Publications by authors named "Eleonore Eymard-Pierre"

33 Publications

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness.

Brain 2021 May 8. Epub 2021 May 8.

Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.

Leukodystrophies are a heterogeneous group of rare inherited disorders that involve preferentially the white matter of the central nervous system (CNS). These conditions are characterized by a primary glial cell and myelin sheath pathology of variable etiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in 5 large consanguineous nuclear families allowed to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness. We report on two homozygous missense variants (p.R363Q and p.R365Q) in the ubiquitin E3 ligase RNF220 as the cause underlying a novel form of leukodystrophy with ataxia and sensorineural deafness having fibrotic cardiomyopathy and hepatopathy as associated features, in seven consanguineous families. Mass spectrometry analysis identified lamin B1 as RNF220 binding protein and co-immunoprecipitation experiments demonstrated reduced binding of both RNF220 mutants to lamin B1. We demonstrate that RNF220 silencing in Drosophila melanogaster specifically affects proper localization of lamin Dm0, the fly lamin B1 orthologue, promotes its aggregation, and causes a neurodegenerative phenotype, strongly supporting the functional link between RNF220 and lamin B1. Finally, we demonstrate that RNF220 plays a crucial role in the maintenance of nuclear morphology: mutations primary skin fibroblasts determine nuclear abnormalities such as blebs, herniations and invaginations, which are typically observed in cells of patients affected by laminopathies. Overall, our data identify RNF220 as a gene implicated in leukodystrophy with ataxia and sensorineural deafness, and document a critical role of RNF220 in the regulation of nuclear lamina. Our findings provide further evidence on the direct link between nuclear lamina dysfunction and neurodegeneration.
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http://dx.doi.org/10.1093/brain/awab185DOI Listing
May 2021

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

Deleterious mutations in suggest a novel cause for neuro-ichthyotic syndrome.

NPJ Genom Med 2019 23;4:17. Epub 2019 Jul 23.

3Nutrition Research Institute, University of North Carolina, Chapel Hill, NC USA.

Neuro-ichthyotic syndromes are a group of rare genetic diseases mainly associated with perturbations in lipid metabolism, intracellular vesicle trafficking, or glycoprotein synthesis. Here, we report a patient with a neuro-ichthyotic syndrome associated with deleterious mutations in the (aldehyde dehydrogenase 1 family member L2) gene encoding for mitochondrial 10-formyltetrahydrofolate dehydrogenase. Using fibroblast culture established from the ALDH1L2-deficient patient, we demonstrated that the enzyme loss impaired mitochondrial function affecting both mitochondrial morphology and the pool of metabolites relevant to β-oxidation of fatty acids. Cells lacking the enzyme had distorted mitochondria, accumulated acylcarnitine derivatives and Krebs cycle intermediates, and had lower ATP and increased ADP/AMP indicative of a low energy index. Re-expression of functional ALDH1L2 enzyme in deficient cells restored the mitochondrial morphology and the metabolic profile of fibroblasts from healthy individuals. Our study underscores the role of ALDH1L2 in the maintenance of mitochondrial integrity and energy balance of the cell, and suggests the loss of the enzyme as the cause of neuro-cutaneous disease.
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http://dx.doi.org/10.1038/s41525-019-0092-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6650503PMC
July 2019

Mutation in causes hypomyelinating leukodystrophy and abnormal ribosomal RNA regulation.

Neurol Genet 2018 Dec 3;4(6):e289. Epub 2018 Dec 3.

INSERM UMR 1141 PROTECT (I.D., P.B., S.S., O.B.-T.), Université Paris Diderot- Sorbonne Paris Cité; INSERM U1212-CNRS UMR 5320 (H.D.-O., M.T.), Université de Bordeaux; Neurologie Pédiatrique et Maladies Métaboliques (K.B., F.R., O.B-.T.), Centre de référence des leucodystrophies et leucoencéphalopathies de cause rare (LEUKOFRANCE), CHU APHP Robert-Debré, Paris, France; LR11IPT05, Biomedical Genomics and Oncogenetics Laboratory (H.J., Y.B.), Institut Pasteur de Tunis; Department of Medical Genetics, UF Molecular Genetics (S.S.), CHU APHP Robert-Debré Paris; Service de Cytogénétique Médicale (E.E.P.), CHU Clermont-Ferrand; Neurologie Pédiatrique (C.C.), Endocrinologie Pédiatrique (C.B.), CHU Hôpital des Enfants, Toulouse; Hôpital Femme Mère Enfant, Neurologie Pédiatrique (A.L.P., C.R.), Hospices Civils de Lyon, Bron; Department of Pediatric Radiology (M.E.-B.), CHU APHP Robert-Debré, Paris, France.

