Research on genetic modification in patients with some rare syndromes/diseases in Vietnam by new generation gene sequencing technology

According to the World Health Organization (WHO), a so-called rare disease is a disease or condition that occurs in less than 6.5-10 in 10,000 people. About 3.5-5.9% of the world's population (about 300 million people) is affected by rare diseases, of which about 70% of patients are children. Patients and their families must undergo repeated clinical trials with the aim of finding information about the etiology of the disease and information about genetic risk in the family. However, there are patients who cannot find a genetic cause with single tests or chromosomal analysis. Whole exome sequencing (WES) is an effective tool for detecting disease-causing mutations in known genes as well as new disease-causing genes. In Vietnam, the application of WES in the diagnosis of rare diseases is very limited.

The latest research in Vietnam on the application of new generation gene sequencing technology to detect disease-causing mutations conducted by the Genome Research Institute, led by Assoc. Prof. Dr Nguyen Huy Hoang, detected the mutation causing disease in 14 patients with 05 rare syndromes/diseases, such as: Cornelia de Lange syndrome, Seckel's syndrome, serocytosis, glycogen storage disease and cyclical disorders of urea process. Specific results were pointed as follows:

• Three heterozygous spontaneous mutations on the NIPBL dominant gene in 3 patients with Cornelia de Lange syndrome, including the false mutation c.6697G>A (p.Val2233Met) in CDL1 patient, a loss of one nucleotide causing frameshift mutation c.4504delG (p.Val1502Tyrfs*87) in CDL2 patients, and nonsense mutation c.2602C>T (p.Arg868*) in CDL3 patients.

● Three new mutations in the PCNT recessive gene in 2 patients with Seckel syndrome, including a double heterozygous frameshift mutation, c.1435delA (p.Thr479Profs*6) and c.8223_8224delTG (p.Ser2741Alafs*8     ) in patient SK1, and nonsense mutation c.5719C>T (p.Gln1907*) in patient SK2.

● Five erroneous mutations in the BCKDHB recessive gene in 3 patients with syrupuria, including double heterozygous mutations c.989A>G (p.Glu330Gly) and c.1103C>T (p.Pro368Leu) on patient MSUD1; heterozygous double mutant c.1A>T (p.Met1Leu) and c.704G>A (p.Cys235Tyr) in MSUD2, and homozygous c.1016C>T (p.Ser339Leu) mutation on MSUD3 patient. A homozygous loss of c.263_265delAAG (p.Glu88del) mutant on the recessive DBT gene in MSUD4.

●  Two heterozygous mutations in the OTC X-linked recessive gene in 2 patients with urea metabolism disorder, including the false mutation c.365A>T (p.Glu122Val) in the patient UCD1 and the gene slippage mutation 717+1G>A (IVS7+1G>A) in patients with UCD2.

●Two homozygous mutations in 3 patients with glycogen storage disease, including the false mutation c.356A>T (p.His119Leu) in the G6PC gene in patients with GD1 and GD2 and the nonsense mutation c. 1193G>A (p.Trp398*) on the SLC37A4 gene in GD3.

With the obtained results, the above research contributes to solving problems that clinicians have not fully explained in the diagnosis and treatment of rare diseases/syndrome, helping doctors to have a better plan in management and care of patients. Doctors can provide genetic counseling for the patient's family, especially if the parents want to have more children. The study also broadened the phenotypic and genotypic spectrum of rare diseases/syndromes. In addition, the results also help improve doctors' capacity and experience in diagnosing rare diseases.

Mutations in the OTC gene in two families of patients with urea metabolism disorder

Illustrated structure of false mutations on BCKDHB protein 3D model

The above research results belong to the project “Research on genetic modification in patients with some rare syndromes/diseases in Vietnam by new generation gene sequencing technology”, code KHCBSS.02/18 -20, led by Assoc. Prof. Dr. Nguyen Huy Hoang and chaired by the Institute of Genome Research. The project is in the field of life science, the program for the development of basic sciences in the fields of chemistry, life science, earth science and marine science in the period 2017-2025. The project has published 04 articles in international journals in the list of SCIE, 03 articles in prestigious national journals, and helped train 01 PhD.

The project was carried out from 2018 to 2020 and classified as Excellent by the Acceptance Council.

Translated by Phuong Huyen
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