Pediatric Traumatology, Orthopaedics and Reconstructive SurgeryPediatric Traumatology, Orthopaedics and Reconstructive SurgeryОртопедия, травматология и восстановительная хирургия детского возрастаPediatric Traumatology, Orthopaedics and Reconstructive Surgery2309-39942410-8731Eco-Vector9111610.17816/PTORS91116Clinical studiesКлинические исследованияClinical studiesResearch ArticleСlinical and genetic characteristics of skeletal cyliopathies – short-rib thoracic dysplasiaКлинико-генетические характеристики скелетных цилиопатий — торакальных дисплазий с короткими ребрами骨骼纤毛病的临床和遗传特征研究： 短肋合并胸廓发育不良https://orcid.org/0000-0002-2672-629457204436561AAJ-8352-20214707-9184MarkovaTatiana V.МарковаТатьяна ВладимировнаMarkovaTatiana V.
Russian Federation

MD, PhD, Cand. Sci. (Med.)

канд. мед. наук

MD, PhD, Cand. Sci. (Med.)

markova@med-gen.ruhttps://orcid.org/0000-0002-7651-848536191914200K-8112-20135597-8832KenisVladimir M.КенисВладимир МарковичKenisVladimir M.
Russian Federation

MD, PhD, Dr. Sci. (Med.), Professor

д-р мед. наук, профессор

MD, PhD, Dr. Sci. (Med.), Professor

kenis@mail.ruhttp://www.rosturner.ru/kl4.htmhttps://orcid.org/0000-0003-1139-5573550228698001552-8550MelchenkoEvgeniy V.МельченкоЕвгений ВикторовичMelchenkoEvgeniy V.
Russian Federation

MD, PhD, Cand. Sci. (Med.)

канд. мед. наук

MD, PhD, Cand. Sci. (Med.)

emelchenko@gmail.comhttps://orcid.org/0000-0002-0021-9008571941850482024-2919KomolkinIgor A.КомолкинИгорь АлександровичKomolkinIgor A.
Russian Federation

MD, PhD, Dr. Sci. (Med.)

д-р мед. наук

MD, PhD, Dr. Sci. (Med.)

igor_komolkin@mail.ruhttps://orcid.org/0000-0003-4527-4518572218528396032-2080NagornovaTatiana S.НагорноваТатьяна СергеевнаNagornovaTatiana S.
Russian Federation

MD, laboratory geneticist

врач лабораторной генетики

MD, laboratory geneticist

t.korotkaya90@gmail.comhttps://orcid.org/0000-0002-5863-354357218497500AAD-6909-2022OsipovaDarya V.ОсиповаДарья ВалерьевнаOsipovaDarya V.
Russian Federation

MD, resident

врач-ординатор

MD, resident

osipova.dasha2013@yandex.ruhttps://orcid.org/0000-0001-7041-045X57196486863AAJ-8854-20217697-7472SemenovaNatalia A.СеменоваНаталия АлександровнаSemenovaNatalia A.
Russian Federation

MD, PhD, Cand. Sci. (Med.)

канд. мед. наук

MD, PhD, Cand. Sci. (Med.)

semenova@med-gen.ruhttps://orcid.org/0000-0003-1286-3842PetukhovaMarina S.ПетуховаМарина СергеевнаPetukhovaMarina S.
Russian Federation

MD, geneticist

врач-генетик

MD, geneticist

petukhova@med-gen.ruhttps://orcid.org/0000-0003-0724-9004DeminaNina A.ДеминаНина АлександровнаDeminaNina A.
Russian Federation

MD, geneticist

врач-генетик

MD, geneticist

demina@med-gen.ruhttps://orcid.org/0000-0002-5020-11807102655877K-3413-20187296-6097ZakharovaEkaterina Y.ЗахароваЕкатерина ЮрьевнаZakharovaEkaterina Y.
Russian Federation

MD, PhD, Dr. Sci. (Med.), Professor

д-р мед. наук, профессор

MD, PhD, Dr. Sci. (Med.), Professor

doctor.zakharova@gmail.comhttps://orcid.org/0000-0001-5602-28056701733307RRR-1000-20083747-7880DadaliElena L.ДадалиЕлена ЛеонидовнаDadaliElena L.
Russian Federation

MD, PhD, Dr. Sci. (Med.), Professor

д-р мед. наук, профессор

MD, PhD, Dr. Sci. (Med.), Professor

genclinic@yandex.ruhttps://orcid.org/0000-0002-3133-80188296960500L-3633-20185544-8742KutsevSergey I.КуцевСергей ИвановичKutsevSergey I.
Russian Federation

