medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2021.09.14-25medgen-1974Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHМутации гена SLC26A4 у пациентов с аномалиями внутреннего уха IP-I, IP-II (Mondini) и/или EVA в ЯкутииMutation analysis of the SLC26A4 gene in patients in Yakutia with inner ear abnormalities: IP-I, IP-II (Mondini) and/or EVAКларовЛ. А.KlarovL. A.noemail@neicon.ruНиколаеваК. Ю.NikolaevaK. Yu.noemail@neicon.ruПшенниковаВ. Г.PshennikovaV. G.noemail@neicon.ruЧердоноваА. М.CherdonovaA. M.noemail@neicon.ruТерютинФ. М.TeryutinF. M.noemail@neicon.ruЛугиновН. В.LuginovN. V.noemail@neicon.ruКотляровП. М.KotlyarovP. M.noemail@neicon.ruБарашковН. А.BarashkovN. A.barashkov2004@mail.ruФГБНУ «Якутский научный центр комплексных медицинских проблем»РоссияYakut Scientific Center of Complex Medical ProblemsRussian FederationФГАОУ ВО «Северо-Восточный федеральный университет им. М.К. Аммосова»РоссияM.K. Ammosov North-Eastern Federal UniversityRussian FederationФГБНУ «Якутский научный центр комплексных медицинских проблем»; ФГАОУ ВО «Северо-Восточный федеральный университет им. М.К. Аммосова»РоссияYakut Scientific Center of Complex Medical Problems; M.K. Ammosov North-Eastern Federal UniversityRussian FederationФГБУ «Российский научный центр рентгенорадиологии» Минздрава РоссииРоссияRussian Scientific Center of Roentgenoradiology (RSCRR) of the Ministry of Healthcare of the Russian FederationRussian Federation2021091220212091425Copyright © Кларов Л.А., Николаева К.Ю., Пшенникова В.Г., Чердонова А.М., Терютин Ф.М., Лугинов Н.В., Котляров П.М., Барашков Н.А., 20212021Кларов Л.А., Николаева К.Ю., Пшенникова В.Г., Чердонова А.М., Терютин Ф.М., Лугинов Н.В., Котляров П.М., Барашков Н.А.Klarov L.A., Nikolaeva K.Y., Pshennikova V.G., Cherdonova A.M., Teryutin F.M., Luginov N.V., Kotlyarov P.M., Barashkov N.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/1974

Мутации гена SLC26A4 могут приводить как к формированию аутосомно-рецессивной тугоухости 4 типа (DFNB4, OMIM #600791), так и к синдрому Пендреда (PDS, OMIM #274600), при котором нейросенсорная потеря слуха сочетается с дисфункцией щитовидной железы, клинически проявляющейся во второй декаде жизни. Обе формы могут сопровождаться специфическими аномалиями внутреннего уха: IP-I, IP-II (Mondini) и/или EVA. В Якутии аудиологическими, рентгенологическими и молекулярно-генетическими методами обследовано 165 пациентов с врожденным нарушением слуха. При компьютерной томографии пирамиды височных костей у 9 из 165 (5,5%) пациентов были обнаружены аномалии IP-I, IP-II (Mondini) и/или EVA. Методом прямого секвенирования по Сэнгеру у этих 9 пациентов было проведено определение нуклеотидной последовательности гена SLC26A4 (21 экзон). В гене SLC26A4 обнаружено 5 ранее известных вариантов, среди которых 4 варианта относились к миссенс-заменам: c.85G>C p.(Glu29Gln), c.441G>A p.(Met147Ile), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln) и один вариант затрагивал донорный сайт сплайсинга - c.2089+1G>A (IVS18+1G>A). У 4-х из 9 пациентов патогенные варианты гена SLC26A4 обнаружены в гомозиготном или компаунд-гетерозиготном состоянии. Доля биаллельных мутаций гена SLС26A4 у пациентов с IP-I, IP-II (Mondini) и/или EVA составила 44,4%. Пациенты с биаллельными мутациями гена SLC26A4 имели тяжелые врожденные нарушения слуха (двусторонняя нейросенсорная тугоухость от III степени до глухоты), при этом доминирующим типом аномалий были IP-II (Mondini)+EVA (62,5%), аномалии IP-I не были выявлены ни у одного пациента. По совокупности полученных клинических и молекулярно-генетических данных у трех пациентов форма заболевания классифицирована как аутосомно-рецессивная тугоухость 4 типа (DFNB4), а у одной пациентки с двусторонней аномалией EVA, нейросенсорной тугоухостью III степени и узловым зобом (оперирован) подтвержден синдром Пендреда.

Mutations in the SLC26A4 gene can lead to both the formation of autosomal recessive deafness type 4 (DFNB4, OMIM#600791), and to Pendred’s syndrome (PDS, OMIM#274600), in which sensorineural hearing loss is combined with thyroid dysfunction, with both forms can be accompanied by specific anomalies of the inner ear: IP-I, IP-II (Mondini) and/or EVA. Using audiological, radiological and molecular genetics methods, 165 patients with congenital hearing impairment in Yakutia were examined. Computed tomography revealed IP-I, IP-II (Mondini) and/or EVA abnormalities in 9 of 165 (5,5%) patients. Then, using direct Sanger sequencing in these 9 patients, the nucleotide sequence of the coding regions of the SLC26A4 gene (21 exons) was determined. In total, 5 previously known variants were found in the SLC26A4 gene, among which 4 variants were missense substitutions: c.85G>C p.(Glu29Gln), c.441G>A p.(Met147Ile), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln) and one variant affected the splice donor site - c.2089+1G>A (IVS18+1G>A). In 4 out of 9 patients, pathogenic variants of the SLC26A4 gene were found in a homozygous or compound heterozygous state. The total contribution of biallelic mutations in the SLC26A4 gene among patients with inner ear anomalies was 44,4%. Patients with biallelic SLC26A4-mutations had several to profound bilateral sensorineural hearing loss. In patients with biallelic SLC26A4-mutations, the dominant type of anomaly was IP-II (Mondini)+EVA (62,5%), IP-I anomalies were not detected in any patient. In three patients we were able to confirm the diagnosis of DFNB4, and in one patient, due to the sum of phenotypic features (operated on for nodular goiter, autosomal recessive deafness with EVA), Pendred’s syndrome was diagnosed.

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The authors declare that there are no conflicts of interest present.