КОМБИНИРОВАННЫЕ ГЕНЕТИЧЕСКИЕ НАРУШЕНИЯ У БОЛЬНЫХ КОАГУЛОПАТИЯМИ

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  • заместитель директора по научному отделу РНПМЦ гематологии
  • Заместитель главного врача Республиканского научно-практического медицинского центра гематологии (РНПМЦ) МЗ РУз
  • Докторант Республиканского научно-практического медицинского центра гематологии (РНПМЦ) МЗ РУз
  • Врач высшей категории. докторант Республиканского научно-практического медицинского центра гематологии (РНПМЦ) МЗ РУз
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Махмудова, А., Berger , I., Madasheva, A., & Ulugova, S. (2022). КОМБИНИРОВАННЫЕ ГЕНЕТИЧЕСКИЕ НАРУШЕНИЯ У БОЛЬНЫХ КОАГУЛОПАТИЯМИ. Международный журнал научной педиатрии, (1), 23–29. извлечено от https://inlibrary.uz/index.php/scientific_pediatrics/article/view/7757
Mahmudova Aziza Dzhumanovna, заместитель директора по научному отделу РНПМЦ гематологии

Доктор медицинских наук

Berger Inna Viktorovna, Заместитель главного врача Республиканского научно-практического медицинского центра гематологии (РНПМЦ) МЗ РУз

Доктор философских (PhD) медицинских наук

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Аннотация

В статье представлены имеющиеся в литературе данные о сочетанной патологии с наследственной коагулопатией и включены собственные статистические расчеты и 4 клинических случая сочетания гемофилии А, болезни фон Виллебранда с дефектами твердого неба, генетический локус которых расположен в непосредственной близости от ген F8. Мутации и изменения в структуре белка гена F8 могут приводить к развитию как спорадических форм гемофилии, так и встречаться у больных с наследственной предрасположенностью. Методы исследования: коагулологический, данные осмотра и опроса. Вывод: необходимо широко внедрять в Узбекистане методы молекулярно-генетического исследования и пренатальной диагностики.


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International Journal of Scientific Pediatrics

COMBINED GENETIC DISORDERS IN PATIENTS WITH COAGULOPATHYЕЙ

Makhmudova A.D.

1

, Berger I.V.

2

, Madasheva O.G.

3

, Ulugova Sh.T.

4

1. Doctor of Medical Sciences, Deputy Director for the Scientific Department of the

RSNPMC of Hematology.

2. Doctor of Philosophy (PhD) of Medical Sciences, Deputy Chief Physician at the

Republican Scientific and Practical Medical Center for Hematology (RNPMCH) of the

Ministry of Health of the Republic of Uzbekistan.

ORCID

.

3. Doctoral student at the Republican Scientific and Practical Medical Center for

Hematology (RNPMCH) of the Ministry of Health of the Republic of Uzbekistan.

4. Doctor of the higher category. doctoral student at the Republican Scientific and Practical

Medical Center for Hematology (RNPMCH) of the Ministry of Health of the Republic of

Uzbekistan,

ORCID

Academic Editor:

Arzikulov A.

Professor, Andijan State Medical

Institute

Received:

20 may 2022

Accepted:

27 May 2022

Published:

31 May 2022

Publisher’s Note:

IJSP stays

neutral with regard to jurisdictional

claims in published maps and

institutional affiliations.

Copyright:

© 2022 by the

authors. Licensee IJSP, Andijan,

Uzbekistan. This article is an open

access article distributed under

the terms and conditions of the

Creative Commons Attribution

(CC BY) license (https://creative-

commons.org/licenses/by/4.0/).

Abstract.

The article presents the available literature data on combined pathologies with

hereditary coagulopathy and includes our own statistical calculations and 4 clinical cases

of a combination of Hemophilia A, von Willebrand disease with hard palate defects, the

genetic locus of which is located in the immediate vicinity of the F8 gene. Mutations

and changes in the protein structure of the F8 gene can lead to the development of

both sporadic forms of hemophilia and occur in patients with a hereditary predisposition.

Research methods: coagulological, examination and questionnaire data. Conclusion: it

is necessary to widely introduce methods of molecular genetic research and prenatal

diagnostics in Uzbekistan.