MD, PhD, Dr. Sci. (Med.), Professor, Сorresponding Member of RAS

д-р мед. наук, профессор, чл.-корр. РАН

MD, PhD, Dr. Sci. (Med.), Professor, Сorresponding Member of RAS

kutsev@mail.ruResearch Centre for Medical GeneticsМедико-генетический научный центр имени академика Н.П. БочковаResearch Centre for Medical GeneticsH. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma SurgeryНациональный медицинский исследовательский центр детской травматологии и ортопедии имени Г.И. ТурнераH. Turner National Medical Research Center for Сhildren’s Orthopedics and Trauma SurgeryNorth-Western State Medical University named after MechnikovСеверо-Западный государственный медицинский университет им. И.И. Мечникова Минздрава РоссииNorth-Western State Medical University named after MechnikovH. Turner National Medical Research Centre for Children’s Orthopedics and Trauma SurgeryНациональный медицинский исследовательский центр детской травматологии и ортопедии имени Г.И. ТурнераH. Turner National Medical Research Centre for Children’s Orthopedics and Trauma SurgerySaint Petersburg State Research Institute of PhthisiopulmonologyСанкт-Петербургский научно-исследовательский институт фтизиопульмонологииSaint Petersburg State Research Institute of Phthisiopulmonology030220222403202210143562612202128012022Copyright ©; 2022, Markova T.V., Kenis V.M., Melchenko E.V., Komolkin I.A., Nagornova T.S., Osipova D.V., Semenova N.A., Petukhova M.S., Demina N.A., Zakharova E.Y., Dadali E.L., Kutsev S.I.Copyright ©; 2022, Маркова Т.В., Кенис В.М., Мельченко Е.В., Комолкин И.А., Нагорнова Т.С., Осипова Д.В., Семенова Н.А., Петухова М.С., Демина Н.А., Захарова Е.Ю., Дадали Е.Л., Куцев С.И.Copyright ©; 2022, Markova T., Kenis V., Melchenko E., Komolkin I., Nagornova T., Osipova D., Semenova N., Petukhova M., Demina N., Zakharova E., Dadali E., Kutsev S.2022Markova T.V., Kenis V.M., Melchenko E.V., Komolkin I.A., Nagornova T.S., Osipova D.V., Semenova N.A., Petukhova M.S., Demina N.A., Zakharova E.Y., Dadali E.L., Kutsev S.I.Маркова Т.В., Кенис В.М., Мельченко Е.В., Комолкин И.А., Нагорнова Т.С., Осипова Д.В., Семенова Н.А., Петухова М.С., Демина Н.А., Захарова Е.Ю., Дадали Е.Л., Куцев С.И.Markova T., Kenis V., Melchenko E., Komolkin I., Nagornova T., Osipova D., Semenova N., Petukhova M., Demina N., Zakharova E., Dadali E., Kutsev S.https://creativecommons.org/licenses/by-nc-nd/4.0/https://journals.eco-vector.com/turner/article/view/91116

BACKGROUND: Ciliopathies include the large group of hereditary diseases caused by mutations in the genes encoding primary cilia components. The largest type of skeletal ciliopathies is short-rib thoracic dysplasia.

AIM: This study describes the clinical and genetic characteristics of Russian patients with STRD with or without polydactyly caused by mutations in the genes DYNC2H1, DYNC2I2, IFT80, and IFT140.

MATERIALS AND METHODS: A comprehensive examination of 10 unrelated children aged from 9 days to 9 years, with phenotypic signs of short-rib thoracic dysplasia with or without polydactyly, was conducted. The diagnosis was confirmed using genealogical analysis, clinical examination, neurological examination, radiography, and targeted sequencing of a panel consisting of 166 genes responsible for the development of inherited skeletal pathology.

RESULTS: As a result of the molecular genetic analysis, four short-rib thoracic dysplasia genetic variants were identified. Seven patients were diagnosed with short-rib thoracic dysplasia type 3, and three unique patients were diagnosed with types 11, 2, and 9 due to mutations in the DYNC2H1 and DYNC2I2, IFT80, and IFT140 genes, respectively. From the 14 detected variants, six were identified for the first time. As in the previously described patient samples, in the analyzed sample, more than half of the cases were due to a mutation in the DYNC2H1 gene, which is responsible for the SRTD type 3. The differences in the severity of clinical manifestations and the disease course in patients with mutations in certain regions of the gene, which have a different effect on its protein product function, have been shown.

