- Email: [email protected]
12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome
Accepted Manuscript 12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome Alice Poisson, Gaetan Lesca, Nicolas Chatron, Caroline Demily, Emilie Favre, Vincent Cottin, Delphine Gamondes, Damien Sanlaville, Patrick Edery, Sophie Giraud, Sophie Dupuis-Girod PII:
S1769-7212(18)30557-3
DOI:
https://doi.org/10.1016/j.ejmg.2018.10.017
Reference:
EJMG 3565
To appear in:
European Journal of Medical Genetics
Received Date: 23 July 2018 Revised Date:
8 October 2018
Accepted Date: 28 October 2018
Please cite this article as: A. Poisson, G. Lesca, N. Chatron, C. Demily, E. Favre, V. Cottin, D. Gamondes, D. Sanlaville, P. Edery, S. Giraud, S. Dupuis-Girod, 12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome, European Journal of Medical Genetics (2018), doi: https://doi.org/10.1016/j.ejmg.2018.10.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: clinical report of a new contiguous gene syndrome.
Alice Poisson1, Gaetan Lesca 3,6, Nicolas Chatron3,6, Caroline Demily 1,6, Emilie Favre 1,
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Vincent Cottin 4,6, Delphine Gamondes 5, Damien Sanlaville 3,6, Patrick Edery 2,6, Sophie
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Giraud 2, Sophie Dupuis-Girod 2
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1 GénoPsy, Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier, Lyon, France ; Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France 2 2 Hospices Civils de Lyon, Genetic Department and National HHT Reference Center, Femme-Mère-Enfants Hospital, Bron F-69677 3 Hospices Civils de Lyon, Genetic Department and Molecular Biology Laboratory, Centre de Biologie Est, Bron F-69677
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4 Hospices Civils de Lyon, Department of Pulmonary Medicine and National Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Bron F-69677. 5 Hospices Civils de Lyon, Department of Radiology, Louis Pradel Hospital, Bron F69677 Université Claude Bernard Lyon 1, F-69100, Villeurbanne, France.
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Corresponding author: Alice Poisson
GénoPsy, CH le Vinatier, 69500, Bron, France. Tel/Fax: 33 4 37 91 51 63; [email protected];
1
ACCEPTED MANUSCRIPT Abstract Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in
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case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene syndrome involving ACVRL1 gene.
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A 50-year-old female patient had a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) with epistaxis, cutaneous-mucous telangiectases, arteriovenous
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malformation. She also presented a cognitive disability. Cognitive assessment showed a heterogeneous cognitive disorder predominating in the executive sphere without intellectual deficiency. She had no peculiar morphological feature. Neurological examination disclosed the presence of contralateral mirror movements during voluntary movement of each hand. A
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heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10) was found to be responsible for the HHT features. To investigate further the dysexecutive syndrome and the mirror movements, we performed oligonucleotide array comparative genomic hybridization (array CGH) study
EP
(180K, Agilent, Santa-Clara, CA, USA). This study revealed a de novo 1.58 Mb deletion on
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chromosome 12q13.12q13.13 encompassing the ACVRL1 and SCN8A genes. To our knowledge, this deletion has not been previously reported and defines a new contiguous gene syndrome. The loss of one ACVRL1 allele is likely to be responsible for the HHT phenotype, while the deletion of the SCN8A gene is likely to be the cause of the mild cognitive disorder. SCN8A haploinsufficiency might also be involved in the occurrence of mirror movements. This report highlights the benefit of searching for large rearrangements in cases including unusual symptoms in association with HHT. On the other hand, an early diagnosis of
2
ACCEPTED MANUSCRIPT 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror
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SC
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movement may allow to prevent HHT complications.
3
ACCEPTED MANUSCRIPT Key words: Hereditary hemorrhagic telangiectasia; deletion; contiguous gene syndrome; ACVRL1; SCN8A. List of abbreviation:
HHT: hereditary hemorrhagic telangiectasia
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CNV: copy number variation
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aCGH: microarray-based comparative genomic hybridization
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AVM: arteriovenous malformation
4
ACCEPTED MANUSCRIPT Letter to the Editor
Dear Editor,
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the loss or gain of expression of more than one gene may lead to an unusual association of clinical features called a “contiguous gene syndrome”. In the 2000s, the development of microarray-based comparative genomic hybridization (aCGH) for routine diagnosis allowed
SC
the description of a wide variety of new micro rearrangement syndromes. However, more
M AN U
than fifteen years later, some of these syndromes remain to be described. We report here a female patient with a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) associated with a cognitive disability and mirror movements due to a 1.58 Mb deletion in chromosome 12q13.12q13.13. The deletion
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encompasses several genes, including the ACVRL1 and SCN8A. To our knowledge, this contiguous gene syndrome has not previously been described. The patient has given consent to publication. The study has been approved by the IRB according to the rules of the Lyon
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University Hospital.
