Publications by authors named "Brigitte Gilbert-Dussardier"

81 Publications

Severe Phenotype in Patients with Large Deletions of .

Cancers (Basel) 2021 Jun 13;13(12). Epub 2021 Jun 13.

Lille University, Inserm, CHU Lille, U1172 - LilNCog - Lille Neuroscience & Cognition, F-59000 Lille, France.

Complete deletion of the gene is identified in 5-10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. -deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed an NF1 reference population. A deletion of the gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of -deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described "classic" NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the -deleted group. We described the largest -deleted cohort to date and clarified the more severe phenotype observed in these patients.
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http://dx.doi.org/10.3390/cancers13122963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231977PMC
June 2021

Heterozygous HMGB1 loss-of-function variants are associated with developmental delay and microcephaly.

Clin Genet 2021 10 28;100(4):386-395. Epub 2021 Jun 28.

Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA.

13q12.3 microdeletion syndrome is a rare cause of syndromic intellectual disability. Identification and genetic characterization of patients with 13q12.3 microdeletion syndrome continues to expand the phenotypic spectrum associated with it. Previous studies identified four genes within the approximately 300 Kb minimal critical region including two candidate protein coding genes: KATNAL1 and HMGB1. To date, no patients carrying a sequence-level variant or a single gene deletion in HMGB1 or KATNAL1 have been described. Here we report six patients with loss-of-function variants involving HMGB1 and who had phenotypic features similar to the previously described 13q12.3 microdeletion syndrome cases. Common features included developmental delay, language delay, microcephaly, obesity and dysmorphic features. In silico analyses suggest that HMGB1 is likely to be intolerant to loss-of-function, and previous in vitro data are in line with the role of HMGB1 in neurodevelopment. These results strongly suggest that haploinsufficiency of the HMGB1 gene may play a critical role in the pathogenesis of the 13q12.3 microdeletion syndrome.
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http://dx.doi.org/10.1111/cge.14015DOI Listing
October 2021

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.

Am J Hum Genet 2021 05 23;108(5):951-961. Epub 2021 Apr 23.

Service de Génétique, Centre Hospitalier Universitaire, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86034 Poitiers, France.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206156PMC
May 2021

NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.

Am J Hum Genet 2020 11;107(5):963-976

Service of Endocrinology, Diabetology, and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.
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http://dx.doi.org/10.1016/j.ajhg.2020.10.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674997PMC
November 2020

Sequence variations of ACVRL1 play a critical role in hepatic vascular malformations in hereditary hemorrhagic telangiectasia.

Orphanet J Rare Dis 2020 09 22;15(1):254. Epub 2020 Sep 22.

Hospices Civils de Lyon, Service de Génétique, Groupement Hospitalier Est, 69677, Bron, France.

Background: Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by multiple telangiectases and caused by germline disease-causing variants in the ENG (HHT1), ACVRL1 (HHT2) and, to a lesser extent MADH4 and GDF2, which encode proteins involved in the TGF-β/BMP9 signaling pathway. Common visceral complications of HHT are caused by pulmonary, cerebral, or hepatic arteriovenous malformations (HAVMs). There is large intrafamilial variability in the severity of visceral involvement, suggesting a role for modifier genes. The objective of the present study was to investigate the potential role of ENG, ACVRL1, and of other candidate genes belonging to the same biological pathway in the development of HAVMs.

Methods: We selected 354 patients from the French HHT patient database who had one disease causing variant in either ENG or ACVRL1 and who underwent hepatic exploration. We first compared the distribution of the different types of variants with the occurrence of HAVMs. Then, we genotyped 51 Tag-SNPs from the Hap Map database located in 8 genes that encode proteins belonging to the TGF-β/BMP9 pathway (ACVRL1, ENG, GDF2, MADH4, SMAD1, SMAD5, TGFB1, TGFBR1), as well as in two additional candidate genes (PTPN14 and ADAM17). We addressed the question of a possible genetic association with the occurrence of HAVMs.

Results: The proportion of patients with germline ACVRL1 variants and the proportion of women were significantly higher in HHT patients with HAVMs. In the HHT2 group, HAVMs were more frequent in patients with truncating variants. Six SNPs (3 in ACVRL1, 1 in ENG, 1 in SMAD5, and 1 in ADAM17) were significantly associated with HAVMs. After correction for multiple testing, only one remained significantly associated (rs2277383).