CONCLUSIONS: The results of this molecular genetic study broaden the spectrum of mutations in the DYNC2H1, DYNC212, and IFT140 genes causing short-rib thoracic dysplasia and confirm the usefulness of the whole-exome sequencing as the most informative method for identifying mutations of the genetically heterogeneous short-rib thoracic dysplasia group.

Обоснование. Цилиопатии — большая группа наследственных заболеваний, обусловленных мутациями в генах, кодирующих различные компоненты первичных ресничек. Наиболее многочисленную группу скелетных цилиопатий составляют торакальные дисплазии с короткими ребрами.

Цель — описание клинико-генетических характеристик российских больных торакальными дисплазиями с короткими ребрами с или без полидактилии, обусловленными мутациями в генах DYNC2H1, DYNC2I2, IFT80, IFT140.

Материалы и методы. Проведено комплексное обследование 10 детей из неродственных семей в возрасте от 9 сут жизни до 9 лет с фенотипическими признаками торакальной дисплазии с короткими ребрами с или без полидактилии. Для уточнения диагноза использовали генеалогический анализ, клиническое обследование, неврологический осмотр по стандартной методике с оценкой психоэмоциональной сферы, рентгенографию и таргетное секвенирование панели, состоящей из 166 генов, ответственных за развитие наследственной скелетной патологии.

Результаты. В результате молекулярно-генетического анализа у наблюдаемых больных выявлено четыре генетических варианта торакальной дисплазии с короткими ребрами. У семерых больных диагностирована торакальная дисплазия с короткими ребрами 3-го типа, по одному больному — дисплазии 11, 2 и 9-го типа, обусловленные мутациями в генах DYNC2H1, DYNC2I2, IFT80 и IFT140 соответственно. Из 14 нуклеотидных замен шесть обнаружены впервые. Как и в ранее описанных выборках, у большинства анализируемых пациентов заболевание обусловлено мутацией в гене DYNC2H1, ответственном за возникновение торакальной дисплазии с короткими ребрами 3-го типа. Существуют различия в тяжести клинических проявлений и течении заболевания у больных с мутациями в отдельных участках гена, оказывающих различное влияние на функцию его белкового продукта.

Заключение. Результаты молекулярно-генетического исследования расширяют спектр мутаций в генах DYNC2H1, DYNC212, IFT140, обусловливающих развитие торакальной дисплазии с короткими ребрами 3, 11 и 9-го типов и подтверждают использование секвенирования экзома как основного метода идентификации мутаций генетически гетерогенной группы торакальных дисплазий с короткими ребрами.

论证。纤毛病是由编码初级纤毛各种成分的基因突变引起的一大类遗传疾病。最常见的一组骨骼纤毛病是胸廓发育不良伴短肋骨。

本研究的目的描述由DYNC2H1、DYNC2I2、IFT80、IFT140基因突变引起的俄罗斯胸段发育不良伴短肋骨患者的临床和遗传特征。

材料与方法。对10例无亲属关系的患儿进行综合检查，年龄9天至9岁，均有胸廓发育不良伴短肋骨表型征象，有多指或无多指。为了阐明诊断，使用了家谱分析、临床检查、神经学检查（根据标准技术进行情绪与心理领域评估）、X射线和对166个负责遗传性骨骼病理发展的基因进行定向测序。

结果。作为分子遗传分析的结果，4个基因变异胸廓发育不良与短肋骨被确定在观察的患者。由于DYNC2H1、DYNC2I2、IFT80和IFT140基因的突变，7名患者被诊断为短肋合并胸廓发育不良3型，1名患者为11型，1名患者为2型，1名患者为9型。在14个核苷酸替换中，有6个是首次检测到的。与前面描述的样本一样，在大多数被分析的患者中，该疾病是由DYNC2H1基因突变引起的，该基因突变导致短肋合并胸廓发育不良3型的发生。基因某些部分发生突变的患者，其临床表现的严重程度和疾病的病程存在差异。这些突变对其蛋白质产物的功能有不同的影响。

结论。分子遗传学研究的结果扩大了DYNC2H1、DYNC212、IFT140等基因的突变范围。这些突变是导致3、11和9型短肋胸廓发育不良的原因，并证实了在短肋胸廓发育不良的遗传异质性群体中使用外显子测序作为识别突变的主要方法。

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