specific low-copy repeats B (LCR22-B) and D (LCR22-D) has been published, but the present report is the first one with a detailed description of physical and developmental features in a patient carrying this kind of atypical 22q11.2 duplication. This case illustrates the importance of reporting unusual 22q11.2 duplications to further evaluate the incidence of these rearrangements in the general population and to improve genotype-phenotype correlations and genetic counseling.
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http://dx.doi.org/10.1016/j.ejmg.2012.06.014DOI Listing
November 2012

Prenatal detection of cryptic rearrangements by multiplex ligation probe amplification in fetuses with ultrasound abnormalities.

Genet Med 2010 Jun;12(6):376-80

Univ Clermont 1, UFR Médecine, Histologie Embryologie Cytogénétique, Clermont-Ferrand, France.

Purpose: Congenital malformations are a major cause of morbidity and mortality in newborn infants, and genomic imbalances are a significant component of their etiology. The aim of this study was to evaluate the ability of prenatal multiplex ligation probe amplification screening to detect cryptic chromosomal imbalances in fetuses with ultrasound abnormalities of unknown etiology.

Methods: Multiplex ligation probe amplification was performed with three separate sets of probes: two for subtelomeric regions and one for mental retardation syndrome loci. Sixty-one fetuses with significant ultrasound anomalies and normal karyotype at a minimum of 400-band resolution were tested between January 2007 and January 2009.

Results: We identified four unbalanced rearrangements: one del 18pter/amp 5pter, one del 9pter, one 15q11q13 microdeletion, and one 22q11 microdeletion with atypical presentation. After genetic counseling, two of the pregnancies were terminated.

Conclusion: Multiplex ligation probe amplification analysis was able to identify clinically significant rearrangements in 6.5% of fetuses with prenatally identified sonographic abnormalities. This prospective study highlights that multiplex ligation probe amplification screening of fetuses with ultrasound abnormalities in the prenatal period is technically feasible and relevant for diagnosis and prognosis.
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http://dx.doi.org/10.1097/GIM.0b013e3181e074c6DOI Listing
June 2010
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