Conclusions: In this large association study, we confirmed the strong relationship between ACVRL1 and the development of HAVMs. Common polymorphisms of ACVRL1 may also play a role in the development of HAVMs, as a modifying factor, independently of the disease-causing variants.
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http://dx.doi.org/10.1186/s13023-020-01533-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507685PMC
September 2020

12q21 deletion syndrome: Narrowing the critical region down to 1.6 Mb including SYT1 and PPP1R12A.

Am J Med Genet A 2020 09 6;182(9):2133-2138. Epub 2020 Jul 6.

Department of Medical Genetics, Centre Hospitalier Universitaire de Poitiers, Poitiers, France.

Deletions in the 12q21 region are rare and non-recurrent CNVs. To date, only 11 patients with deletions in this region have been reported in the literature. These patients most often presented with syndromic intellectual deficiency, ventriculomegaly or hydrocephalus, ectodermal abnormalities, growth retardation and renal and cardiac malformations, suggesting a recognizable microdeletion syndrome. We report three new patients with overlapping deletions of the 12q21 region, including the smallest deletion reported to date and the first case characterized by array CGH during pregnancy. We describe specific clinical findings and shared facial features as developmental delay, ectodermal abnormalities, ventriculomegaly or hydrocephalus, axial hypotonia or spastic diplegia, growth retardation, heart defect, hydronephrosis, ureteral reflux or horseshoe kidney, large thorax or pectus excavatum, syndactyly of 2-3 toes, pterygium coli or excess nuchal skin, large anterior fontanel, low set ears, prominent forehead, short-upturned nose with nostril hypoplasia, microretrognathia and hypertelorism. These new patients and a comprehensive review of the literature allow us to define a minimum critical region spanning 1.6 Mb in 12q21. By screening the critical region using prediction tools, we identified two candidate genes: SYT1and PPP1R12A.
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http://dx.doi.org/10.1002/ajmg.a.61734DOI Listing
September 2020

Should autism spectrum disorder be considered part of CHARGE syndrome? A cross-sectional study of 46 patients.

Orphanet J Rare Dis 2020 06 3;15(1):136. Epub 2020 Jun 3.

Faculty of Medicine, University of Paris, Paris, France.

Background: Behavioral problems are an important issue for people with CHARGE syndrome. The similarity of their behavioral traits with those of people with autism raises questions. In a large national cross-sectional study, we used specific standardized tools for diagnosing autism (Autism Diagnostic Interview-Revised and Diagnostic and Statistical Manual of Mental Disorders, 5th edition, DSM-5) and evaluating behavioral disorders (Developmental Behavior Checklist-Parents, DBC-P) to investigate a series of individuals with CHARGE syndrome, defined by Verloes's criteria. We evaluated their adaptive functioning level and sensory particularities and extracted several data items from medical files to assess as potential risk factors for autism and/or behavioral disorders.

Results: We investigated 64 individuals with CHARGE syndrome (35 females; mean age 10.7 years, SD 7.1 years). Among 46 participants with complete results for the Autism Diagnostic Interview-Revised (ADI-R), 13 (28%) had a diagnosis of autism according to the ADI-R, and 25 (54%) had a diagnosis of autism spectrum disorder (ASD) according to the DSM-5 criteria. The frequency of autistic traits in the entire group was a continuum. We did not identify any risk factor for ASD but found a negative correlation between the ADI-R score and adaptive functioning level. Among 48 participants with data for the DBC-P, 26 (55%) had behavioral disorders, which were more frequent in patients with radiological brain anomalies, impaired adaptive functioning, later independent walking, and more sensory particularities.

Conclusions: ASD should be considered to be an independent risk requiring early screening and management in children born with CHARGE syndrome.
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http://dx.doi.org/10.1186/s13023-020-01421-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268350PMC
June 2020

De Novo SOX6 Variants Cause a Neurodevelopmental Syndrome Associated with ADHD, Craniosynostosis, and Osteochondromas.

Am J Hum Genet 2020 06 21;106(6):830-845. Epub 2020 May 21.

Roberts Individualized Medical Genetics Center, Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.