Objective: To identify the genetic cause of hypomyelinating leukodystrophy in 2 consanguineous families.

Methods: Homozygosity mapping combined with whole-exome sequencing of consanguineous families was performed. Mutation consequences were determined by studying the structural change of the protein and by the RNA analysis of patients' fibroblasts.

Results: We identified a biallelic mutation in a gene coding for a Pol III-specific subunit, (c.121C>T/p.Arg41Trp), that cosegregates with the disease in 2 unrelated patients. Patients expressed neurologic and extraneurologic signs found in - and -related leukodystrophies with a peculiar severe digestive dysfunction. The mutation impaired the POLR3K-POLR3B interactions resulting in zebrafish in abnormal gut development. Functional studies in the 2 patients' fibroblasts revealed a severe decrease (60%-80%) in the expression of 5S and 7S ribosomal RNAs in comparison with control.

Conclusions: These analyses underlined the key role of ribosomal RNA regulation in the development and maintenance of the white matter and the cerebellum as already reported for diseases related to genes involved in transfer RNA or translation initiation factors.
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http://dx.doi.org/10.1212/NXG.0000000000000289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283457PMC
December 2018

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

promoter status and gene copy number gains: effect on expression and association with prognosis in breast cancer.

Oncotarget 2017 Sep 24;8(44):77540-77551. Epub 2017 Aug 24.

Université Clermont Auvergne, INSERM, U1240 Imagerie Moléculaire et Stratégies Théranostiques, F-63000 Clermont Ferrand, France.

Upregulation of the telomerase reverse transcriptase () gene in human cancers leads to telomerase activation, which contributes to the growth advantage and survival of tumor cells. Molecular mechanisms of upregulation are complex, tumor-specific and can be clinically relevant. To investigate these mechanisms in breast cancer, we sequenced the promoter, evaluated copy number changes and assessed the expression of the oncogene, a known transcriptional regulator, in two breast cancer cohorts comprising a total of 122 patients. No activating promoter mutations were found, suggesting that this mutational mechanism is not likely to be involved in upregulation in breast cancer. The T349C promoter polymorphism found in up to 50% of cases was not correlated with expression, but T349C carriers had significantly shorter disease-free survival. gains (15-25% of cases) were strongly correlated with increased mRNA expression and worse patient prognosis in terms of disease-free and overall survival. Particularly aggressive breast cancers were characterized by an association of gains with overexpression. These results evidence a significant effect of gene copy number gain on the level of expression and provide a new insight into the clinical significance of and upregulation in breast cancer.
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http://dx.doi.org/10.18632/oncotarget.20560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5652798PMC
September 2017

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

Determination of arylsulfatase A pseudodeficiency allele and haplotype frequency in the Tunisian population.

Neurol Sci 2016 Mar 14;37(3):403-9. Epub 2015 Nov 14.

Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Belvédère, Tunisia.

