Mucopolysaccharidosis-plus syndrome (MPSPS) is an autosomal-recessive disorder caused by c.1492C>T (p.R498W) in the VPS33A gene. MPSPS is a severe disorder that causes a short lifespan in patients. Currently, there is no specific treatment for patients. The Yakut population is more prone to this disease than others. Diagnosing MPSPS relies on clinical manifestations, and genetic testing (GT) is used to confirm the diagnosis. In this research, we examined two pregnancy cases, one of which involved a prenatal diagnosis for MPSPS. Notably, neither pregnant woman had a known family history of the disorder. During their pregnancies, both women underwent prenatal ultrasonography, which revealed increased prenasal thickness during the second trimester. In the first case, ultrasonography indicated increased prenasal thickness in the second trimester, but a definitive diagnosis was not made at that time. The patient was eventually diagnosed with MPSPS at 11 months of age. On the contrary, in the second case, GT uncovered that the parents were carriers of MPSPS. Consequently, a placental biopsy was performed, leading to an early diagnosis of MPSPS. This study emphasizes the importance of ultrasonography findings in prenatal MPSPS diagnosis. Combining ultrasonography with GT can be a valuable approach to confirming MPSPS at an early stage, allowing for the appropriate planning of delivery methods and medical care. Ultimately, this comprehensive approach can significantly enhance the quality of life of both affected patients and their parents.
В статье представлены результаты молекулярно-генетических исследованиий больных с множественной экзостозной хондродисплазией (МЭХД), причиной которой явилась редкая мутация в гене EXT2. Исследованы 65 больных с МЭХД и их родственников из 30 неродственных семей. Для молекулярно-генетического анализа было использовано массовое параллельное секвенирование и прямое секвенирование по Сэнгеру. У 16 больных из 4 семей с клиническим диагнозом МЭХД была выявлена редкая нонсенс-мутация c.751С>T в экзоне 5 гена EXT2 в гетерозиготном состоянии. Here we present molecular genetic studies of Yakut patients with hereditary multiple exostoses (HME), which caused by a rare mutation in the EXT2 gene. A total of 65 patients with clinical diagnosis of HME and their relatives from 30 unrelated families were examined. For molecular genetic analysis, massive parallel sequencing (MPS) and direct Sanger sequencing were used. In 16 patients from 4 families with a clinical diagnosis of HME, a rare heterozygous nonsense mutation c.751C> T was detected in exon 5 of the EXT2.
Введение. Множественная экзостозная хондродисплазия (МЭХД) - наследственное аутосомно-доминантное заболевание скелета, которое характеризуется образованием множественных хрящевых экзостозов в зонах роста костей. Консультирование семей с МЭХД является сложной задачей для врача-генетика. В статье приведены клинические, молекулярно-генетические данные обследования большой якутской семьи с аутосомно-доминантной наследственной МЭХД, причиной которой является редкая мутация в гене EXT2. Цель: проведение клинико-генеалогического, молекулярно-генетического обследования больных с клиническим диагнозом МЭХД. Методы. В исследование включены 4 поколения одной якутской семьи (11 больных и здоровых членов). Секвенирование экзома одного члена семьи (ДНК пробанда) проводилось на секвенаторе MiSeq Illumina с использованием панели, включающей 4800 генов. Патогенность выявленной мутации подтверждалась in silico, а также секвенированием по Сэнгеру с использованием ДНК пробанда, его родителей. Данный метод также был использован для выявления мутации у остальных членов семьи. Результаты. В результате молекулярно-генетического исследования у 7 членов семьи с клиническим диагнозом МЭХД была выявлена редкая нонсенс-мутация c.751С>T в экзоне 5 гена EXT2 в гетерозиготном состоянии. Данная мутация отсутствовала у 4 здоровых членов этой семьи, а также в 10 образцах из контрольной группы. Оценка патогенности выявленной мутации показала, что данная мутация является причиной возникновения МЭХД в якутской семье. Заключение. Ранняя медицинская помощь пациентам с диагнозом МЭХД может дать возможность оказания медицинской помощи пациентам специалистами разного профиля, а также сосредоточить внимание врачей на ортопедических проблемах в раннем возрасте. Introduction. Multiple osteohondromas (MO) is an autosomal dominant inherited skeletal disease characterized by the formation of multiple cartilaginous exostoses in the areas of growth in a long bones. Difficult issues arise for the genetic counseling of families with MO. We presents the clinical and molecular genetic analysis of four-generation Yakut family with an autosomal dominant inherited MO, caused by a rare mutation in the EXT2 gene. Aim: сonducting a clinical, genealogical, molecular genetic study of patients with a clinical diagnosis MO. Methods. Targeted panel sequencing performed for the 4800 known candidate genes using Trusight One Sequencing Panel (Illumina Inc., USA) on one sample (DNA of proband). Sanger sequencing was performed for validation of candidate disease causing mutation in DNA from a proband and family members. Results. A rare EXT2 nonsense mutation (c.751C> T, p.Gln251*) was revealed by targeted exome sequencing and validated by Sanger sequencing in the 7 MO-affected members of this family. The variant was interpreted as pathogenic based on an in silico analysis. This mutation was absent in 4 healthy members of this family and in 10 controls. Conclusions. This is the first study of EXT2 gene mutation in a Russian patients from Yakut family with MO. Timely health care of patients with diagnosis of MO can contribute to establishment coordinated multispecialty management of the patient focusing on the orthopedic problems issues through childhood.
Multiple hereditary exostoses (MHE) is a genetically heterogeneous disease with an autosomal dominant type of inheritance, a very large proportion of family cases. The incidence of the disease in various Caucasian populations is from 1.3 to 2 per 100 thousand. The clinical picture is characterized by the presence of multiple cartilaginous outgrowths in the metaphysics of long tubular bones. The most common variant is mutations in EXT genes. For the first time in the Republic of Sakha (Yakutia), a molecular genetic analysis of multiple exostosis chondrodysplasia was carried out. We investigated 57 patients from 31 unrelated families with a clinical diagnosis of MECHD by mass parallel sequencing (MPS) for all coding EXT2 regions followed by validation of results by direct Sanger sequencing. As a result, frequent major mutations c.409delA (p.Ile137fs), c.751C > T (p.Gln251 *) in the ЕХТ2 gene in Yakuts were revealed.
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