Key words:

F8 gene, Hemophilia A, von Willebrand disease, hereditary pathologies,

chromosomal disorders, cleft palate, color blindness.

Article

OPEN ACCESS

www.ijsp.uz

published: 31 May 2022

doi.org/10.56121/2181-2926-2022-1-23-29

May 2022 / Issue 01 / Article 03

23

IJSP

Introduction.

The X chromosome contains 867 identified genes;

most of these genes are responsible for the development of tissues

such as bones, nerves, blood, liver, kidneys, retina, ears, ear, heart,

skin, and teeth. There are at least 533 disorders due to the involvement

of genes on the X chromosome. A «trait» or «disorder» defined by a

gene on the X chromosome demonstrates X-linked inheritance [1].

The normal human karyotype includes 22 autosomes and

2 sex chromosomes (XX for women and XY for men). Figure 1

shows a photo of a male karyotype obtained in the laboratory of

molecular genetics and cytogenetics on a direct light fluorescent

microscope Axio Scope.A1 (Zeiss, Germany) at the RSNPMC of

Hematology of the Ministry of Health of the Republic of Uzbekistan.

It is known that the F8 and F9 genes located on the X

chromosome at the Xq28 and Xq27 loci are responsible for the

formation of blood coagulation factors VIII and IX [2,8,9]. Changing

genes in these locations leads to the development of such pathologies

as Hemophilia A, Hemophilia B and von Willebrand disease.

Figure 2 shows a map of the X chromosome and loci responsible

for the development of sex-related hereditary diseases, in particular

hemophilia A, hemophilia B, and von Willebrand disease. In these

regions of the gene, many different mutations can occur, which

also lead to the development of such diseases as hemolytic

anemia, adrenoleukodystrophy, blinding with bright colors, etc. [1].


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Rice. 1 Chromosome set of a healthy person, male karyotype, normal (46, XY).

The photo was taken in the Laboratory of Molecular Cytogenetics of the Republican

Scientific and Practical Center for Hematology of the Ministry of Health of the Republic

of Uzbekistan. Ph.D. Assesorova Yu.Yu.

Rice. 2 X-chromosome with an ideogram. Location of the F8 and F genes 9. The arrows

mark the Xq28 and Xq2 loci responsible for the development of hemophilia A and B.

P is the short arm, q is the long arm. Dark and light stripes are segments conditionally

taken as a gene. Photo taken by Ph.D. Assesorova Yu.Yu. in the laboratory of molecular

cytogenetics of the SRCPM of Hematology of the Ministry of Health of the Republic of

Uzbekistan.

27 exons contains the F8 gene and encodes two alternative transcripts.

The first option contains instructions for making the large glycoprotein

isoform A, the ß-globulin (antihemophilic globulin) protein, which is called

coagulation factor VIII. The second transcript encodes a small protein

(isoform B), which mainly consists of the phospholipid-binding domain of

factor VIIIa and is required for coagulant activity [1,8].

The F8 gene can be called by its content as a “gene within a gene”,

since an RNA gene (MIR1184-1) and two pseudogenes (EEF1A1P31,

LOC100419792) are nested in its structure, and 2 protein-coding genes

(F8A1) are located on the opposite positive strand , H2AB1) and 2

recombination regions (LOC106146150, LOC106146143). Coagulation

factor VIII is composed of multiple Cu-oxidase (CuRO) and FA58C

domains. This protein circulates in the blood in an inactive form, which is

associated with another molecule, von Willebrand factor [7].

Changes in these genes of factors VIII and IX, leading to the

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development of pathology, can be represented by single nucleotide

substitutions that change the reading frames, deletions of chromosome

fragments containing these loci, inversions, and other genetic

rearrangements [12]. Until recently, the genetic diagnosis of hemophilia,

taking into account the subtype of the disease, was difficult due to the

fact that the construction of this gene is extremely complex and rather

voluminous, and also due to the wide range of potential mutations. An

effective study of the genetic determinant of the disease has become

possible due to the development of DNA sequencing techniques and the

improvement of molecular cytogenetic equipment.

M.J. McGinniss et all. (USA, 1993) it was shown that 40% of patients

with severe hemophilia A, who previously failed to identify any mutation

during screening or sequencing, have inversions of the F8 gene. Patients

have one of two major inversions—with a breakpoint in intron 22 or with

a breakpoint in either of the two copies of the F8 gene (Inversion with a

breakpoint in the distal portion of the F8 gene is the more common variant)

[7]. These inversions explain why deletions and point mutations have not

yet been found in such patients and why transcription of intron 22 and

exon 23 is impossible [11].

