Russian Journal of Child NeurologyRussian Journal of Child NeurologyРусский журнал детской неврологии2073-88032412-9178Publishing House ABV Press28610.17650/2073-8803-2019-14-1-49-53CLINICAL OBSERVATIONSКЛИНИЧЕСКИЕ НАБЛЮДЕНИЯGillespiе syndrome, caused by previously undescribed mutation in the gene ITPR1Синдром Гиллеспи, обусловленный ранее не описанной мутацией в гене ITPR1SharkovaI. V.ШарковаИ. B.
Russian Federation

1 Moskvorechye St., Moscow 115522

Инна Валентиновна Шаркова 

115522 Москва, ул. Москворечье, 1

sharkova-inna@rambler.ruAkimovaI. A.АкимоваИ. А.
Russian Federation

1 Moskvorechye St., Moscow 115522

115522 Москва, ул. Москворечье, 1

KhlebnikovaO. V.ХлебниковаО. В.
Russian Federation

1 Moskvorechye St., Moscow 115522

115522 Москва, ул. Москворечье, 1

DadaliE. L.ДадалиЕ. Л.
Russian Federation

1 Moskvorechye St., Moscow 115522

115522 Москва, ул. Москворечье, 1

Research Centre for Medical GeneticsФГБНУ «Медико-генетический научный центр»1501201914149532305201923052019Copyright ©; 2019, ABV-PressCopyright ©; 2019, АБВ-пресс2019ABV-PressАБВ-прессhttps://rjdn.abvpress.ru/jour/about/editorialPolicieshttps://rjdn.abvpress.ru/jour/article/view/286

Gillespie syndrome is one of the rare monogenic syndromes characterized by a combination of congenital muscular hypotonia, delayed psychomotor and speech development, ataxia and hypoplasia of the iris. The cause of disease – homozygous, compound heterozygous and heterozygous mutations in the gene ITPR1.

We described a case history of a child of 1 year and 8 months whose parents were complaining of severe delay in psychomotor and speech development, and a violation of the functions of the visual analyzer. Neurological and ophthalmologic examinations were performed according to a standard procedure. Search for mutations was carried out using high-performance exome sequencing on NextSeg 500 (Illumina, USA) with an average coverage of at least 70–100x.

Clinical and genetic characteristics of the patient with Gillespie syndrome due to the newly identified heterozygous missense mutation are presented. Mutation 1865T˃S in the 18 exon of the ITPR1 gene was found during the new generation sequencing of the exome. In the future, these data can be used to predict the characteristics of clinical manifestations and the severity of Gillespie syndrome, when a similar nucleotide substitution will be found in other patients.

Синдром Гиллеспи – один из редких моногенных синдромов, характерным признаком которого является сочетание врожденной мышечной гипотонии, задержки психомоторного и речевого развития, атаксии и гипоплазии радужки. К его возникновению приводят гомозиготные, компаунд-гетерозиготные и гетерозиготные мутации в гене ITPR1.

Под нашим наблюдением находился ребенок в возрасте 1 года 8 мес по поводу жалоб родителей на грубую задержку психомоторного и речевого развития и нарушение функций зрительного анализатора. Неврологический и офтальмологический осмотры больного проводили по стандартной методике. Поиск мутаций выполняли с использованием высокопроизводительного экзомного секвенирования на платформе NextSeg 500 (Illumina, США) со средним покрытием не менее 70–100х.

Представлены клинико-генетические характеристики больного с синдромом Гиллеспи, обусловленным впервые выявленной при секвенировании экзома нового поколения гетерозиготной миссенс-мутацией с.1865Т˃С в 18-м экзоне гена ITPR1. В дальнейшем эти данные могут быть использованы для прогнозирования особенностей клинических проявлений и тяжести течения при обнаружении сходной нуклеотидной замены у других больных с синдромом Гиллеспи.