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The patient is a 50-year-old female born from an uneventful pregnancy with an eutocic delivery. She had learning difficulties and was working in a warehouse. She had also been suffering from severe recurrent epistaxis since the age of 22. Clinical examination disclosed numerous telangiectases on the lips, tongue, hands, and cheekbones. Pulse oximetry yielded a blood oxygen saturation of 93 percent with dyspnea. Liver Doppler ultrasound revealed hepatic hypervascularization, dilatation of the hepatic artery (diameter of the proper hepatic artery = 8 mm). A chest and abdominal CT scan confirmed the presence of one voluminous
5
ACCEPTED MANUSCRIPT and complex pulmonary arteriovenous malformation (AVM) and disclosed liver AVMs. The patient fulfilled the Curaçao criteria for HHT, despite the lack of familial history. The patient also complained of difficulty managing her budget, planning appointments, and
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even cleaning her house. She also suffered from anxiety with anxious ruminations. Neurological examination disclosed brisk reflexes, contralateral mirror movements during voluntary movement of each hand, and a mild postural tremor without cerebellar features.
SC
Brain and spine MRIs were unremarkable. Cognitive assessment revealed heterogeneous abilities. Long-term memory and verbal reasoning were spared, and apraxia was not present.
M AN U
Conversely, working memory, speed processing, visuospatial reasoning, mental flexibility, and planning were disabled. Overall, there was no intellectual disability, but heterogeneous cognitive disorders marked in the executive sphere. This aspect aptly explained the patient’s complaints, especially the difficulties in handling her budget, but it does not belong to the
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clinical features associated with HHT.
Sanger sequencing ruled out the presence of a pathogenic mutation in the ENG and ACVRL1
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genes. Detection of large genomic rearrangements was performed by MLPA analysis using a SALSA MLPA P093-C2 HHT/HPAH kit (MRC-Holland, Amsterdam, The Netherlands) on a 313xl
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sequencer (Thermofisher, Waltham, MA, USA). This analysis disclosed a heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10), responsible for the clinical picture of HHT. Large deletions represent 7 % of all mutations in the ACVRL1 gene, according to the international HHT mutation database (http: //arup.utah.edu/database). However, the observed deletion did not explain the dysexecutive syndrome or the mirror movements; therefore, an oligonucleotide array comparative genomic hybridization (array CGH; 180K, Agilent, Santa-Clara, CA, USA) study was performed to study whether this deletion was
6
ACCEPTED MANUSCRIPT encompassing additional genes. Array CGH revealed a 1.58 Mb deletion of chromosome 12q13.12q13.13 (arr[GRCh37] 12q13.12q13.13(51347169_52929181)x1 dn) encompassing 27 genes including ACVRL1 but also a cluster of 13 keratin genes (Figure 1B), SCL11A2, and
the lack of family history of HHT or cognitive impairment.