SOX6 belongs to a family of 20 SRY-related HMG-box-containing (SOX) genes that encode transcription factors controlling cell fate and differentiation in many developmental and adult processes. For SOX6, these processes include, but are not limited to, neurogenesis and skeletogenesis. Variants in half of the SOX genes have been shown to cause severe developmental and adult syndromes, referred to as SOXopathies. We here provide evidence that SOX6 variants also cause a SOXopathy. Using clinical and genetic data, we identify 19 individuals harboring various types of SOX6 alterations and exhibiting developmental delay and/or intellectual disability; the individuals are from 17 unrelated families. Additional, inconstant features include attention-deficit/hyperactivity disorder (ADHD), autism, mild facial dysmorphism, craniosynostosis, and multiple osteochondromas. All variants are heterozygous. Fourteen are de novo, one is inherited from a mosaic father, and four offspring from two families have a paternally inherited variant. Intragenic microdeletions, balanced structural rearrangements, frameshifts, and nonsense variants are predicted to inactivate the SOX6 variant allele. Four missense variants occur in residues and protein regions highly conserved evolutionarily. These variants are not detected in the gnomAD control cohort, and the amino acid substitutions are predicted to be damaging. Two of these variants are located in the HMG domain and abolish SOX6 transcriptional activity in vitro. No clear genotype-phenotype correlations are found. Taken together, these findings concur that SOX6 haploinsufficiency leads to a neurodevelopmental SOXopathy that often includes ADHD and abnormal skeletal and other features.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273536PMC
June 2020

Comprehensive In Vivo Interrogation Reveals Phenotypic Impact of Human Enhancer Variants.

Cell 2020 03 12;180(6):1262-1271.e15. Epub 2020 Mar 12.

Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA; U.S. Department of Energy Joint Genome Institute, Berkeley, CA 94720, USA; Comparative Biochemistry Program, University of California, Berkeley, CA 94720, USA. Electronic address:

Establishing causal links between non-coding variants and human phenotypes is an increasing challenge. Here, we introduce a high-throughput mouse reporter assay for assessing the pathogenic potential of human enhancer variants in vivo and examine nearly a thousand variants in an enhancer repeatedly linked to polydactyly. We show that 71% of all rare non-coding variants previously proposed as causal lead to reporter gene expression in a pattern consistent with their pathogenic role. Variants observed to alter enhancer activity were further confirmed to cause polydactyly in knockin mice. We also used combinatorial and single-nucleotide mutagenesis to evaluate the in vivo impact of mutations affecting all positions of the enhancer and identified additional functional substitutions, including potentially pathogenic variants hitherto not observed in humans. Our results uncover the functional consequences of hundreds of mutations in a phenotype-associated enhancer and establish a widely applicable strategy for systematic in vivo evaluation of human enhancer variants.
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http://dx.doi.org/10.1016/j.cell.2020.02.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179509PMC
March 2020

Growth charts in Kabuki syndrome 1.

Am J Med Genet A 2020 03 26;182(3):446-453. Epub 2019 Dec 26.

Service de Génétique, Hôpital Saint Pierre, GH Sud Réunion, Ile de la Réunion, Saint Pierre, France.

Kabuki syndrome (KS, KS1: OMIM 147920 and KS2: OMIM 300867) is caused by pathogenic variations in KMT2D or KDM6A. KS is characterized by multiple congenital anomalies and neurodevelopmental disorders. Growth restriction is frequently reported. Here we aimed to create specific growth charts for individuals with KS1, identify parameters used for size prognosis and investigate the impact of growth hormone therapy on adult height. Growth parameters and parental size were obtained for 95 KS1 individuals (41 females). Growth charts for height, weight, body mass index (BMI) and occipitofrontal circumference were generated in standard deviation values for the first time in KS1. Statural growth of KS1 individuals was compared to parental target size. According to the charts, height, weight, BMI, and occipitofrontal circumference were lower for KS1 individuals than the normative French population. For males and females, the mean growth of KS1 individuals was -2 and -1.8 SD of their parental target size, respectively. Growth hormone therapy did not increase size beyond the predicted size. This study, from the largest cohort available, proposes growth charts for widespread use in the management of KS1, especially for size prognosis and screening of other diseases responsible for growth impairment beyond a calculated specific target size.
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http://dx.doi.org/10.1002/ajmg.a.61462DOI Listing
March 2020

One Mutation may Conceal Another.