Gillespie syndromesequencing of new generation exomeITPR1 genemonogenic syndromessevere retardation of motor and speech developmentintellectual deficiencyiris hypoplasiaaniridiamental retardationcerebellar ataxiaсиндром Гиллесписеквенирование экзома нового поколенияген ITPR1инозитол-145-трифосфатный рецептор кальциевых каналовмоногенные синдромытяжелая задержка психомоторного и речевого развитиягипоплазия радужкианиридияумственная отсталостьмозжечковая атаксия1. Berridge M.J. Inositol trisphosphate and calcium signalling mechanisms. Biochim Biophys Acta 2009;1793(6):933–40. PMID: 19010359. DOI: 10.1016/j.bbamcr.2008.10.005.Berridge M.J. Inositol trisphosphate and calcium signalling mechanisms. Biochim Biophys Acta 2009;1793(6):933–40. PMID: 19010359. DOI: 10.1016/j.bbamcr.2008.10.005.2. Foskett J.K., White C., Cheung K.H., Mak D.O. Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 2007;87(2):593–658. PMID: 17429043. DOI: 10.1152/physrev.00035.2006.Foskett J.K., White C., Cheung K.H., Mak D.O. Inositol trisphosphate receptor Ca2+ release channels. Physiol Rev 2007;87(2):593–658. PMID: 17429043. DOI: 10.1152/physrev.00035.2006.3. Gerber S., Alzayady K.J., Burglen L. et al. Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome. Am J Hum Genet 2016;98(5):971–80. PMID: 27108797. DOI: 10.1016/j.ajhg.2016.03.004.Gerber S., Alzayady K.J., Burglen L. et al. Recessive and dominant de novo ITPR1 mutations cause Gillespie syndrome. Am J Hum Genet 2016;98(5):971–80. PMID: 27108797. DOI: 10.1016/j.ajhg.2016.03.004.4. Gillespie F.D. Aniridia, cerebellar ataxia, and oligophrenia in siblings. Arch Ophthal 1965;73:338–41. PMID: 14246186. DOI: 10.1001/archopht.1965.00970030340008.Gillespie F.D. Aniridia, cerebellar ataxia, and oligophrenia in siblings. Arch Ophthal 1965;73:338–41. PMID: 14246186. DOI: 10.1001/archopht.1965.00970030340008.5. Hara K., Shiga A., Nozaki H. et al. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology 2008;71(8):547–51. PMID: 18579805. DOI: 10.1212/01.wnl.0000311277.71046.a0.Hara K., Shiga A., Nozaki H. et al. Total deletion and a missense mutation of ITPR1 in Japanese SCA15 families. Neurology 2008;71(8):547–51. PMID: 18579805. DOI: 10.1212/01.wnl.0000311277.71046.a0.6. Human Gene Mutation Database. Available at: https://portal.biobase-international.com/hgmd/pro/all.php.Human Gene Mutation Database. Available at: https://portal.biobase-international.com/hgmd/pro/all.php.7. Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders. Inositol 1,4,5-triphosphate receptor, type 1; ITPR1. Available at: http://omim.org/entry/147265.Online Mendelian Inheritance in Man. An Online Catalog of Human Genes and Genetic Disorders. Inositol 1,4,5-triphosphate receptor, type 1; ITPR1. Available at: http://omim.org/entry/147265.8. Huang L., Warman J., Carter M.T. et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphan J Rare Dis 2012;7:67–73. PMID: 22986007. DOI: 10.1186/1750-1172-7-67.Huang L., Warman J., Carter M.T. et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphan J Rare Dis 2012;7:67–73. PMID: 22986007. DOI: 10.1186/1750-1172-7-67.9. Marelli C., van de Leemput J., Johnson J.O. et al. SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. Arch Neurol 2011;68(5):637–43. PMID: 2155563. DOI: 10.1001/archneurol.2011.81.Marelli C., van de Leemput J., Johnson J.O. et