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SCN8A. Parental studies (qPCR) demonstrated that it had occurred de novo, consistent with
This copy number variation (CNV) is not reported in the DGV database. Two overlapping
SC
deletions encompassing the ACVRL1, SCN8A and some keratin genes have been previously reported in DECIPHER (276695; 273643). Both patients presented with intellectual deficiency
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and one suffered from recurrent epistaxis. The lack of clear HHT feature in the second case may be linked to the variable penetrance of the disease and to the young age of the patient (6 years old). Interestingly, another contiguous gene syndrome has previously been reported for HHT, due to a de novo 9q33.3q34.11 microdeletion that includes the ENG,
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STXBP1 and LMX1B genes. The clinical features consist of facial dysmorphism, features from nail patella syndrome, HHT symptoms, epilepsy, and intellectual deficiency (Nambot et al., 2016). In the current case, the HHT features were due to the loss of ACVRL1. ACVRL1 belongs
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to the TGFβ receptor family and is mainly expressed by arterial endothelial cells (Barbara et
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al., 1999; Blanco et al., 2005). Autosomal dominant intragenic mutations or large rearrangements involving one or more exons of ACVRL1 define HHT type 2 (Johnson et al., 1996). Pulmonary AVMs are present in 18 % of patients with ACVRL1 mutations, without any demonstrated correlation with the mutation type (Lesca et al., 2017). To our knowledge, there are currently no available data concerning the association of ACVRL1 with cognitive or behavioral impairment. In 2008, Shoukeir et al. reported a much smaller ACVRL1 deletion in an HHT-family with no associated developmental delay. That deletion did not include SCN8A but did reach into the keratin-gene cluster. SCL11A2 (# 206100) and KRT-genes are not 7
ACCEPTED MANUSCRIPT expected to give a neurophenotype. Interestingly our patient has no hematological disease nor skin feature. On the other hand, SCN8A is known to be involved in neurodevelopmental disorders (#600702),
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SCN8A encodes the voltage-gated sodium channel Nav1.6 alpha subunit 8, which is widely expressed in central and peripheral nervous systems (Plummer et al., 1998) and is involved in the initiation and propagation of neuronal action potentials. (Lorincz and Nusser, 2010)
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Patients carrying deleterious SCN8A variants exhibit variable intellectual deficiency, ataxia, epilepsy and autism spectrum disorder (Trudeau et al., 2006; O’Brien and Meisler, 2013;
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Rauch et al., 2012; Helbig and Tayoun, 2016; Anand et al., 2016; Larsen et al., 2015; Ohba et al., 2014; Wagnon et al., 2017; Veeramah et al., 2012). Here, the complete SCN8A deletion is likely to cause the moderate cognitive disability with probably no or little participation of the other genes included in the deletion. Movement disorders known to be associated with
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SCN8A mutations consist mainly of ataxia, paroxysmal kinesigenic dyskinesia and choreoathetosis (Larsen et al., 2015; Gardella et al., 2016). In our patient, neurological examination revealed the presence of mirror movements. Mirror movements are physiologic
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during childhood. They usually disappear by the age of 10 and their persistence in adulthood
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have been linked to various genetic conditions (Mayston et al., 1999; Farmer, 2005; Mayston et al., 1997; Depienne et al., 2011). Since SCN8A is widely expressed in central nervous system, mirror movements might be due to SCN8A haploinsufficiency, suggesting that this symptom may expand the phenotypic spectrum of movement disorders associated with SCN8A mutations. We suggest to consider this new clinical association linked to ACVRL1 and SCN8A as a new contiguous gene syndrome. In 1986, Schimkel proposed the term of continuous gene
8
ACCEPTED MANUSCRIPT syndrome to explain the clinical association due to the deletion of several genes lying in proximity. For example, the well-known WAGR contiguous gene syndrome consists of the association of Wilms' tumor secondary to WT1 gene haploinsufficiency and aniridia due to PAX6 gene haploinsufficiency. In our case, the patient's phenotype is secondary to the
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haploinsufficiency of two very close genes. However, further cases are necessary to confirm the existence of a recurrent deletion.
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In sum, we proposed that the association of HHT features and mild cognitive disorders with mirror movement due to a large deletion encompassing the ACVRL1 and SCN8A genes
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constitutes a new contiguous gene syndrome. HHT features may be absent in childhood but an early diagnosis of 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror movement will allow to prevent some HHT complications. On the other hand, this report also highlights the benefit of searching for large rearrangements in
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the rare cases including unusual symptoms in association with HHT. Last but not least, it
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suggests that SCN8A might represent a new target for future research on mirror movement.
9
ACCEPTED MANUSCRIPT Figure legend Figure 1. A: Array CGH showing the 1.58 Mb deletion in chromosome 12q13.12q13.13
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encompassing ACVRL1 and SCN8A. B: Decipher diagram for interval 12:51347169-52929181.
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ACCEPTED MANUSCRIPT Acknowledgements: The authors thank the patient and her family for their participation in the study and their agreement to this publication and Ms Chantal Silarakis from Lyon
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University Hospital’s library.
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ACCEPTED MANUSCRIPT References Anand G, Collett-White F, Orsini A, Thomas S, Jayapal S, Trump N et al. Autosomal dominant SCN8A mutation with an unusually mild phenotype. Eur J Paediatr Neurol. 2016;20:761-5
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Barbara NP, Wrana JL, Letarte M. Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily. J Biol Chem. 1999;274:584–94.