Genes (Basel) 2019 08 22;10(9). Epub 2019 Aug 22.

Service de Génétique et Biologie Moléculaires, Hôpital Cochin, HUPC, Assistance Publique-Hôpitaux de Paris, 75014 Paris, France.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance but high variable expressivity. NF1 is caused by loss-of-function mutations in the gene, a negative regulator of the RAS-MAPK pathway. The gene has one of the highest mutation rates in human disorders, which may explain the outbreak of independent de novo variants in the same family. Here, we report the co-occurrence of pathogenic variants in the and genes in six families with NF1 and Legius syndrome, using next-generation sequencing. In five of these families, we observed the co-occurrence of two independent variants. All variants were classified as pathogenic, according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines. In the sixth family, one sibling inherited a complete deletion of the gene from her mother and carried a variant of unknown significance in the gene. This variant was also present in her brother, who was diagnosed with Legius syndrome, a differential diagnosis of NF1. This work illustrates the complexity of molecular diagnosis in a not-so-rare genetic disease.
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http://dx.doi.org/10.3390/genes10090633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769760PMC
August 2019

A functional assay to study the pathogenicity of CHD7 protein variants encountered in CHARGE syndrome patients.

Eur J Hum Genet 2019 11 9;27(11):1683-1691. Epub 2019 Jul 9.

Neurovascular Unit and Cognitive Disorders (EA-3808 NEUVACOD), Université de Poitiers, Poitiers, France.

CHARGE syndrome is a rare genetic disease characterized by numerous congenital abnormalities, mainly caused by de novo alterations of the CHD7 gene. It encodes a chromodomain protein, involved in the ATP-dependent remodeling of chromatin. The vast majority of CHD7 alterations consists in null alleles like deletions, nonsense substitutions or frameshift-causing variations. The aim of this study was to develop a biological test of CHD7 protein, to study the impact upon protein functionality of rare allelic variants in the CHD7 gene that elicits changes in the amino acid sequence. Using an expression vector encoding CHD7, three amino acid substitutions and one five-amino acid insertion were generated via site-directed mutagenesis. Then CHD7 proteins, either wild-type (WT) or variants, were overexpressed in HeLa cell line. Protein expression was highlighted by western blot and immunofluorescence. We then used real-time RT-PCR to study CHD7 functionality by evaluating the transcript amounts of five genes whose expression is regulated by CHD7 according to the literature. These reporter genes are 45S rDNA, SOX4, SOX10, ID2, and MYRF. We observed that, upon WT-CHD7 expression, the reporter gene transcriptions were downregulated, whereas the four variant alleles of CHD7 had no impact. This suggests that these alleles are not polymorphisms because the variant proteins appeared nonfunctional. Therefore, these variations can be considered as disease-causing of CHARGE syndrome.
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http://dx.doi.org/10.1038/s41431-019-0465-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871090PMC
November 2019

Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder.

Orphanet J Rare Dis 2019 05 31;14(1):121. Epub 2019 May 31.

Service de Génétique, Centre de Référence Anomalies du Développement, Hospices Civils de Lyon, Bron, France.

Williams Beuren syndrome (WBS) is a multiple malformations/intellectual disability (ID) syndrome caused by 7q11.23 microdeletion and clinically characterized by a typical neurocognitive profile including excessive talkativeness and social disinhibition, often defined as "overfriendliness" and "hyersociability". WBS is generally considered as the polar opposite phenotype to Autism Spectrum Disorder (ASD). Surprisingly, the prevalence of ASD has been reported to be significantly higher in WBS (12%) than in general population (1%). Our study aims to investigate the molecular basis of the peculiar association of ASD and WBS. We performed chromosomal microarray analysis and whole exome sequencing in six patients presenting with WBS and ASD, in order to evaluate the possible presence of chromosomal or gene variants considered as pathogenic.Our study shows that the presence of ASD in the recruited WBS patients is due to i) neither atypically large deletions; ii) nor the presence of pathogenic variants in genes localized in the non-deleted 7q11.23 allele which would unmask recessive conditions; iii) moreover, we did not identify a second, indisputable independent genetic diagnosis, related to pathogenic Copy Number Variations or rare pathogenic exonic variants in known ID/ASD causing genes, although several variants of unknown significance were found. Finally, imprinting effect does not appear to be the only cause of autism in WBS patients, since the deletions occurred in alleles of both maternal and paternal origin.The social disinhibition observed in WBS does not follow common social norms and symptoms overlapping with ASD, such as restricted interests and repetitive behavior, can be observed in "typical" WBS patients: therefore, the terms "overfriendliness" and "hypersociability" appear to be a misleading oversimplification.The etiology of ASD in WBS is likely to be heterogeneous. Further studies on large series of patients are needed to clarify the observed variability in WBS social communication, ranging from excessive talkativeness and social disinhibition to absence of verbal language and social deficit.
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http://dx.doi.org/10.1186/s13023-019-1094-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545013PMC
May 2019

