Publications by authors named "Valérie Malan"

73 Publications

Hydrothorax in fetal cases of Opitz G/BBB diagnosis: Extending the phenotype?

Clin Genet 2020 Dec 14;98(6):620-621. Epub 2020 Sep 14.

Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Assistance Publique - Hôpitaux de Paris, Paris, France.

We report two fetal cases carrying a de novo MID1 mutation and presenting with severe hydrothorax, suggesting the expansion of the phenotype of Opitz GBBB syndrome.
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http://dx.doi.org/10.1111/cge.13840DOI Listing
December 2020

Genome sequencing in cytogenetics: Comparison of short-read and linked-read approaches for germline structural variant detection and characterization.

Mol Genet Genomic Med 2020 03 27;8(3):e1114. Epub 2020 Jan 27.

HCL, Service de Génétique, BRON Cedex, France.

Background: Structural variants (SVs) include copy number variants (CNVs) and apparently balanced chromosomal rearrangements (ABCRs). Genome sequencing (GS) enables SV detection at base-pair resolution, but the use of short-read sequencing is limited by repetitive sequences, and long-read approaches are not yet validated for diagnosis. Recently, 10X Genomics proposed Chromium, a technology providing linked-reads to reconstruct long DNA fragments and which could represent a good alternative. No study has compared short-read to linked-read technologies to detect SVs in a constitutional diagnostic setting yet. The aim of this work was to determine whether the 10X Genomics technology enables better detection and comprehension of SVs than short-read WGS.

Methods: We included 13 patients carrying various SVs. Whole genome analyses were performed using paired-end HiSeq X sequencing with (linked-read strategy) or without (short-read strategy) Chromium library preparation. Two different bioinformatic pipelines were used: Variants are called using BreakDancer for short-read strategy and LongRanger for long-read strategy. Variant interpretations were first blinded.

Results: The short-read strategy allowed diagnosis of known SV in 10/13 patients. After unblinding, the linked-read strategy identified 10/13 SVs, including one (patient 7) missed by the short-read strategy.

Conclusion: In conclusion, regarding the results of this study, 10X Genomics solution did not improve the detection and characterization of SV.
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http://dx.doi.org/10.1002/mgg3.1114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057128PMC
March 2020

[Twenty years of on-site clinical genetics consultations for people with ASD].

Med Sci (Paris) 2019 Nov 17;35(11):843-851. Epub 2019 Dec 17.

Fédération de Génétique Médicale et Institute Imagine, UMR Inserm 1163, Université Paris-Descartes, Hôpital Necker Enfants-Malades et Fondation Elan Retrouvé, 149 rue de Sèvres, 75015 Paris, France.

Despite advances in neurogenetics of autism spectrum disorders (ASD), many patients fail to be systematically investigated, owing to preconceived ideas, limited access to genetics facilities and inadequacy of consultations to children with behavioural problems. To improve access to services, we reversed the paradigm and delivered on-site genetics consultations to ASD children of Greater Paris day care hospitals and specialized institutions. Since 1998, an ambulatory medical genetics team has been in operation, offering on-site consultations and services to patients and relatives in their usual environment. Because the mobile medical genetics unit operates under the umbrella of a university hospital, service laboratories were shared, including molecular cytogenetics and next generation sequencing (NGS). For the past 20 years, 502 patients from 26 institutions benefited from on-site consultations and genetics services in their usual environment. Less than 1 % of parents declined the offer. Previously undiagnosed genetics conditions were recognized in 71 ASD children, including pathogenic CNV variants (34/388 : 8.8 ; de novo : 19, inherited : 4), Fragile X (4/312 : 1.3 %) and deleterious variants in disease causing genes (33/141 ; 23.4 % : de novo : 23 ; inherited : 10, including 5 X-linked and 5 compound heterozygote mutations). Brain MRI were possible in 347 patients and 42 % were considered abnormal (146/347). All diagnosed patients presented atypical/syndromic ASD with moderate to severe intellectual disability. Thanks to such flexible organisation, a considerable number of missed consultations were tracked and families first benefited from medical genetics services. Owing to constraints imposed by behavioural problems in ASD, we suggest considering on-site genetics services to implement standard of care and counteract the loss of chance to patients and relatives.
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http://dx.doi.org/10.1051/medsci/2019170DOI Listing
November 2019

Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.

Mol Autism 2019 7;10:33. Epub 2019 Aug 7.

Fondation Elan Retrouvé, Paris, France.

Background: Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated.

Methods: To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders.

Results: Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone ( value 0.009). No inborn errors of metabolism were detected with the metabolic screening.

Conclusion: Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability.
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http://dx.doi.org/10.1186/s13229-019-0284-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686526PMC
June 2020

SOX3 duplication: A genetic cause to investigate in fetuses with neural tube defects.

Prenat Diagn 2019 10 9;39(11):1026-1034. Epub 2019 Aug 9.

Department of Histology Embryology and Cytogenetics, Necker-Enfants Malades Hospital, APHP, Paris, France.