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Blanchard MG, Willemsen MH, Walker JB, Dib-Hajj SD, Waxman SG, Jongmans MC et al. De
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novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy. J Med Genet. 2015;52:330-7.
Blanco FJ, Santibanez JF, Guerrero-Esteo, M, Langa C, Vary CP, Bernabeu C. Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial
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transforming growth factor-beta receptor complex. J cell physiol. 2005;204:574–84. de Kovel CG, Meisler MH, Brilstra EH, van Berkestijn FM, van't Slot R, van Lieshout S et al. Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy.
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Epilepsy Res. 2014;108:1511-8.
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Depienne C, Cincotta M, Billot S, Bouteiller D, Groppa S, Brochard V, et al. A novel DCC mutation and genetic heterogeneity in congenital mirror movements. Neurology. 2011;76:260-4.
Dupuis-Girod S, Cottin V, Shovlin CL. The Lung in Hereditary Hemorrhagic Telangiectasia. Respiration. 2017;94:315-30.
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ACCEPTED MANUSCRIPT Estacion M, O'Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD et al. A novel de novo mutation of SCN8A(Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis. 2014;69:117-23.
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Farmer SF. Mirror movements in neurology. J Neurol Neurosurg Psychiatry. 2005;76;1330. Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LH et al. Benign infantile
seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol. 2016;79:428-
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36.
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Helbig I, Tayoun AA. Understanding Genotypes and Phenotypes in Epileptic Encephalopathies. Mol Syndromol. 2016;4:172-181.
Johnson DW, Berg JN, Baldwin MA, Gallione CJ, Marondel I, Yoon J, et al. Mutations in the activin receptor-like kinase 1 gene in hereditary haemorrhagic telangiectasia type 2. Nat
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Genet. 1996;13:189–195.
Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, et al. The phenotypic
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spectrum of SCN8A encephalopathy. Neurology. 2015;84:480-9. Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, et al., French-
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Italian-Rendu-Osler Network. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med. 2007;9:14-22. Lorincz A, Nusser Z. Molecular identify of dendritic voltage-gated sodium channels. Science. 2010;328:906-9. Mayston MJ, Harrison LM, Stephens JA. A neurophysiological study of mirror movements in adults and children. Ann Neurol. 1999;45:583-94.
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ACCEPTED MANUSCRIPT Nambot S, Masurel A, El Chehadeh S, Mosca-Boidron AL, Thauvin-Robinet C, Lefebvre M et al. 9q33.3q34.11 microdeletion: new contiguous gene syndrome encompassing STXBP1, LMX1B and ENG genes assessed using reverse phenotyping. Euro J Hum Genet. 2016;24:830-
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7. O'Brien JE, Meisler MH. Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability. Front Genet. 2013;28:213.
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Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al. Early onset epileptic
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encephalopathy caused by de novo SCN8A mutations. Epilepsia. 2014;55:994-1000. Plummer NW, Galt J, Jones JM, Burgess DL, Sprunger LK, Kohrman DC et al. Exon organization, coding sequence, physical mapping, and polymorphic intragenic markers for the human neuronal sodium channel gene SCN8A. Genomics. 1998;54:287-96.
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Rauch A, Wieczorek D, Graf E, Wieland T, Endele S, Schwarzmayr T, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 2012;380:1674-82.
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Schmickel RD. Contiguous gene syndromes: a component of recognizable syndromes. J
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Pediatr. 1986;109:231-41.
Shoukier M, Teske U, Weise A, Engel W, Argyriou L. Characterization of five novel large deletions causing hereditary haemorrhagic telangiectasia. Clin Genet. 2008;73:320-30.
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ACCEPTED MANUSCRIPT Trudeau MM, Dalton JC, Day JW, Ranum LPW, Meisler MH. Heterozygosity for a protein truncation mutation of sodium channel SCN8A in a patient with cerebellar atrophy, ataxia, and mental retardation. J Med Genet. 2006;43:527-30.
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Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG et al. De novo pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet. 2012;90:502-10.
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Wagnon JL, Barker BS, Ottolini M, Park Y, Volkheimer A, Valdez P, et al. Loss-of-function
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variants of SCN8A in intellectual disability without seizures. Neurol Genet. 2017;3-e170.