Minoxidil versus placebo in the treatment of arterial wall hypertrophy in children with Williams Beuren Syndrome: a randomized controlled trial.

BMC Pediatr 2019 05 28;19(1):170. Epub 2019 May 28.

Hospices Civils de Lyon, Service de Néphrologie Pédiatrique, et centre de référence maladies rénales rares- Néphrogones, Filière ORKiD, -69500, Bron, France.

Background: Insufficient elastin synthesis leads to vascular complications and arterial hypertension in children with Williams-Beuren syndrome. Restoring sufficient quantity of elastin should then result in prevention or inhibition of vascular malformations and improvement in arterial blood pressure.

Methods: The aim of this study was to assess the efficacy and safety of minoxidil on Intima Media Thickness (IMT) on the right common carotid artery after twelve-month treatment in patient with Williams-Beuren syndrome. We performed a randomized placebo controlled double blind trial. All participants were treated for 12 months and followed for 18 months. The principal outcome was assessed by an independent adjudication committee blinded to the allocated treatment groups.

Results: The principal outcome was available for 9 patients in the placebo group and 8 patients in the minoxidil group. After 12-month treatment, the IMT in the minoxidil group increased by 0.03 mm (95% CI -0.002, 0.06) compared with 0.01 mm (95%CI - 0.02, 0.04 mm) in the placebo group (p = 0.4). Two serious adverse events unrelated to the treatment occurred, one in the minoxidil and 1 in the placebo group. After 18 months, the IMT increased by 0.07 mm (95% CI 0.04, 0.10 mm) in the minoxidil compared with 0.01 mm (95% CI -0.02, 0.04 mm) in the placebo group (p = 0.008).

Conclusion: Our results suggest a slight increase after 12 and 18-month follow-up in IMT. More understanding of the biological changes induced by minoxidil should better explain its potential role on elastogenesis in Williams-Beuren syndrome.

Trials Registration: US National Institutes of Health Clinical Trial Register (NCT00876200). Registered 3 April 2009 (retrospectively registered).
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http://dx.doi.org/10.1186/s12887-019-1544-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537216PMC
May 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.

Laboratoire de Cytogénétique, CHU Strasbourg, Strasbourg, France.

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

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

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

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

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Clin Genet 2019 03;95(3):384-397

Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.
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http://dx.doi.org/10.1111/cge.13500DOI Listing
March 2019

NBEA: Developmental disease gene with early generalized epilepsy phenotypes.

Ann Neurol 2018 11 25;84(5):788-795. Epub 2018 Oct 25.

Department of Pediatrics, University of Washington, Seattle, WA.

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.
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http://dx.doi.org/10.1002/ana.25350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249120PMC
November 2018

1q21.1 microduplication: large verbal-nonverbal performance discrepancy and ddPCR assays of HYDIN/HYDIN2 copy number.

NPJ Genom Med 2018 22;3:24. Epub 2018 Aug 22.

1Sorbonne Université, Faculté de Médecine, Groupe de Recherche Clinique n°15 (PSYDEV), AP-HP, Hôpital Pitié-Salpêtrière, F-75013 Paris, France.