Objective: Neural tube defects (NTDs) are one of the most common congenital anomalies caused by a complex interaction of many genetic and environmental factors. In about 10% of cases, NTDs are associated with genetic syndromes or chromosomal anomalies. Among these, SOX3 duplication has been reported in some isolated cases. The phenotype associated with this microduplication is variable and includes myelomeningocele (MMC) in both sexes as well as hypopituitarism and cognitive impairment in males. In order to determine the prevalence of this anomaly in fetuses with MMC, a retrospective cohort of fetuses with MMC was analyzed by quantitative PCR (qPCR) targeting SOX3 locus.

Methods: The detection of an SOX3 microduplication by chromosomal microarray analysis (CMA) in two female fetuses with MMC prompted us to analyze retrospectively by qPCR this gene in a cohort of 53 fetuses with MMC.

Results: In addition to our two initial cases, one fetus harboring an Xq27.1q28 duplication that encompasses the SOX3 gene was detected.

Conclusion: Our data demonstrate that SOX3 duplication is a genomic imbalance involved in the pathogenesis of NTDs. In addition, our survey highlights the importance of CMA testing in fetuses with NTDs to enable genetic counseling upstream of any considerations of in utero fetal surgery.
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http://dx.doi.org/10.1002/pd.5523DOI Listing
October 2019

Prenatal findings in 1p36 deletion syndrome: New cases and a literature review.

Prenat Diagn 2019 09 5;39(10):871-882. Epub 2019 Jul 5.

Fédération de Génétique, Centre Hospitalier Intercommunal Poissy-St-Germain-en-Laye, Poissy, France.

Objective/method: 1p36 deletion syndrome is considered to be the most common deletion after 22q11.2 deletion. It is characterized by specific facial features, developmental delay, and organ defects. The primary objective of the present multicenter study was to survey all the cases of 1p36 deletion diagnosed prenatally by French cytogenetics laboratories using a chromosomal microarray. We then compared these new cases with the literature data.

Results: Ten new cases were reported. On average, the 1p36 deletion was diagnosed at 19 weeks of gestation. The size of the deletion ranged from 1.6 to 16 Mb. The 1p36 deletion was the only chromosomal abnormality in eight cases and was associated with a complex chromosome 1 rearrangement in the two remaining cases. The invasive diagnostic procedure had always been prompted by abnormal ultrasound findings: elevated nuchal translucency, structural brain abnormality, retrognathia, or a cardiac defect. Multiple anomalies were present in all cases.

Discussion: We conclude that 1p36 deletion is not associated with any specific prenatal signs. We suggest that a prenatal observation of ventriculomegaly, congenital heart defect, or facial dysmorphism should prompt the clinician to consider a diagnosis of 1p36 deletion syndrome.
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http://dx.doi.org/10.1002/pd.5498DOI Listing
September 2019

Delineation of MidXq28-duplication syndrome distal to MECP2 and proximal to RAB39B genes.

Clin Genet 2019 09 17;96(3):246-253. Epub 2019 Jun 17.

Medical Genetics Unit, Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo (FG), Italy.

Two distinct genomic disorders have been linked to Xq28-gains, namely Xq28-duplications including MECP2 and Int22h1/Int22h2-mediated duplications involving RAB39B. Here, we describe six unrelated patients, five males and one female, with Xq28-gains distal to MECP2 and proximal to the Int22h1/Int22h2 low copy repeats. Comparison with patients carrying overlapping duplications in the literature defined the MidXq28-duplication syndrome featuring intellectual disability, language impairment, structural brain malformations, microcephaly, seizures and minor craniofacial features. The duplications overlapped for 108 kb including FLNA, RPL10 and GDI1 genes, highly expressed in brain and candidates for the neurologic phenotype.
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http://dx.doi.org/10.1111/cge.13565DOI Listing
September 2019

Women's Attitudes Toward Invasive and Noninvasive Testing When Facing a High Risk of Fetal Down Syndrome.

JAMA Netw Open 2019 03 1;2(3):e191062. Epub 2019 Mar 1.

Department of Obstetrics and Gynecology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France.

Importance: Noninvasive prenatal testing (NIPT) using cell-free DNA in maternal blood is increasingly common compared with invasive testing (IT) in routine antenatal detection of Down syndrome (DS).

Objective: To assess attitudes and decision making in pregnant women facing a risk of fetal DS greater than 1 in 250 as established by combined first trimester screening at 11 to 14 weeks of gestation.

Design, Setting, And Participants: Survey study in which data were collected from pregnant women at high risk of fetal DS participating in a randomized clinical trial. Data were collected from April 8, 2014, to April 7, 2016, in 57 prenatal diagnosis centers in France. Data were analyzed in 2018.

Interventions: Data on attitudes were collected prior to offering randomization between NIPT and IT, whereas data on decision making and test results were collected as part of the clinical trial.

Main Outcome And Measures: The primary outcome related to attitudes. A hierarchical cluster analysis was conducted to identify clusters with contrasting attitudes. Logistic regression analyses were used to identify factors associated with attitudes.