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ACCEPTED MANUSCRIPT
S1769-7212(18)30557-3
DOI:
https://doi.org/10.1016/j.ejmg.2018.10.017
Reference:
EJMG 3565
To appear in:
European Journal of Medical Genetics
Received Date: 23 July 2018 Revised Date:
8 October 2018
Accepted Date: 28 October 2018
Please cite this article as: A. Poisson, G. Lesca, N. Chatron, C. Demily, E. Favre, V. Cottin, D. Gamondes, D. Sanlaville, P. Edery, S. Giraud, S. Dupuis-Girod, 12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome, European Journal of Medical Genetics (2018), doi: https://doi.org/10.1016/j.ejmg.2018.10.017. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT 12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: clinical report of a new contiguous gene syndrome.
Alice Poisson1, Gaetan Lesca 3,6, Nicolas Chatron3,6, Caroline Demily 1,6, Emilie Favre 1,
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Vincent Cottin 4,6, Delphine Gamondes 5, Damien Sanlaville 3,6, Patrick Edery 2,6, Sophie
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Giraud 2, Sophie Dupuis-Girod 2
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1 GénoPsy, Center for Diagnosis and Management of Genetic Psychiatric Disorders, Centre Hospitalier le Vinatier, Lyon, France ; Lyon Neuroscience Research Centre, CNRS UMR5292, INSERM U1028, Lyon, France 2 2 Hospices Civils de Lyon, Genetic Department and National HHT Reference Center, Femme-Mère-Enfants Hospital, Bron F-69677 3 Hospices Civils de Lyon, Genetic Department and Molecular Biology Laboratory, Centre de Biologie Est, Bron F-69677
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4 Hospices Civils de Lyon, Department of Pulmonary Medicine and National Reference Center for Rare Pulmonary Diseases, Louis Pradel Hospital, Bron F-69677. 5 Hospices Civils de Lyon, Department of Radiology, Louis Pradel Hospital, Bron F69677 Université Claude Bernard Lyon 1, F-69100, Villeurbanne, France.
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Corresponding author: Alice Poisson
GénoPsy, CH le Vinatier, 69500, Bron, France. Tel/Fax: 33 4 37 91 51 63; [email protected];
1
ACCEPTED MANUSCRIPT Abstract Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in
RI PT
case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene syndrome involving ACVRL1 gene.
SC
A 50-year-old female patient had a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) with epistaxis, cutaneous-mucous telangiectases, arteriovenous
M AN U
malformation. She also presented a cognitive disability. Cognitive assessment showed a heterogeneous cognitive disorder predominating in the executive sphere without intellectual deficiency. She had no peculiar morphological feature. Neurological examination disclosed the presence of contralateral mirror movements during voluntary movement of each hand. A
TE D
heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10) was found to be responsible for the HHT features. To investigate further the dysexecutive syndrome and the mirror movements, we performed oligonucleotide array comparative genomic hybridization (array CGH) study
EP
(180K, Agilent, Santa-Clara, CA, USA). This study revealed a de novo 1.58 Mb deletion on
AC C
chromosome 12q13.12q13.13 encompassing the ACVRL1 and SCN8A genes. To our knowledge, this deletion has not been previously reported and defines a new contiguous gene syndrome. The loss of one ACVRL1 allele is likely to be responsible for the HHT phenotype, while the deletion of the SCN8A gene is likely to be the cause of the mild cognitive disorder. SCN8A haploinsufficiency might also be involved in the occurrence of mirror movements. This report highlights the benefit of searching for large rearrangements in cases including unusual symptoms in association with HHT. On the other hand, an early diagnosis of
2
ACCEPTED MANUSCRIPT 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror
AC C
EP
TE D
M AN U
SC
RI PT
movement may allow to prevent HHT complications.
3
ACCEPTED MANUSCRIPT Key words: Hereditary hemorrhagic telangiectasia; deletion; contiguous gene syndrome; ACVRL1; SCN8A. List of abbreviation:
HHT: hereditary hemorrhagic telangiectasia
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CNV: copy number variation
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aCGH: microarray-based comparative genomic hybridization
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AVM: arteriovenous malformation
4
ACCEPTED MANUSCRIPT Letter to the Editor
Dear Editor,
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the loss or gain of expression of more than one gene may lead to an unusual association of clinical features called a “contiguous gene syndrome”. In the 2000s, the development of microarray-based comparative genomic hybridization (aCGH) for routine diagnosis allowed
SC
the description of a wide variety of new micro rearrangement syndromes. However, more
M AN U
than fifteen years later, some of these syndromes remain to be described. We report here a female patient with a typical clinical presentation of hereditary hemorrhagic telangiectasia (HHT) associated with a cognitive disability and mirror movements due to a 1.58 Mb deletion in chromosome 12q13.12q13.13. The deletion
TE D
encompasses several genes, including the ACVRL1 and SCN8A. To our knowledge, this contiguous gene syndrome has not previously been described. The patient has given consent to publication. The study has been approved by the IRB according to the rules of the Lyon
EP
University Hospital.