Microduplication of chromosome 1q21.1 is observed in ~0.03% of adults. It has a highly variable, incompletely penetrant phenotype that can include intellectual disability, global developmental delay, specific learning disabilities, autism, schizophrenia, heart anomalies and dysmorphic features. We evaluated a 10-year-old-male with a 1q21.1 duplication by CGH microarray. He presented with major attention deficits, phonological dysphasia, poor fine motor skills, dysmorphia and mild autistic features, but not the typical macrocephaly. Neuropsychiatric evaluation demonstrated a novel phenotype: an unusually large discrepancy between non-verbal capacities (borderline-impaired WISC-IV index scores of 70 for Working Memory and 68 for Processing Speed) vs. strong verbal skills - scores of 126 for Verbal Comprehension (superior) and 111 for Perceptual Reasoning (normal). has been hypothesized to underlie macrocephaly and perhaps cognitive deficits in this syndrome, but assessment of copy number by microarray is difficult because of extensive segmental duplications. We performed whole-genome sequencing which supported duplication (chr1:146,370,001-148,590,000, 2.22 Mb, hg38). To evaluate copy number more rigorously we developed droplet digital PCR assays of (targeting unique 1 kb and 6 kb insertions) and its paralog (targeting a unique 154 bp segment outside the overlap). In an independent cohort, ddPCR was concordant with previous microarray data. Duplication of was confirmed in the patient by ddPCR. This case demonstrates that a large discrepancy of verbal and non-verbal abilities can occur in 1q21.1 duplication syndrome, but it remains unclear whether this has a specific genomic basis. These ddPCR assays may be useful for future research on copy number.
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http://dx.doi.org/10.1038/s41525-018-0059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6105585PMC
August 2018

Twenty-four-hour ambulatory ECG monitoring relevancy in myotonic dystrophy type 1 follow-up: Prognostic value and heart rate variability evolution.

Ann Noninvasive Electrocardiol 2019 01 12;24(1):e12587. Epub 2018 Aug 12.

Department of Cardiology, CHU Poitiers, Poitiers, France.

Background: Patient prognosis in type 1 myotonic dystrophy (DM1) is very poor. Annual 24-hour holter ECG monitoring is recommended but its relevance is debated. Main objective was to determine whether holter ECG parameters could predict global death in DM1 patients and secondarily to assess whether they could predict cardiovascular events and sudden cardiac death, to compare DM1 patients and healthy controls, and to assess their evolution in DM1 over a 5-year period.

Methods: This retrospective study included genetically confirmed DM1. Primary endpoint was global death. Secondary endpoints were labeled "sudden cardiac death" which was a composite of sudden cardiac death, aborted sudden cardiac death, implantable cardioverter defibrillator therapy, sustained ventricular tachycardia, atrioventricular block grade 3, pause >3 s; and "cardiovascular events" which was a composite of all-cause mortality, pacemaker or cardioverter defibrillator implantation, sustained ventricular tachycardia, supraventricular tachycardia, hospitalization for acute cardiac cause and heart failure.

Results: Forty-seven patients (22 women, 40 ± 13 years old) were included. Three (7%) DM1 patients died, 9 (19%) experienced "sudden cardiac death" endpoint and 21 (45%) experienced "cardiovascular event" endpoint during mean follow-up of 95 ± 22 months. None of holter ECG parameters were discriminant to predict death or secondary endpoints. Compared to healthy controls, DM1 patients had higher SDNN and LF/HF ratio. Finally, heart rate variability parameters remained stable over a mean interval of 61 ± 15 months excepting pNN50 which decreased significantly.

Conclusion: Results suggest that annually-repeated holter ECG in DM1 is not useful for stratifying risk of sudden death and cardiovascular outcomes.
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http://dx.doi.org/10.1111/anec.12587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931664PMC
January 2019

Expanding the phenotypic spectrum of variants in PDE4D/PRKAR1A: from acrodysostosis to acroscyphodysplasia.

Eur J Hum Genet 2018 11 13;26(11):1611-1622. Epub 2018 Jul 13.

Department of Medical Genetics, INSERM UMR 1163, Paris Descartes-Sorbonne Paris Cité University, IMAGINE Institute, Necker Enfants Malades Hospital, Paris, France.