Results: All 2436 consecutive women to whom the study was proposed (mean [SD] age, 36.3 [5.0] years) answered the questionnaire: 515 (21.1%) expressed preference toward IT with complete karyotyping, whereas 1843 (75.7%) favored NIPT with almost certain but limited information. Hierarchical cluster analysis yielded 4 different clusters that mainly differed in attitudes toward risk taking and extent of information seeking. Factors likely associated with attitudes driven by risk aversion were mostly age and religious beliefs (adjusted odds ratio [aOR], 1.03; 95% CI, 1.00-1.05; P = .03 and aOR, 1.62; 95% CI, 1.29-2.04; P < .001, respectively), whereas higher nuchal translucency measurements by ultrasonography were associated with attitudes driven by ambiguity aversion (aOR, 1.67; 95% CI, 1.27-2.20; P < .001). For attitudes involving both risk and ambiguity aversion at different extents, lower education was associated with highly valuing all possibilities of getting information on pregnancy, whereas higher education was associated with highly valuing information on fetal DS as a primary concern (aOR, 0.54; 95% CI, 0.44-0.67; P < .001 and aOR, 1.44; 95% CI, 1.20-1.74; P < .001, respectively). In all, decision making was in line with attitudes.

Conclusions And Relevance: Aversion to risk of fetal loss related to IT and aversion to ambiguity generated by incomplete information from NIPT played a major role in shaping attitudes and decision making. Informed decision making should require pregnant women at high risk of DS to receive extensive information on targeted abnormalities by both tests.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.1062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6450316PMC
March 2019

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.

Service de Génétique, Hospices Civils de Lyon, Bron, 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

Chromosomal microarray analysis in fetuses with an isolated congenital heart defect: A retrospective, nationwide, multicenter study in France.

Prenat Diagn 2019 05 29;39(6):464-470. Epub 2019 Apr 29.

EA7404-GIG, UFR des sciences de la Santé Simone Veil, UVSQ, Montigny le Bretonneux, France.

Objectives: Congenital heart defects (CHDs) may be isolated or associated with other malformations. The use of chromosome microarray (CMA) can increase the genetic diagnostic yield for CHDs by between 4% and 10%. The objective of this study was to evaluate the value of CMA after the prenatal diagnosis of an isolated CHD.

Methods: In a retrospective, nationwide study performed in France, we collected data on all cases of isolated CHD that had been explored using CMAs in 2015.

Results: A total of 239 fetuses were included and 33 copy number variations (CNVs) were reported; 19 were considered to be pathogenic, six were variants of unknown significance, and eight were benign variants. The anomaly detection rate was 10.4% overall but ranged from 0% to 16.7% as a function of the isolated CHD in question. The known CNVs were 22q11.21 deletions (n = 10), 22q11.21 duplications (n = 2), 8p23 deletions (n = 2), an Alagille syndrome (n = 1), and a Kleefstra syndrome (n = 1).

Conclusion: The additional diagnostic yield was clinically significant (3.1%), even when anomalies in the 22q11.21 region were not taken into account. Hence, patients with a suspected isolated CHD and a normal karyotype must be screened for chromosome anomalies other than 22q11.21 duplications and deletions.
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http://dx.doi.org/10.1002/pd.5449DOI Listing
May 2019

Author Correction: 22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype.

Transl Psychiatry 2019 02 28;9(1):101. Epub 2019 Feb 28.

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.

Since the online publication of the above article, the authors have noted errors with the author list. The author names were listed as '(last name)(first name)' instead of '(first name)(last name)'.
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http://dx.doi.org/10.1038/s41398-019-0435-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6393414PMC
February 2019

SMCHD1 is involved in de novo methylation of the DUX4-encoding D4Z4 macrosatellite.

Nucleic Acids Res 2019 04;47(6):2822-2839

Aix Marseille Univ, INSERM MMG, Nerve and Muscle Department, Marseille, France.

The DNA methylation epigenetic signature is a key determinant during development. Rules governing its establishment and maintenance remain elusive especially at repetitive sequences, which account for the majority of methylated CGs. DNA methylation is altered in a number of diseases including those linked to mutations in factors that modify chromatin. Among them, SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain Containing 1) has been of major interest following identification of germline mutations in Facio-Scapulo-Humeral Dystrophy (FSHD) and in an unrelated developmental disorder, Bosma Arhinia Microphthalmia Syndrome (BAMS). By investigating why germline SMCHD1 mutations lead to these two different diseases, we uncovered a role for this factor in de novo methylation at the pluripotent stage. SMCHD1 is required for the dynamic methylation of the D4Z4 macrosatellite upon reprogramming but seems dispensable for methylation maintenance. We find that FSHD and BAMS patient's cells carrying SMCHD1 mutations are both permissive for DUX4 expression, a transcription factor whose regulation has been proposed as the main trigger for FSHD. These findings open new questions as to what is the true aetiology for FSHD, the epigenetic events associated with the disease thus calling the current model into question and opening new perspectives for understanding repetitive DNA sequences regulation.
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http://dx.doi.org/10.1093/nar/gkz005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451109PMC
April 2019

Distal duplication of chromosome 16q22.1q23.1 in a Vietnamese patient with midface hypoplasia and intellectual disability.

Am J Med Genet A 2018 09 4;176(9):1981-1984. Epub 2018 Sep 4.

Laboratory of Molecular and Pathophysiological Bases of Cognitive Disorders, Imagine Institute, Paris, France.