Arylsulfatase A (ASA) is a lysosomal enzyme involved in the catabolism of cerebroside sulfate. ASA deficiency is associated with metachromatic leukodystrophy (MLD). Low ASA activities have also been reported in a more common condition with no apparent clinical consequences termed ASA pseudo-deficiency (ASA-PD) which is associated with two linked mutations in the ASA gene (c.1049A>G and c.*96A>G). This study aimed to investigate the frequency of the two ASA-PD variants and their linkage disequilibrium (LD) among Tunisians. ASA-PD variants were detected in 129 healthy Tunisians and their frequencies were compared to those described worldwide. The frequency of the PD allele was estimated at 17.4% for the overall sample, with c.1049A>G and c.*96A>G frequencies of 25.6 and 17.4%, respectively. This study also revealed a high LD between the two ASA-PD variants (r(2) = 0.61). Inter-population analysis revealed similarities in the ASA-PD genetic structure between Tunisians and populations from Middle East with c.*96A>G frequencies being the highest in the world. A significant North vs. South genetic differentiation in the ASA-PD frequency was also observed in Tunisian population who seems genetically intermediate between Africans, Middle-Easterners and Europeans. This is the first report on the allele frequency of the ASA-PD in North Africa, revealing a relatively high frequency of the PD allele among Tunisians. This study gives also evidence on the importance of discriminating ASA-PD allele from pathological mutations causing MLD and supporting enzymatic activity testing with both sulfatiduria determination and genetic testing in the differential diagnosis of MLD in the Tunisian population.
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http://dx.doi.org/10.1007/s10072-015-2417-5DOI Listing
March 2016

Insertion of an extra copy of Xq22.2 into 1p36 results in functional duplication of the PLP1 gene in a girl with classical Pelizaeus-Merzbacher disease.

BMC Med Genet 2015 Sep 2;16:77. Epub 2015 Sep 2.

Inserm U1141, Université Paris Diderot, Sorbonne Paris Cité, Hôpital Robert Debré, Paris, France.

Background: Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disorder characterized by nystagmus, hypotonia, ataxia, progressive spasticity, and cognitive decline. PMD classically results from a duplication of a genomic segment encompassing the entire PLP1 gene. Since the PLP1 gene is located in Xq22, PMD affects mostly boys.

Methods And Results: Here we report the case of a girl with typical PMD. Copy number analysis of the PLP1 locus revealed a duplication of the entire gene and FISH analysis showed that the extra copy of the PLP1 gene was actually inserted in chromosome 1p36. This insertion of an additional copy of PLP1 in an autosome led to a functional duplication irrespective of the X-inactivation pattern. Subsequent overexpression of PLP1 was the cause of the PMD phenotype observed in this girl. Further sequencing of the breakpoint junction revealed a microhomology and thus suggested a replication based mechanism (such as FoSTeS or MMBIR).

Conclusion: This case emphasizes the susceptibility of the PLP1 locus to complex rearrangement likely driven by the Xq22 local genomic architecture. In addition, careful consideration should be given to girls with classical PMD clinical features since they usually experience complex PLP1 genomic alteration with a distinct risk of inheritance.
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http://dx.doi.org/10.1186/s12881-015-0226-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557901PMC
September 2015

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

Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides insights into duplication mechanisms and allele-specific expression.

Hum Mutat 2013 Aug 28;34(8):1160-71. Epub 2013 May 28.

Department of Medical Sciences,University of Torino, Torino, Italy.

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.
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http://dx.doi.org/10.1002/humu.22348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714349PMC
August 2013

Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation.

Hum Mutat 2013 Jul 1;34(7):1018-25. Epub 2013 May 1.

INSERM/UMR 1103, CNRS 6293, GReD, Medical school, Clermont-Ferrand, France.

SLC 16A2, the gene for the second member of the solute carrier family 16 (monocarboxylic acid transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone transporter: monocarboxylate transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here, we describe three novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype-phenotype correlation.
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http://dx.doi.org/10.1002/humu.22331DOI Listing
July 2013

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

Relevance of SOX17 variants for hypomyelinating leukodystrophies and congenital anomalies of the kidney and urinary tract (CAKUT).

Ann Hum Genet 2012 May 20;76(3):261-7. Epub 2012 Feb 20.

INSERM, UMR, CNRS, GReD, Medical School, Clermont-Ferrand, France.