al. SCA15 due to large ITPR1 deletions in a cohort of 333 white families with dominant ataxia. Arch Neurol 2011;68(5):637–43. PMID: 2155563. DOI: 10.1001/archneurol.2011.81.10. McEntagart M., Williamson K.A., Rainger J.K. et al. A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominantnegative effect. Am J Hum Genet 2016;98: 981–92. DOI: 10.1016/j.ajhg.2016.03.018.McEntagart M., Williamson K.A., Rainger J.K. et al. A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominantnegative effect. Am J Hum Genet 2016;98: 981–92. DOI: 10.1016/j.ajhg.2016.03.018.11. Sasaki M., Ohba C., Iai M. et al. Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. J Neurol 2015;262(5):1278–84. PMID: 27108798ю DOI: 10.1007/s00415015-7705-8.Sasaki M., Ohba C., Iai M. et al. Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. J Neurol 2015;262(5):1278–84. PMID: 27108798ю DOI: 10.1007/s00415015-7705-8.12. Statland J., Phillips L., Trivedi J.R. Muscle channelopathies. Neurol Clin 2014;32(3):801–15. PMID: 25037091. DOI: 10.1016/j.ncl.2014.04.002.Statland J., Phillips L., Trivedi J.R. Muscle channelopathies. Neurol Clin 2014;32(3):801–15. PMID: 25037091. DOI: 10.1016/j.ncl.2014.04.002.13. Synofzik M., Beetz C., Bauer C. et al. Spinocerebellar ataxia type 15: diagnostic assessment, frequency and phenotypic features. J Med Genet 2011;48(6):407–12. PMID: 2136776. DOI: 10.1136/jmg.2010.087023Synofzik M., Beetz C., Bauer C. et al. Spinocerebellar ataxia type 15: diagnostic assessment, frequency and phenotypic features. J Med Genet 2011;48(6):407–12. PMID: 2136776. DOI: 10.1136/jmg.2010.08702314. Van Dijk T., Barth P., Reneman L. et al. A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias. Am J Med Genet 2017;173(1):207–12. PMID: 27862915. DOI: 10.1002/ajmg.a.37962.Van Dijk T., Barth P., Reneman L. et al. A de novo missense mutation in the inositol 1,4,5-triphosphate receptor type 1 gene causing severe pontine and cerebellar hypoplasia: expanding the phenotype of ITPR1-related spinocerebellar ataxias. Am J Med Genet 2017;173(1):207–12. PMID: 27862915. DOI: 10.1002/ajmg.a.37962.15. Webster G., Berul C.I. An update on channelopathies: from mechanisms to management. Circulation 2013;127(1):126–40. PMID: 23283857. DOI: 10.1161/circulationaha.111.060343.Webster G., Berul C.I. An update on channelopathies: from mechanisms to management. Circulation 2013;127(1):126–40. PMID: 23283857. DOI: 10.1161/circulationaha.111.060343.16. Yamada N., Makino Y., Clark R.A. et al. Human inositol 1,4,5-triphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization. Biochem J 1994;302(Pt 3): 781–90. PMID: 7945203. DOI: 10.1042/bj3020781.Yamada N., Makino Y., Clark R.A. et al. Human inositol 1,4,5-triphosphate type-1 receptor, InsP3R1: structure, function, regulation of expression and chromosomal localization. Biochem J 1994;302(Pt 3): 781–90. PMID: 7945203. DOI: 10.1042/bj3020781.17. Yule D.I., Betzenhauser M.J., Joseph S.K. Linking structure to function: recent lessons from inositol 1,4,5-trisphosphate receptor mutagenesis. Cell Calcium 2010;47(6):469–79. PMID: 20510450. DOI: 10.1016/j.ceca.2010.04.005.Yule D.I., Betzenhauser M.J., Joseph S.K. Linking structure to function: recent lessons from inositol 1,4,5-trisphosphate receptor mutagenesis. Cell Calcium 2010;47(6):469–79. PMID: 20510450. DOI: 10.1016/j.ceca.2010.04.005.