The clinical presentation of distal duplications of the long arm of chromosome (chr) 16 is currently not well described. Only one case of microduplication of chr16q22.1 and another involving the chr16q22.1q23.1 region have been reported so far. Here, using array comparative genomic hybridization, we identified a second case of chr16q22.1q23.1 duplication in a Vietnamese boy, who shares significant clinical phenotype with the previously described case. Aside from developmental delay, intellectual disability and midface hypoplasia, our patient also displays a forked tongue, visual impairment and external ptosis. Our report further expands the clinical spectrum associated with duplication of this region.
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http://dx.doi.org/10.1002/ajmg.a.40375DOI Listing
September 2018

Effect of Cell-Free DNA Screening vs Direct Invasive Diagnosis on Miscarriage Rates in Women With Pregnancies at High Risk of Trisomy 21: A Randomized Clinical Trial.

JAMA 2018 08;320(6):557-565

Paris Descartes University, Sorbonne Paris Cité, Institut Imagine, Paris, France.

Importance: Cell-free DNA (cfDNA) tests are increasingly being offered to women in the first trimester of pregnancies at a high risk of trisomy 21 to decrease the number of required invasive fetal karyotyping procedures and their associated miscarriages. The effect of this strategy has not been evaluated.

Objective: To compare the rates of miscarriage following invasive procedures only in the case of positive cfDNA test results vs immediate invasive testing procedures (amniocentesis or chorionic villus sampling) in women with pregnancies at high risk of trisomy 21 as identified by first-trimester combined screening.

Design, Setting, And Participants: Randomized clinical trial conducted from April 8, 2014, to April 7, 2016, in 57 centers in France among 2111 women with pregnancies with a risk of trisomy 21 between 1 in 5 and 1 in 250 following combined first-trimester screening.

Interventions: Patients were randomized to receive either cfDNA testing followed by invasive testing procedures only when cfDNA tests results were positive (n = 1034) or to receive immediate invasive testing procedures (n = 1017). The cfDNA testing was performed using an in-house validated method based on next-generation sequencing.

Main Outcomes And Measures: The primary outcome was number of miscarriages before 24 weeks' gestation. Secondary outcomes included cfDNA testing detection rate for trisomy 21. The primary outcome underwent 1-sided testing; secondary outcomes underwent 2-sided testing.

Results: Among 2051 women who were randomized and analyzed (mean age, 36.3 [SD, 5.0] years), 1997 (97.4%) completed the trial. The miscarriage rate was not significantly different between groups at 8 (0.8%) vs 8 (0.8%), for a risk difference of -0.03% (1-sided 95% CI, -0.68% to ∞; P = .47). The cfDNA detection rate for trisomy 21 was 100% (95% CI, 87.2%-100%).

Conclusions And Relevance: Among women with pregnancies at high risk of trisomy 21, offering cfDNA screening, followed by invasive testing if cfDNA test results were positive, compared with invasive testing procedures alone, did not result in a significant reduction in miscarriage before 24 weeks. The study may have been underpowered to detect clinically important differences in miscarriage rates.

Trial Registration: ClinicalTrials.gov Identifier: NCT02127515.
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http://dx.doi.org/10.1001/jama.2018.9396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583003PMC
August 2018

22q13 deletion syndrome: communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype.

Transl Psychiatry 2018 08 8;8(1):146. Epub 2018 Aug 8.

UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.

Phelan-McDermid syndrome is related to terminal 22q13 deletions of various sizes affecting the SHANK3 gene. In this neurodevelopmental disorder, behavioural symptoms of autism spectrum disorder (ASD) are reported in half of cases. Extensive clinical and neurophysiological characterization is lacking to understand the genotype-phenotype correlation. Eighteen patients (8 males, mean age 12.7 years, SD = 9.2) with known 22q13 deletions were fully explored with determination of deletion size, along with behavioural, language and cognitive standardized assessments. Neurophysiological indices previously reported to be altered in autism (i.e., eye tracking in a social/non-social task and auditory evoked potential mismatch) were also recorded. Thirty-nine percent met ASD clinical criteria, exceeding cut-off scores on both ADI-R (Autism Diagnosis Interview based on the period spanning 4-5 years of age) and ADOS-2 (Autism Diagnosis Observation Schedule for the current period). All patients had intellectual disability and language disability. Deletion size was significantly correlated with expressive and receptive language disability but not with ASD standardized assessment scores. Developmental Quotient tended to be lower in patients with the largest deletions. Using Eye Tracking, smaller pupil size, which is typically described in ASD, was not observed in these patients. Furthermore, atypical shortened latency of mismatch negativity response previously reported in ASD was not observed, whereas the N250 pattern, related to language, was affected. Language disability combined with cognitive deficits may lead to autistic behavioural symptoms, but with different neurophysiological networks compared to typical autism. These results highlight the indication for early speech therapy rather than intensive autism programme to treat these patients.
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http://dx.doi.org/10.1038/s41398-018-0212-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082846PMC
August 2018

Further delineation of the duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features.