Quite a few cases of a combination of congenital FVIII deficiency and

color blindness are known in the world [12], since the segments responsible

for color perception and hemophilia gene loci are quite close to each other.

The OPN1LW, OPN1MW, and OPN1SW genes code for red, green, and

blue-sensitive receptors. Mutations in the OPN1LW and OPN1MW genes

lead to the development of red-green color blindness, and in the OPN1SW

gene, blue-yellow color blindness. If a mutation simultaneously affects two

genes, OPN1LW and OPN1MW, monochromasia develops [2].

Back in 1991, when working with data from the decoding of the human

genome, a gene was found that is also located on the X chromosome and

is responsible for the development of the “cleft palate” - an altered TBX22

gene [1].

Cleft palate is one of the most common congenital malformations

and, according to different authors, occurs in 1 born baby per 1000, which

is 0.1%, most of which are boys [6]. In some European regions (Denmark,

Czech Republic) and the Russian Federation, these figures are an order

of magnitude higher, and 1 child out of 600–700 babies is born with this

defect, and half of them also have a defect in the form of a cleft lip [3].

Most often, the cleft palate is registered in infants born in Asia and North

America, and is almost never found among the inhabitants of Africa [4].

The results of whole genome sequencing conducted in 2004 in

Scandinavia from 574 families from 13 populations showed the relationship

of different loci of chromosomes 1, 2, 4, 6, 14, 17 and 19 (IRF6, TGF-α,

MSX1, T-βr1, FOXFE1, RTCH, ROR2, TGF-β3, RARA, PVRL1) with the

risk of developing non-syndromic congenital cleft lip with/without palate

[5]. Some of the candidate genes in the development of facial cleft belong

to the growth factor genes (TGF-α, TGF-β3) and transcription factor genes

(MSX1, IRF6, TBX22), some to the genes that control the synthesis of

enzymes involved in the metabolism of xenobiotics (CYP1A1, GSTM1,

NAT2) or folic acid (MTHFR), some of the genes regulate the div’s immune

responses (PVRL1, IRF6) [10]. Studies of IRF6 gene polymorphisms have

also revealed associations with congenital cleft palate in many populations


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[5].

Own data.

In 2010, our research group created and is still maintaining

an electronic national register of patients with hemophilia and other

coagulopathies covering all regions of the Republic of Uzbekistan.

Research methods:

coagulological, examination and questionnaire

data.

According to our registry, by the end of 2021, 1987 patients with

hereditary coagulopathy are registered. Analysis of the data showed that

among all patients - 30% are sporadic cases of the onset of diseases.

Since hemophilia is not always registered at the birth of a child, moderate

and mild forms of the disease can be detected at the age of 3, we provide

statistical data for 2019. According to the State Statistics Committee,

815.9 thousand newborns were born in the Republic of Uzbekistan in

2019. The number of registered patients born in 2019 was 16 patients

with Hemophilia A, 5 patients with Hemophilia B and 29 children with von

Willebrand disease. Thus, there are 6 children suffering from hemophilia

per 100,000 newborns in Uzbekistan, while according to world statistics,

this figure is 10:100,000 newborns. 50% of all cases reported each year

are severe (i.e. less than 1% of clotting factors).

Among the patients of the Republic, children with Hemophilia A and

von Willebrand disease with combined pathology in the form of a cleft

palate (cleft palate) were identified. 2 patients diagnosed with hemophilia

A and 2 patients with von Willebrand disease. Patients with hereditary

coagulopathy and color blindness were not registered in the Republic of

Uzbekistan.

Child, 11 months (2020). von Willebrand disease, factor VIIIa level of 3%, and complete

cleft palate. Heredity is favored through the maternal line. Also in the family there are 2

more children with a mild severity of the disease, without pathology of the hard palate.


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Child, 2021 Hemophilia A severe (factor VIII level - 1%), heredity is not traced.

Complete cleft palate.

Child, 4 years old (2018). von Willebrand disease, factor VIIIa 7%, and partial cleft

palate. Heredity is burdened, there are cases of the disease in male relatives on the

maternal side.