The SRY-BOX17 gene (SOX17) encodes a transcription factor playing a key role in different developmental processes including endoderm formation, cardiac myogenesis, kidney/urinary development and differentiation of oligodendrocytes, the brain myelinating cells. In a candidate gene approach, we analyzed the SOX17 gene in hypomyelinating leukodystrophies (HL) characterized by a permanent deficit in the amount of central nervous system myelin. Five genes are involved in the aetiology of HL but 40% of HL remains without known genetic origin (UHL). New sequence variations in SOX17 were identified but all correspond to nonpathogenic variants, suggesting that SOX17 is not involved in UHL phenotype. In one patient, we identified the c.775T>A (p.Tyr259Asn) variation already reported as causative of congenital kidney and urinary tract abnormalities (CAKUT). Nevertheless, since our patient did not present such a phenotype, we propose that this variant may alternatively represent an "at-risk" allele for CAKUT rather than a causative allele. This observation strengthens the idea that caution must be taken when linking genetic variation to disease, especially in discrete phenotypes such as CAKUT.
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http://dx.doi.org/10.1111/j.1469-1809.2011.00702.xDOI Listing
May 2012

Sjögren-Larsson syndrome: novel mutations in the ALDH3A2 gene in a French cohort.

J Neurol Sci 2012 Jan 26;312(1-2):123-6. Epub 2011 Aug 26.

Génétique, Reproduction et Développement, Unité Mixte de Recherche 931 (Institut National de la Santé et de la Recherche médicale), Faculté de médecine, Clermont-Ferrand, France.

Sjogren-Larsson syndrome (SLS) is a rare autosomal recessive disorder characterized by ichthyosis, spastic di- or tetraplegia and mental retardation due a defect of the fatty aldehyde dehydrogenase (FALDH), related to mutations in the ALDH3A2 gene. In this study, we screened a French cohort of patients with Sjögren-Larsson syndrome (SLS) for mutations in the ALDH3A2 gene. The five unrelated patients with typical SLS all present mutations in this gene. Three novel mutations were identified whereas three other ones were previously described. We also realized functional analyses at the mRNA level for two splice site mutations to study their deleterious consequences. Two of the previously described mutations had already been identified in the same region of Europe, suggesting a putative founder effect. We suggest that, (1) when clinical and MR features are present, direct sequencing of the ALDH3A2 gene in SLS is of particular interest without necessity of a skin biopsy for enzymatic assay in order to propose genetic counsel and (2) identification of mutations already described in the same population with putative founder effects may simplify genetic analysis in this context.
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http://dx.doi.org/10.1016/j.jns.2011.08.006DOI Listing
January 2012

Elevated CSF N-acetylaspartylglutamate suggests specific molecular diagnostic abnormalities in patients with white matter diseases.

Biochim Biophys Acta 2010 Nov 13;1802(11):1112-7. Epub 2010 Jul 13.

APHP, Department of Genetics, Hôpital de La Salpêtrière, Paris, France.

Background: In order to identify biomarkers useful for the diagnosis of genetic white matter disorders we compared the metabolic profile of patients with leukodystrophies with a hypomyelinating or a non-hypomyelinating MRI pattern.

Methods: We used a non-a priori method of in vitro ¹H-NMR spectroscopy on CSF samples of 74 patients with leukodystrophies.

Results: We found an elevation of CSF N-acetylaspartylglutamate (NAAG) in patients with Pelizaeus-Merzbacher disease (PMD)-PLP1 gene, Pelizaeus-Merzbacher-like disease-GJC2 gene and Canavan disease-ASPA gene. In the PMD group, NAAG was significantly elevated in the CSF of all patients with PLP1 duplication (19/19) but was strictly normal in 6 out of 7 patients with PLP1 point mutations. Additionally, we previously reported increased CSF NAAG in patients with SLC17A5 mutations.

Conclusions: Elevated CSF NAAG is a biomarker that suggests specific molecular diagnostic abnormalities in patients with white matter diseases. Our findings also point to unique pathological functions of the overexpressed PLP in PMD patients with duplication of this gene.
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http://dx.doi.org/10.1016/j.bbadis.2010.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943030PMC
November 2010

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

Identification of a new Arylsulfatase A (ARSA) gene mutation in Tunisian patients with metachromatic leukodystrophy (MLD).

J Neurol Sci 2009 Dec 21;287(1-2):278-80. Epub 2009 Aug 21.

Child Neurological Diseases Unit, Faculty of Medicine, Tunis, Tunisia.