Authors:
Marguerite Miguet Laurence Faivre Jeanne Amiel Mathilde Nizon Renaud Touraine Fabienne Prieur Laurent Pasquier Mathilde Lefebvre Julien Thevenon Christèle Dubourg Sophie Julia Catherine Sarret Ganaëlle Remerand Christine Francannet Fanny Laffargue Odile Boespflug-Tanguy Albert David Bertrand Isidor Jacqueline Vigneron Bruno Leheup Laetitia Lambert Christophe Philippe Mylène Béri-Dexheimer Jean-Marie Cuisset Joris Andrieux Ghislaine Plessis Annick Toutain Laurent Guibaud Valérie Cormier-Daire Marlene Rio Jean-Paul Bonnefont Bernard Echenne Hubert Journel Lydie Burglen Sandrine Chantot-Bastaraud Thierry Bienvenu Clarisse Baumann Laurence Perrin Séverine Drunat Pierre-Simon Jouk Klaus Dieterich Françoise Devillard Didier Lacombe Nicole Philip Sabine Sigaudy Anne Moncla Chantal Missirian Catherine Badens Nathalie Perreton Christel Thauvin-Robinet Réseau AChro-Puce Jean-Michel Pedespan Caroline Rooryck Cyril Goizet Catherine Vincent-Delorme Bénédicte Duban-Bedu Nadia Bahi-Buisson Alexandra Afenjar Kim Maincent Delphine Héron Jean-Luc Alessandri Dominique Martin-Coignard Gaëtan Lesca Massimiliano Rossi Martine Raynaud Patrick Callier Anne-Laure Mosca-Boidron Nathalie Marle Charles Coutton Véronique Satre Cédric Le Caignec Valérie Malan Serge Romana Boris Keren Anne-Claude Tabet Valérie Kremer Sophie Scheidecker Adeline Vigouroux Marilyn Lackmy-Port-Lis Damien Sanlaville Marianne Till Maryline Carneiro Brigitte Gilbert-Dussardier Marjolaine Willems Hilde Van Esch Vincent Des Portes Salima El Chehadeh

J Med Genet 2018 Jun 4;55(6):359-371. Epub 2018 Apr 4.

Service de génétique médicale, Institut de Génétique Médicale d'Alsace (IGMA), Centre de Référence Maladies Rares "Anomalies du développement et syndromes malformatifs", Centre de Référence Maladies Rares "Des déficiences intellectuelles de causes rares", Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.

The Xq28 duplication involving the gene ( duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life.
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http://dx.doi.org/10.1136/jmedgenet-2017-104956DOI Listing
June 2018

Whole-exome sequence analysis highlights the role of unmasked recessive mutations in copy number variants with incomplete penetrance.

Eur J Hum Genet 2018 06 26;26(6):912-918. Epub 2018 Feb 26.

Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants-Malades, Université Paris Descartes, 149, rue de Sèvres, 75015, Paris, France.

Several hypotheses have been proposed to explain the phenotypic variability between parent and offspring carrying the same genomic imbalance, including unmasking of a recessive variant by a chromosomal deletion. Here, 19 patients with neurodevelopmental disorders harboring a rare deletion inherited from a healthy parent were investigated by whole-exome sequencing to search for SNV on the contralateral segment. This strategy allowed us to identify a candidate variant in two patients in the NUP214 and NCOR1 genes. This result demonstrates that the analysis of the genes included in non-deleted contralateral allele is a key point in the etiological investigation of patients harboring a deletion inherited from a parent. Finally, this strategy is also an interesting approach to identify new recessive intellectual disability genes.
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http://dx.doi.org/10.1038/s41431-018-0124-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974246PMC
June 2018

Efficiency of prenatal diagnosis in Pierre Robin sequence.

Prenat Diagn 2017 Nov 26;37(11):1169-1175. Epub 2017 Oct 26.

Paris Descartes-Sorbonne Paris Cité University, Paris, France.

Objectives: To analyze the efficiency of prenatal diagnosis of Pierre Robin sequence (PRS) regarding the final specific diagnosis and to determine whether infants have more severe respiratory disorders with than without prenatally suspected PRS.

Methods: Review of the outcome of all prenatal cases of suspected PRS managed in our prenatal diagnosis center during the last 15 years; analysis of the consistency between prenatal and postnatal diagnoses in 2 groups of women with and without a family history of PRS; comparison of the grades of disease severity for infants with and without prenatally suspected PRS.

Results: Fifty-nine files were studied. Prenatal and postnatal consistencies of a specific diagnosis of PRS were 100% for women with a family history of PRS and with prenatally suspected nonisolated PRS. It was 78.6% for those with prenatally suspected isolated PRS. We describe 13 terminations of pregnancy. The 41 children living beyond 18 months seem to have more functionally severe phenotypes than the 227 children without prenatally suspected PRS.

Conclusion: Prenatal diagnosis of isolated PRS is a challenge as other features can be missed. Use of prenatal chromosomal microarray can improve the accuracy of diagnosis. In all cases, adequate neonatal care should be offered.
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http://dx.doi.org/10.1002/pd.5162DOI Listing
November 2017

Fetal Cerebral Ventricular Dilatation: Etiopathogenic Study of 130 Observations.

Birth Defects Res 2017 Nov 31;109(19):1586-1595. Epub 2017 Jul 31.

Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, APHP, Paris, France.