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The patient is a 50-year-old female born from an uneventful pregnancy with an eutocic delivery. She had learning difficulties and was working in a warehouse. She had also been suffering from severe recurrent epistaxis since the age of 22. Clinical examination disclosed numerous telangiectases on the lips, tongue, hands, and cheekbones. Pulse oximetry yielded a blood oxygen saturation of 93 percent with dyspnea. Liver Doppler ultrasound revealed hepatic hypervascularization, dilatation of the hepatic artery (diameter of the proper hepatic artery = 8 mm). A chest and abdominal CT scan confirmed the presence of one voluminous
5
ACCEPTED MANUSCRIPT and complex pulmonary arteriovenous malformation (AVM) and disclosed liver AVMs. The patient fulfilled the Curaçao criteria for HHT, despite the lack of familial history. The patient also complained of difficulty managing her budget, planning appointments, and
RI PT
even cleaning her house. She also suffered from anxiety with anxious ruminations. Neurological examination disclosed brisk reflexes, contralateral mirror movements during voluntary movement of each hand, and a mild postural tremor without cerebellar features.
SC
Brain and spine MRIs were unremarkable. Cognitive assessment revealed heterogeneous abilities. Long-term memory and verbal reasoning were spared, and apraxia was not present.
M AN U
Conversely, working memory, speed processing, visuospatial reasoning, mental flexibility, and planning were disabled. Overall, there was no intellectual disability, but heterogeneous cognitive disorders marked in the executive sphere. This aspect aptly explained the patient’s complaints, especially the difficulties in handling her budget, but it does not belong to the
TE D
clinical features associated with HHT.
Sanger sequencing ruled out the presence of a pathogenic mutation in the ENG and ACVRL1
EP
genes. Detection of large genomic rearrangements was performed by MLPA analysis using a SALSA MLPA P093-C2 HHT/HPAH kit (MRC-Holland, Amsterdam, The Netherlands) on a 313xl
AC C
sequencer (Thermofisher, Waltham, MA, USA). This analysis disclosed a heterozygous deletion of the whole ACVRL1 gene (exons 1 to 10), responsible for the clinical picture of HHT. Large deletions represent 7 % of all mutations in the ACVRL1 gene, according to the international HHT mutation database (http: //arup.utah.edu/database). However, the observed deletion did not explain the dysexecutive syndrome or the mirror movements; therefore, an oligonucleotide array comparative genomic hybridization (array CGH; 180K, Agilent, Santa-Clara, CA, USA) study was performed to study whether this deletion was
6
ACCEPTED MANUSCRIPT encompassing additional genes. Array CGH revealed a 1.58 Mb deletion of chromosome 12q13.12q13.13 (arr[GRCh37] 12q13.12q13.13(51347169_52929181)x1 dn) encompassing 27 genes including ACVRL1 but also a cluster of 13 keratin genes (Figure 1B), SCL11A2, and
the lack of family history of HHT or cognitive impairment.