Metachromatic leukodystrophy (MLD) is an autosomal recessive, lysosomal storage disease caused by a deficiency of the enzyme arylsulfatase A (ARSA). The aim of the present study was to identify the molecular basis of MLD in Tunisian population. Two Tunisian patients with late infantile MLD were studied. Both patients were homozygous for a new missense mutation that causes a substitution of Trp in Gly p.W124G. This is the first mutation of ARSA gene described in Tunisian population.
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http://dx.doi.org/10.1016/j.jns.2009.07.023DOI Listing
December 2009

Novel missense mutation in ALS2 gene results in infantile ascending hereditary spastic paralysis.

Ann Neurol 2006 Jun;59(6):976-80

Institut National de la Sante et de la Recherche Médicale U384 and Human Genetics Department, CHU, Clermont-Ferrand, France.

Objective: Recessive mutations in ALS2 (juvenile amyotrophic lateral sclerosis) are causative for early-onset upper motor neuron diseases, including infantile ascending hereditary spastic paralysis (IAHSP). The goal of this study is to identify novel disease-causing ALS2 mutations.

Methods: Mutations in ALS2 were screened by direct sequencing of complementary DNA obtained from patients' lymphoblasts.

Results: We report a novel ALS2 missense mutation in patients affected by IAHSP. This homozygous G669A mutation in exon 4 is predicted to result in a tyrosine substitution at cysteine 156 of the RCC1 (regulator of chromatin condensation)-like domain, encoding a putative guanine exchange factor for Ran guanosine triphosphatase, leading to a loss of ALS2 function due to instability of mutant protein.

Interpretation: These results highlight the important role of the RCC1-like domain in ALS2 stability and function that is essential for upper motor neuron maintenance.
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http://dx.doi.org/10.1002/ana.20879DOI Listing
June 2006

Vacuolating megalencephalic leukoencephalopathy with subcortical cysts: functional studies of novel variants in MLC1.

Hum Mutat 2006 Mar;27(3):292

Molecular Medicine, IRCCS-Bambino Gesù Children's Hospital, Rome, Italy.

Nine new unrelated patients presenting vacuolating myelinopathy with subcortical cysts were identified and analyzed for variations in the MLC1 gene. We detected 12 mutations (p.Leu37fs, p.Met80Val, p.Leu83Phe, p.Pro92Ser, p.Ser93Leu, p.Ile108fs, p.Gly130Arg, p.Cys171fs, p.Glu202Lys, p.Ser269Tyr, p.Ala275Asn, and p.Leu310_311insLeu) of which nine were novel. In one patient we did not detect mutations. Using a heterologous system, three new missense variants (p.Glu202Lys, p.Ser269Tyr, and p.Ala275Asn) and a single leucine insertion (p.Leu310insLeu)--lying in a stretch of seven leucines--were functionally assayed by determining total protein levels and mutant protein expression at the plasma membrane. No correlation was observed between mutation, clinical features, and plasma membrane expression of mutant protein.
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http://dx.doi.org/10.1002/humu.9407DOI Listing
March 2006

Unstable mutants in the peripheral endosomal membrane component ALS2 cause early-onset motor neuron disease.

Proc Natl Acad Sci U S A 2003 Dec 10;100(26):16041-6. Epub 2003 Dec 10.

Ludwig Institute for Cancer Research and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.

Mutations in ALS2, carrying three putative guanine exchange factor (GEF) domains, are causative for a juvenile, autosomal recessive form of amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, and infantile-ascending hereditary spastic paralysis. Endogenous ALS2 is shown here to be enriched in nervous tissue and to be peripherally bound to the cytoplasmic face of endosomal membranes, an association that requires the amino-terminal "RCC1 (regulator of chromatin condensation)-like" GEF domain. Disease-causing mutants and a naturally truncated isoform of ALS2 are shown to be rapidly degraded when expressed in cultured human cells, including lymphocytes derived from patients with ALS2 mutations. Thus, mutations in the ALS2 gene linked to early-onset motor neuron disease uniformly produce loss of activity through decreased protein stability of this endosomal GEF.
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http://dx.doi.org/10.1073/pnas.2635267100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC307689PMC
December 2003