Background: Fetal cerebral ventricular dilatation (CVD) is a common abnormal prenatal finding that often predicts a poor prognosis. The etiology involves both genetic and nongenetic factors with diverse pathogenic mechanisms. We describe the neuropathological features of CVD in a large cohort of fetuses. The goals are to determine the physiopathological mechanisms and etiologies.

Methods: We retrospectively analyzed a series of 130 fetuses examined at the Necker University Hospital following termination of pregnancy between January 2000 and December 2014. Chiari II and Dandy-Walker malformations were excluded from our study population. Karyotype and/or array comparative genomic hybridization were performed in all cases. Targeted Sanger sequencing or next generation sequencing were carried out in 34 and 5 cases, respectively.

Results: We distinguished four groups of pathological entities: (1) midbrain/hindbrain patterning defects (54 cases, 42%), mainly related to aqueduct of Sylvius anomalies (atresia or stenosis); (2) cerebral cytoarchitectonic disorders (16 cases, 12%), essentially resulting from arachnoidal neuroglial ectopia; (3) hemorrhagic and perfusion failure (42 cases, 32%); and (4) nonspecific CVD (18 cases, 14%), without apparent obstruction, cortical malformation, or clastic injury. Although the pathogenic mechanisms of CVD were identified in 86% of cases, the causes, both acquired and genetic, were recognized in 21% of cases only.

Conclusion: The neuropathological analysis is a powerful tool in the diagnosis of the fetal CVD pathogenic mechanisms and to identify homogeneous groups. The paucity of molecular diagnosis, notably in the major groups of midbrain/hindbrain patterning defects and hemorrhagic and perfusion failure, highlights the needs of future research to improve our current knowledge on CVD causes. Birth Defects Research 109:1586-1595, 2017. © 2017 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/bdr2.1093DOI Listing
November 2017

Targeted Exome Sequencing Identifies as Involved in Monogenic Congenital Anomalies of the Kidney and Urinary Tract.

J Am Soc Nephrol 2017 Oct 31;28(10):2901-2914. Epub 2017 May 31.

Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1163, Laboratory of Hereditary Kidney Diseases,

Congenital anomalies of the kidney and urinary tract (CAKUT) occur in three to six of 1000 live births, represent about 20% of the prenatally detected anomalies, and constitute the main cause of CKD in children. These disorders are phenotypically and genetically heterogeneous. Monogenic causes of CAKUT in humans and mice have been identified. However, despite high-throughput sequencing studies, the cause of the disease remains unknown in most patients, and several studies support more complex inheritance and the role of environmental factors and/or epigenetics in the pathophysiology of CAKUT. Here, we report the targeted exome sequencing of 330 genes, including genes known to be involved in CAKUT and candidate genes, in a cohort of 204 unrelated patients with CAKUT; 45% of the patients were severe fetal cases. We identified pathogenic mutations in 36 of 204 (17.6%) patients. These mutations included five heterozygous loss of function mutations/deletions in the PBX homeobox 1 gene (), a gene known to have a crucial role in kidney development. In contrast, the frequency of and variants recently reported as pathogenic in CAKUT did not indicate causality. These findings suggest that is involved in monogenic CAKUT in humans and call into question the role of some gene variants recently reported as pathogenic in CAKUT. Targeted exome sequencing also proved to be an efficient and cost-effective strategy to identify pathogenic mutations and deletions in known CAKUT genes.
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http://dx.doi.org/10.1681/ASN.2017010043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5619971PMC
October 2017

Kaposi sarcoma, oral malformations, mitral dysplasia, and scoliosis associated with 7q34-q36.3 heterozygous terminal deletion.

Am J Med Genet A 2017 Jul 9;173(7):1858-1865. Epub 2017 May 9.

Pediatric Immunology-Hematology-Rheumatology Unit, Necker-Enfants Malades Hospital, Paris, France.

Chromosome 7 germline macrodeletions have been implicated in human congenital malformations and developmental delays. We herein report a novel heterozygous macrodeletion of 7q34-q36.3 in a 16-year-old girl originally from West Indies. Similar to previously reported cases of germline chromosome 7q terminal deletions, our patient has dental malposition, and developmental (growth and intellectual) delay. Novel phenotypic features include endemic Kaposi sarcoma (KS), furrowed tongue, thoracolumbar scoliosis, and mild mitral valve dysplasia. The occurrence of human herpes virus 8-driven KS, in a child otherwise normally resistant to other infectious agents and without any other tumoral lesion, points to a very selective immunodeficiency. While defects in organogenesis have been described with such macrodeletions, this is the first report of immunodeficiency and cancer predisposition.
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http://dx.doi.org/10.1002/ajmg.a.38275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680148PMC
July 2017

Large Duplications Can Be Benign Copy Number Variants: A Case of a 3.6-Mb Xq21.33 Duplication.

Cytogenet Genome Res 2017 9;151(3):115-118. Epub 2017 Mar 9.

Service de Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France.