Acrodysostosis (MIM 101800) is a dominantly inherited condition associating (1) skeletal features (short stature, facial dysostosis, and brachydactyly with cone-shaped epiphyses), (2) resistance to hormones and (3) possible intellectual disability. Acroscyphodysplasia (MIM 250215) is characterized by growth retardation, brachydactyly, and knee epiphyses embedded in cup-shaped metaphyses. We and others have identified PDE4D or PRKAR1A variants in acrodysostosis; PDE4D variants have been reported in three cases of acroscyphodysplasia. Our study aimed at reviewing the clinical and molecular findings in a cohort of 27 acrodysostosis and 5 acroscyphodysplasia cases. Among the acrodysostosis cases, we identified 9 heterozygous de novo PRKAR1A variants and 11 heterozygous PDE4D variants. The 7 patients without variants presented with symptoms of acrodysostosis (brachydactyly and cone-shaped epiphyses), but none had the characteristic facial dysostosis. In the acroscyphodysplasia cases, we identified 2 PDE4D variants. For 2 of the 3 negative cases, medical records revealed early severe infection, which has been described in some reports of acroscyphodysplasia. Subdividing our series of acrodysostosis based on the disease-causing gene, we confirmed genotype-phenotype correlations. Hormone resistance was consistently observed in patients carrying PRKAR1A variants, whereas no hormone resistance was observed in 9 patients with PDE4D variants. All patients with PDE4D variants shared characteristic facial features (midface hypoplasia with nasal hypoplasia) and some degree of intellectual disability. Our findings of PDE4D variants in two cases of acroscyphodysplasia support that PDE4D may be responsible for this severe skeletal dysplasia. We eventually emphasize the importance of some specific assessments in the long-term follow up, including cardiovascular and thromboembolic risk factors.
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http://dx.doi.org/10.1038/s41431-018-0135-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6189044PMC
November 2018

Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort.

Hum Mutat 2018 09 4;39(9):1246-1261. Epub 2018 Jul 4.

Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.

Adams-Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype-phenotype correlations. This cohort offers potential for further gene identification to address missing heritability.
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http://dx.doi.org/10.1002/humu.23567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175364PMC
September 2018

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

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

Service de Génétique Clinique, Hôpital Necker Enfants Malades, APHP, Paris, 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

CHARGE syndrome: a recurrent hotspot of mutations in CHD7 IVS25 analyzed by bioinformatic tools and minigene assays.

Eur J Hum Genet 2018 02 18;26(2):287-292. Epub 2017 Dec 18.

Service de Génétique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Poitiers, France.

CHARGE syndrome is a rare genetic disorder mainly due to de novo and private truncating mutations of CHD7 gene. Here we report an intriguing hot spot of intronic mutations (c.5405-7G > A, c.5405-13G > A, c.5405-17G > A and c.5405-18C > A) located in CHD7 IVS25. Combining computational in silico analysis, experimental branch-point determination and in vitro minigene assays, our study explains this mutation hot spot by a particular genomic context, including the weakness of the IVS25 natural acceptor-site and an unconventional lariat sequence localized outside the common 40 bp upstream the acceptor splice site. For each of the mutations reported here, bioinformatic tools indicated a newly created 3' splice site, of which the existence was confirmed using pSpliceExpress, an easy-to-use and reliable splicing reporter tool. Our study emphasizes the idea that combining these two complementary approaches could increase the efficiency of routine molecular diagnosis.
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http://dx.doi.org/10.1038/s41431-017-0007-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839049PMC
February 2018

Phenotype and genotype analysis of a French cohort of 119 patients with CHARGE syndrome.

Am J Med Genet C Semin Med Genet 2017 12 27;175(4):417-430. Epub 2017 Nov 27.

Service de Génétique, CHU de Lyon, Bron, France.

CHARGE syndrome (CS) is a genetic disorder whose first description included Coloboma, Heart disease, Atresia of choanae, Retarded growth and development, Genital hypoplasia, and Ear anomalies and deafness, most often caused by a genetic mutation in the CHD7 gene. Two features were then added: semicircular canal anomalies and arhinencephaly/olfactory bulb agenesis, with classification of typical, partial, or atypical forms on the basis of major and minor clinical criteria. The detection rate of a pathogenic variant in the CHD7 gene varies from 67% to 90%. To try to have an overview of this heterogenous clinical condition and specify a genotype-phenotype relation, we conducted a national study of phenotype and genotype in 119 patients with CS. Selected clinical diagnostic criteria were from Verloes (2005), updated by Blake & Prasad (). Besides obtaining a detailed clinical description, when possible, patients underwent a full ophthalmologic examination, audiometry, temporal bone CT scan, gonadotropin analysis, and olfactory-bulb MRI. All patients underwent CHD7 sequencing and MLPA analysis. We found a pathogenic CHD7 variant in 83% of typical CS cases and 58% of atypical cases. Pathogenic variants in the CHD7 gene were classified by the expected impact on the protein. In all, 90% of patients had a typical form of CS and 10% an atypical form. The most frequent features were deafness/semicircular canal hypoplasia (94%), pituitary defect/hypogonadism (89%), external ear anomalies (87%), square-shaped face (81%), and arhinencephaly/anosmia (80%). Coloboma (73%), heart defects (65%), and choanal atresia (43%) were less frequent.
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http://dx.doi.org/10.1002/ajmg.c.31591DOI Listing
December 2017