Child, born in 2016 Hemophilia A factor VIII level - 3%, and complete cleft palate.


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Heredity is burdened. The child underwent a successful operation and restoration of

the defect. The operation was carried out under constant monitoring of hemostasis

parameters and the corresponding administration of blood coagulation factor

preparations.

The only treatment for such patients with congenital pathology of the

palate is surgery with suturing the defect or installing an implant. For patients

with a deficiency of blood coagulation factors, these operations should be

carried out exclusively with the replacement of an adequate amount of

blood coagulation drugs, at the rate of 50-60 mg / kg - at least 3 times a

day. It is recommended to maintain the missing clotting factor at least 50%

for a minimum of 14 days. Otherwise, the operation may be complicated

by profuse bleeding, failure of the sutures and the development of other

complications associated with the failure of the coagulation link of hemostasis.

With timely surgical intervention and defect plasty, this anomaly does

not pose a danger to life. If the defect is not corrected in time, then numerous

complications and inflammatory diseases of the nasopharynx develop.

Conclusion:

The solution to this problem is the possibility of

determining X-linked diseases before the birth of a child. For all regions of

Uzbekistan and neighboring countries of the CIS, it is necessary to introduce

mandatory molecular genetic testing for chromosomal pathologies for

all couples entering into marriage and persons with a predisposition to

hereditary diseases, as well as to actively introduce prenatal diagnostics.

Prenatal diagnosis will allow, long before the moment of birth, to find

out whether everything is in order with the health of the child or whether

he has inherited any pathological abnormalities in the genetic material.

Bibliography:

1. Гороховский А.Н. Ген F8: [Электронный ресурс] // ГЕНОКАРТА

Генетическая энциклопедия. 2020. – URL: https://www.genokarta.ru/

gene/F8.

2. Масленников Д.Н. Дальтонизм: [Электронный ресурс] //

ГЕНОКАРТА Генетическая энциклопедия. 2022. – URL: https://www.

genokarta.ru/disease/Daltonizm.

3. Таалайбеков, Н. Т. Статистика рождаемости детей с

врожденными пороками развития и использование современных

технологий в реабилитации / Н. Т. Таалайбеков, А. М. Ешиев. — Текст

: непосредственный // Молодой ученый. — 2016. — № 3 (107). — С.

310-312. — URL: https://moluch.ru/archive/107/25592

4. Chapel Hill// American Cleft Palate-Craniofacial Association.

Parameters for evaluation and treatment of patients with cleft lip/palate

or other craniofacial anomalies. Revised edition, Nov 2009., NC. P.

1-34. https://acpa-cpf.org/wpontent/uploads/2017/06/Parameters_

Rev_2009_9_.pdf

5. Jugessur A., Shi M., Gjessing H.K., et al. Fetal genetic risk of

isolated cleft lip only (CLO) versus isolated cleft lip and palate (CLP): A

sub-phenotype analysis using two population-based studies of orofacial

clefts in Scandinavia // Birth Defects Res A Clin. Mol. Teratol. - 2011. - V.91

(2). - P. 85-92.

6. Mai CT, Isenburg JL, Canfield MA, Meyer RE, Correa A,

Alverson CJ, Lupo PJ, Riehle-Colarusso T, Cho SJ, Aggarwal D, Kirby

RS. Национальные популяционные оценки основных врожденных


background image

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International Journal of Scientific Pediatrics

May 2022 / Issue 01 / Article 03

29

published: 31 May 2022

дефектов, 2010–2014 гг. Исследование врожденных дефектов. 2019;

111(18): 1420-1435.

7. McGinniss M. J., Kazazian H. H., Hoyer L. W., Bi L., Inaba H.,

Antonarakis S. E. Spectrum of mutations in CRM-positive and CRM-

reduced hemophilia A. Genomics 15: 392- 398, 1993. PMID: 8449505.

8. McVey J. H., Rallapalli P. M., Kemball-Cook G., et al. The European

Association for Haemophilia and Allied Disorders (EAHAD) Coagulation

Factor Variant Databases: Important resources for haemostasis clinicians

and researchers. Haemophilia. 2020; 26: 306– 313. PMID: 32166871

9. “Peyvandi F., Garagiola I. Clinical advances in gene therapy

updates on clinical trials of gene therapy in haemophilia. Haemophilia.