Segmental aneusomies are usually associated with clinical consequences, but an increasing number of nonpathogenic cytogenetically visible as well as large cryptic chromosomal imbalances have been reported. Here, we report a 3.6-Mb Xq21.33 microduplication detected prenatally on a female fetus which was inherited from a phenotypically normal mother and grandfather. It is assumed that male patients harboring Xq or Xp duplication present with syndromic intellectual disability because of functional disomy of the corresponding genes. Female carriers are generally asymptomatic because of preferential inactivation of the abnormal X. In the present case, the 3.6-Mb-duplicated segment encompasses only 2 genes, DIAPH2 and RPL4A. Since the asymptomatic grandfather carries the duplication, we hypothesize that these genes are not dosage sensitive and/or involved in cognitive function. Our observation further illustrates that large copy number variants can be associated with a normal phenotype, especially where gene density is low. Reporting rare cases of large genomic imbalances without a phenotypic effect can be very helpful, especially for genetic counseling in the prenatal setting.
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http://dx.doi.org/10.1159/000460278DOI Listing
September 2017

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder.

Am J Hum Genet 2017 Feb 26;100(2):352-363. Epub 2017 Jan 26.

Service de Génétique Médicale, CHU de Nantes, 9 quai Moncousu, 44093 Nantes Cedex 1, France. Electronic address:

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.
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http://dx.doi.org/10.1016/j.ajhg.2017.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5294671PMC
February 2017

Microduplication of the ARID1A gene causes intellectual disability with recognizable syndromic features.

Genet Med 2017 06 1;19(6):701-710. Epub 2016 Dec 1.

Université Grenoble-Alpes, Grenoble, France.

Purpose: To determine whether duplication of the ARID1A gene is responsible for a new recognizable syndrome.

Methods: We describe four patients with a 1p36.11 microduplication involving ARID1A as identified by array-comparative genomic hybridization . We performed comparative transcriptomic analysis of patient-derived fibroblasts using RNA sequencing and evaluated the impact of ARID1A duplication on the cell cycle using fluorescence-activated cell sorting. Functional relationships between differentially expressed genes were investigated with ingenuity pathway analysis (IPA).

Results: Combining the genomic data, we defined a small (122 kb), minimally critical region that overlaps the full ARID1A gene. The four patients shared a strikingly similar phenotype that included intellectual disability and microcephaly. Transcriptomic analysis revealed the deregulated expression of several genes previously linked to microcephaly and developmental disorders as well as the involvement of signaling pathways relevant to microcephaly, among which the polo-like kinase (PLK) pathway was especially notable. Cell-cycle analysis of patient-derived fibroblasts showed a significant increase in the proportion of cells in G1 phase at the expense of G2-M cells.

Conclusion: Our study reports a new microduplication syndrome involving the ARID1A gene. This work is the first step in clarifying the pathophysiological mechanism that links changes in the gene dosage of ARID1A with intellectual disability and microcephaly.Genet Med advance online publication 01 December 2016.
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http://dx.doi.org/10.1038/gim.2016.180DOI Listing
June 2017

A French Approach to Test Fetuses with Ultrasound Abnormalities Using a Customized Microarray as First-Tier Genetic Test.

Cytogenet Genome Res 2015 7;147(2-3):103-10. Epub 2016 Jan 7.

Service d'Histologie-Embryologie-Cytogx00E9;nx00E9;tique, Hx00F4;pital Necker-Enfants Malades, AP-HP, Paris, France.

Cytogenetic microarray analysis is now the first-tier genetic test used in a postnatal clinical setting to explore genomic imbalances in individuals with developmental disability and/or birth defects. However, in a prenatal setting, this technique is not widely implemented, largely because the clinical impact of some copy number variants (CNVs) remains difficult to assess. This limitation is especially true in France where termination of pregnancy for medical reasons may be performed at any stage of gestation. During a period of 15 months, we investigated 382 fetuses presenting with ultrasound anomalies, using a customized microarray designed to avoid the detection of CNVs raising challenges for genetic counseling. After excluding common aneuploidies, 20/374 (5.3%) fetuses had a pathogenic CNV, among which 12/374 (3.2%) could have been detected by karyotyping, whereas 8/374 (2.1%) were cryptic. Within these 374 cases, 300 were ongoing pregnancies at the time of array comparative genomic hybridization (aCGH) testing. For these pregnancies, we detected 18/300 (6%) pathogenic CNVs, among which 6/300 (2%) were cryptic. Using this approach, only 2/300 (0.6%) of the detected CNVs raised difficulties for genetic counseling. This study confirms the added value of this strategy in a prenatal clinical setting to minimize ethical issues for genetic counseling while enhancing the detection of genomic imbalances.
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http://dx.doi.org/10.1159/000442904DOI Listing
August 2016

Clinical, genetic and neuropathological findings in a series of 138 fetuses with a corpus callosum malformation.

Birth Defects Res A Clin Mol Teratol 2016 Jan 14;106(1):36-46. Epub 2015 Dec 14.

INSERM U1163, Institut Imagine, Hôpital Necker-Enfants Malades.

Background: Corpus callosum malformation (CCM) is the most frequent brain malformation observed at birth. Because CCM is a highly heterogeneous condition, the prognosis of fetuses diagnosed prenatally remains uncertain, making prenatal counseling difficult.

Methods And Results: We evaluated retrospectively a total of 138 fetuses, 117 with CCM observed on prenatal imaging examination, and 21 after postmortem autopsy. On ultrasound and/or magnetic resonance imaging, CCM was either isolated (N = 40) or associated with other neurological (N = 57) or extra cerebral findings (N = 21/20, respectively).