RI PT
SCN8A. Parental studies (qPCR) demonstrated that it had occurred de novo, consistent with
This copy number variation (CNV) is not reported in the DGV database. Two overlapping
SC
deletions encompassing the ACVRL1, SCN8A and some keratin genes have been previously reported in DECIPHER (276695; 273643). Both patients presented with intellectual deficiency
M AN U
and one suffered from recurrent epistaxis. The lack of clear HHT feature in the second case may be linked to the variable penetrance of the disease and to the young age of the patient (6 years old). Interestingly, another contiguous gene syndrome has previously been reported for HHT, due to a de novo 9q33.3q34.11 microdeletion that includes the ENG,
TE D
STXBP1 and LMX1B genes. The clinical features consist of facial dysmorphism, features from nail patella syndrome, HHT symptoms, epilepsy, and intellectual deficiency (Nambot et al., 2016). In the current case, the HHT features were due to the loss of ACVRL1. ACVRL1 belongs
EP
to the TGFβ receptor family and is mainly expressed by arterial endothelial cells (Barbara et
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al., 1999; Blanco et al., 2005). Autosomal dominant intragenic mutations or large rearrangements involving one or more exons of ACVRL1 define HHT type 2 (Johnson et al., 1996). Pulmonary AVMs are present in 18 % of patients with ACVRL1 mutations, without any demonstrated correlation with the mutation type (Lesca et al., 2017). To our knowledge, there are currently no available data concerning the association of ACVRL1 with cognitive or behavioral impairment. In 2008, Shoukeir et al. reported a much smaller ACVRL1 deletion in an HHT-family with no associated developmental delay. That deletion did not include SCN8A but did reach into the keratin-gene cluster. SCL11A2 (# 206100) and KRT-genes are not 7
ACCEPTED MANUSCRIPT expected to give a neurophenotype. Interestingly our patient has no hematological disease nor skin feature. On the other hand, SCN8A is known to be involved in neurodevelopmental disorders (#600702),
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SCN8A encodes the voltage-gated sodium channel Nav1.6 alpha subunit 8, which is widely expressed in central and peripheral nervous systems (Plummer et al., 1998) and is involved in the initiation and propagation of neuronal action potentials. (Lorincz and Nusser, 2010)
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Patients carrying deleterious SCN8A variants exhibit variable intellectual deficiency, ataxia, epilepsy and autism spectrum disorder (Trudeau et al., 2006; O’Brien and Meisler, 2013;
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Rauch et al., 2012; Helbig and Tayoun, 2016; Anand et al., 2016; Larsen et al., 2015; Ohba et al., 2014; Wagnon et al., 2017; Veeramah et al., 2012). Here, the complete SCN8A deletion is likely to cause the moderate cognitive disability with probably no or little participation of the other genes included in the deletion. Movement disorders known to be associated with
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SCN8A mutations consist mainly of ataxia, paroxysmal kinesigenic dyskinesia and choreoathetosis (Larsen et al., 2015; Gardella et al., 2016). In our patient, neurological examination revealed the presence of mirror movements. Mirror movements are physiologic
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during childhood. They usually disappear by the age of 10 and their persistence in adulthood
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have been linked to various genetic conditions (Mayston et al., 1999; Farmer, 2005; Mayston et al., 1997; Depienne et al., 2011). Since SCN8A is widely expressed in central nervous system, mirror movements might be due to SCN8A haploinsufficiency, suggesting that this symptom may expand the phenotypic spectrum of movement disorders associated with SCN8A mutations. We suggest to consider this new clinical association linked to ACVRL1 and SCN8A as a new contiguous gene syndrome. In 1986, Schimkel proposed the term of continuous gene
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ACCEPTED MANUSCRIPT syndrome to explain the clinical association due to the deletion of several genes lying in proximity. For example, the well-known WAGR contiguous gene syndrome consists of the association of Wilms' tumor secondary to WT1 gene haploinsufficiency and aniridia due to PAX6 gene haploinsufficiency. In our case, the patient's phenotype is secondary to the
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haploinsufficiency of two very close genes. However, further cases are necessary to confirm the existence of a recurrent deletion.
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In sum, we proposed that the association of HHT features and mild cognitive disorders with mirror movement due to a large deletion encompassing the ACVRL1 and SCN8A genes
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constitutes a new contiguous gene syndrome. HHT features may be absent in childhood but an early diagnosis of 12q13.12q13.13 microdeletion based on the presence of a dysexecutive syndrome and/or mirror movement will allow to prevent some HHT complications. On the other hand, this report also highlights the benefit of searching for large rearrangements in
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the rare cases including unusual symptoms in association with HHT. Last but not least, it
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suggests that SCN8A might represent a new target for future research on mirror movement.
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ACCEPTED MANUSCRIPT Figure legend Figure 1. A: Array CGH showing the 1.58 Mb deletion in chromosome 12q13.12q13.13
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encompassing ACVRL1 and SCN8A. B: Decipher diagram for interval 12:51347169-52929181.
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ACCEPTED MANUSCRIPT Acknowledgements: The authors thank the patient and her family for their participation in the study and their agreement to this publication and Ms Chantal Silarakis from Lyon
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University Hospital’s library.
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