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Am J Hum Genet 2017 Nov;101(5):768-788

Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673671PMC
November 2017

Telomere length, ATM mutation status and cancer risk in Ataxia-Telangiectasia families.

Carcinogenesis 2017 10;38(10):994-1003

INSERM, U900, Paris, France.

Recent studies have linked constitutive telomere length (TL) to aging-related diseases including cancer at different sites. ATM participates in the signaling of telomere erosion, and inherited mutations in ATM have been associated with increased risk of cancer, particularly breast cancer. The goal of this study was to investigate whether carriage of an ATM mutation and TL interplay to modify cancer risk in ataxia-telangiectasia (A-T) families.The study population consisted of 284 heterozygous ATM mutation carriers (HetAT) and 174 non-carriers (non-HetAT) from 103 A-T families. Forty-eight HetAT and 14 non-HetAT individuals had cancer, among them 25 HetAT and 6 non-HetAT were diagnosed after blood sample collection. We measured mean TL using a quantitative PCR assay and genotyped seven single-nucleotide polymorphisms (SNPs) recurrently associated with TL in large population-based studies.HetAT individuals were at increased risk of cancer (OR = 2.3, 95%CI = 1.2-4.4, P = 0.01), and particularly of breast cancer for women (OR = 2.9, 95%CI = 1.2-7.1, P = 0.02), in comparison to their non-HetAT relatives. HetAT individuals had longer telomeres than non-HetAT individuals (P = 0.0008) but TL was not associated with cancer risk, and no significant interaction was observed between ATM mutation status and TL. Furthermore, rs9257445 (ZNF311) was associated with TL in HetAT subjects and rs6060627 (BCL2L1) modified cancer risk in HetAT and non-HetAT women.Our findings suggest that carriage of an ATM mutation impacts on the age-related TL shortening and that TL per se is not related to cancer risk in ATM carriers. TL measurement alone is not a good marker for predicting cancer risk in A-T families.
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http://dx.doi.org/10.1093/carcin/bgx074DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862273PMC
October 2017

Sex chromosome aneuploidies and copy-number variants: a further explanation for neurodevelopmental prognosis variability?

Eur J Hum Genet 2017 08 14;25(8):930-934. Epub 2017 Jun 14.

Service de Génétique Médicale, CHU Nantes, Nantes, France.

Sex chromosome aneuploidies (SCA) is a group of conditions in which individuals have an abnormal number of sex chromosomes. SCA, such as Klinefelter's syndrome, XYY syndrome, and Triple X syndrome are associated with a large range of neurological outcome. Another genetic event such as another cytogenetic abnormality may explain a part of this variable expressivity. In this study, we have recruited fourteen patients with intellectual disability or developmental delay carrying SCA associated with a copy-number variant (CNV). In our cohort (four patients 47,XXY, four patients 47,XXX, and six patients 47,XYY), seven patients were carrying a pathogenic CNV, two a likely pathogenic CNV and five a variant of uncertain significance. Our analysis suggests that CNV might be considered as an additional independent genetic factor for intellectual disability and developmental delay for patients with SCA and neurodevelopmental disorder.
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http://dx.doi.org/10.1038/ejhg.2017.93DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567159PMC
August 2017

CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions.

Am J Hum Genet 2017 May;100(5):773-788

Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address:

Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7) and lysine (K) methyltransferase 2D (KMT2D), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7 or KMT2D identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.
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http://dx.doi.org/10.1016/j.ajhg.2017.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5420353PMC
May 2017
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