2019 Sep;25(5):738-746. doi: 10.1111/hae.13816. Epub 2019 Jul 8. PMID:

31282050.

10. Nathwani A. C., Davidoff A. M., Tuddenham E. G. D. Advances

in Gene Therapy for Hemophilia. Hum Gene Ther. 2017 Nov;28(11):1004-

1012. doi: 10.1089/hum.2017.167. PMID: 28835123

11. Sherief, L.M., Gaber, O.A., Youssef, H.M. et al. Развитие

ингибитора фактора VIII у пациентов с египетской гемофилией: играет

ли роль мутация инверсии интрона 22. Ital J. Pediatr 46, 129 (2020).

https://doi.org/10.1186/s13052-020-00878-5

12. Whittaker D L, D L Copeland, J B Graham. Linkage of color

blindness to hemophilias A and B. Am J Hum Genet 1962 Jun;14(2):149-

58. PMID: 14006651 PMCID: PMC1932287

Библиографические ссылки

Гороховский А.Н. Ген F8: [Электронный ресурс] // ГЕНОКАРТА Генетическая энциклопедия. 2020. – URL: https://www.genokarta.ru/gene/F8.

Масленников Д.Н. Дальтонизм: [Электронный ресурс] // ГЕНОКАРТА Генетическая энциклопедия. 2022. – URL: https://www.genokarta.ru/disease/Daltonizm.

Таалайбеков, Н. Т. Статистика рождаемости детей с врожденными пороками развития и использование современных технологий в реабилитации / Н. Т. Таалайбеков, А. М. Ешиев. — Текст : непосредственный // Молодой ученый. — 2016. — № 3 (107). — С. 310-312. — URL: https://moluch.ru/archive/107/25592

Chapel Hill// American Cleft Palate-Craniofacial Association. Parameters for evaluation and treatment of patients with cleft lip/palate or other craniofacial anomalies. Revised edition, Nov 2009., NC. P. 1-34. https://acpa-cpf.org/wpontent/uploads/2017/06/Parameters_Rev_2009_9_.pdf

Jugessur A., Shi M., Gjessing H.K., et al. Fetal genetic risk of isolated cleft lip only (CLO) versus isolated cleft lip and palate (CLP): A sub-phenotype analysis using two population-based studies of orofacial clefts in Scandinavia // Birth Defects Res A Clin. Mol. Teratol. - 2011. - V.91 (2). - P. 85-92.

Mai CT, Isenburg JL, Canfield MA, Meyer RE, Correa A, Alverson CJ, Lupo PJ, Riehle‐Colarusso T, Cho SJ, Aggarwal D, Kirby RS. Национальные популяционные оценки основных врожденных дефектов, 2010–2014 гг. Исследование врожденных дефектов. 2019; 111(18): 1420-1435.

McGinniss M. J., Kazazian H. H., Hoyer L. W., Bi L., Inaba H., Antonarakis S. E. Spectrum of mutations in CRM-positive and CRM-reduced hemophilia A. Genomics 15: 392- 398, 1993. PMID: 8449505.

McVey J. H., Rallapalli P. M., Kemball‐Cook G., et al. The European Association for Haemophilia and Allied Disorders (EAHAD) Coagulation Factor Variant Databases: Important resources for haemostasis clinicians and researchers. Haemophilia. 2020; 26: 306– 313. PMID: 32166871

"Peyvandi F., Garagiola I. Clinical advances in gene therapy updates on clinical trials of gene therapy in haemophilia. Haemophilia. 2019 Sep;25(5):738-746. doi: 10.1111/hae.13816. Epub 2019 Jul 8. PMID: 31282050.

Nathwani A. C., Davidoff A. M., Tuddenham E. G. D. Advances in Gene Therapy for Hemophilia. Hum Gene Ther. 2017 Nov;28(11):1004-1012. doi: 10.1089/hum.2017.167. PMID: 28835123

Sherief, L.M., Gaber, O.A., Youssef, H.M. et al. Развитие ингибитора фактора VIII у пациентов с египетской гемофилией: играет ли роль мутация инверсии интрона 22. Ital J. Pediatr 46, 129 (2020). https://doi.org/10.1186/s13052-020-00878-5

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