Results: Most fetuses (N = 132) remained without a diagnosis at the time of pregnancy termination. This emphasizes the need to establish a neuropathological classification and to perform a genomic screening using comparative genomic hybridization. A neuropathological examination performed on 138 cases revealed a spectrum of CCMs, classified as follows: agenesis of corpus callosum (55), CC hypoplasia (30), CC dysmorphism (24), and CCM associated with a malformation of cortical development (29). Of interest, after fetopathological examination, only 16/40 malformations were classified as isolated, highlighting the importance of the autopsy following termination of pregnancy. Among the 138 cases, the underlying etiology was found in 46 cases: diabetes (one case), cytomegalovirus infection (one case), 23 chromosome abnormalities, and 21 mendelian conditions.

Conclusion: In our series of 138 cases of CCM, prenatal and postmortem examinations identified a variety of genetic causes. However, no diagnosis could be established in 67% of cases. The classification based on the underlying neurodevelopmental defects paves the way for further genetic studies and genotype-phenotype correlations.
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http://dx.doi.org/10.1002/bdra.23472DOI Listing
January 2016

Clinical and neuroradiological features of the 9p deletion syndrome.

Childs Nerv Syst 2016 Feb 23;32(2):327-35. Epub 2015 Nov 23.

Department of Pediatric Neurosurgery, Craniofacial Unit, Necker Enfants Malades Hospital, 156 rue de Vaugirard, 75015, Paris, France.

Background: The 9p deletion syndrome is a rare condition, which associates trigonocephaly, facial dysmorphism and developmental delay. The neuroradiological aspects of this syndrome have not yet been described. The purpose of this article is to identify the clinical and neuroradiological features, that should be recognized by all specialists treating these children, for a proper and early diagnosis.

Methods: Among patients with trigonocephaly treated at our institution, we retrospectively analyzed the clinical and neuroradiological aspects of children with genetically confirmed 9p deletion syndrome.

Results: 6 patients were identified. Beside trigonocephaly, the most frequent clinical findings were small ears, long philtrum, upslanting palpebral fissures, flat nasal bridge and variable psycho-motor delay. Hypertelorism was present in 4 of 6 patient, which is opposite to the hypotelorism typical of non-syndromic trigonocephaly. Among neuroradiological findings, large, anteriorly rotated sylvian cisterns and altered shape of the septum pellucidum were found in all patients, as well as the compression of the frontal cortex due to the metopic synostosis (MS). A thin or dysmorphic corpus callosum and a diffuse white matter hypoplasia were present in more than half of the cases. Futhermore we compared these MRI findings with those of a control group of 30 non-syndromic trigonocephalies.

Conclusions: Some recurrent neuroradiological alterations can be found in 9p deletion syndrome. The presence of these signs on MRI of a trigonocephalic patient should raise the suspicion of an underlying chromosomal alteration, such as the 9p deletion syndrome and prompt genetic investigations.
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http://dx.doi.org/10.1007/s00381-015-2957-2DOI Listing
February 2016

Nonrecurrent 17p11.2p12 Rearrangement Events that Result in Two Concomitant Genomic Disorders: The PMP22-RAI1 Contiguous Gene Duplication Syndrome.

Am J Hum Genet 2015 Nov;97(5):691-707

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

The genomic duplication associated with Potocki-Lupski syndrome (PTLS) maps in close proximity to the duplication associated with Charcot-Marie-Tooth disease type 1A (CMT1A). PTLS is characterized by hypotonia, failure to thrive, reduced body weight, intellectual disability, and autistic features. CMT1A is a common autosomal dominant distal symmetric peripheral polyneuropathy. The key dosage-sensitive genes RAI1 and PMP22 are respectively associated with PTLS and CMT1A. Recurrent duplications accounting for the majority of subjects with these conditions are mediated by nonallelic homologous recombination between distinct low-copy repeat (LCR) substrates. The LCRs flanking a contiguous genomic interval encompassing both RAI1 and PMP22 do not share extensive homology; thus, duplications encompassing both loci are rare and potentially generated by a different mutational mechanism. We characterized genomic rearrangements that simultaneously duplicate PMP22 and RAI1, including nine potential complex genomic rearrangements, in 23 subjects by high-resolution array comparative genomic hybridization and breakpoint junction sequencing. Insertions and microhomologies were found at the breakpoint junctions, suggesting potential replicative mechanisms for rearrangement formation. At the breakpoint junctions of these nonrecurrent rearrangements, enrichment of repetitive DNA sequences was observed, indicating that they might predispose to genomic instability and rearrangement. Clinical evaluation revealed blended PTLS and CMT1A phenotypes with a potential earlier onset of neuropathy. Moreover, additional clinical findings might be observed due to the extra duplicated material included in the rearrangements. Our genomic analysis suggests replicative mechanisms as a predominant mechanism underlying PMP22-RAI1 contiguous gene duplications and provides further evidence supporting the role of complex genomic architecture in genomic instability.
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http://dx.doi.org/10.1016/j.ajhg.2015.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667131PMC
November 2015