Abstract
Patients with rare diseases, undiagnosed diseases, disabilities and genetic diseases
account for more than 5% of the population. Each patient needs tremendous resources for
medical care. The conditions have consequences to physical and mental health, economy
and society at the individual, family, community, and national levels. 80% of these conditions
have genetic contribution. At present, there is an efficient DNA sequencing technology,
especially next generation sequencing (NGS) which can rapidly sequence all the 3 billion basepairs of human genome. Identification of the underlying genetic mutations gives a definite
diagnosis which will in turn give guideline for personalized and precision medicine, information
for genetic counselling and options to decrease the risk of having more family members with
the same disabilities specific to a particular family such as offering a prenatal diagnosis using
molecular genetics. However, DNA sequencing and its interpretation is still complicated and
challenging. It needs 1) sequencers which are expensive and require skilled technicians 2) high
performance computer; HPC 3) database of Thai people and 4) personnel including medical
geneticists, computer scientists, and bioinformaticians. We therefore proposed to do this
research project to develop a system, guideline and network which will be a prototype for
diagnosis, management, referral and research for rare diseases, undiagnosed diseases,
disabilities and genetic diseases. The network involves all parts of the country.
Our research team has established the Thailand – Rare and Undiagnosed Diseases
Network (T-RUN) which involves nine core medical centers and 24 additional hospitals. It also
includes personnel from Health Systems Research Institute, Medical Science Department of
the Ministry of Public Health, and National Science and Technology Development Agency
(NSTDA). The Network has had regular meeting every two months. With this collaboration,
there have been 8,725 samples from rare and undiagnosed disease area being sent to the
Medical Science Department of the Ministry of Public Health accounting for 37.8% of all
submitted samples in the Genomics Thailand Project. In addition, we have collaborated with
NSTDA to develop programs and platforms to manage samples under Genomics Thailand
including 1) Enrollment system 2) a system to collect and archive phenotype using Phenotips
and 3) a program for analysis of pathogenic variants (V@PP).
In the research aspect to find new knowledge, we have performed or sent 200 samples
for rapid exome sequencing. We successfully analyzed the exome/genome sequencing and
have delivered genetic counselling to 180 families. Twenty international articles in academic
peer review journals have been published. The main findings are as below.
1) Identified differences in the gene expression of human dental pulp stem cells
between the upper and lower teeth during permanent teeth development.
2) Novel variants of the RUNX2 gene causes shortening of the toe bone of one foot, a
new feature of Cleidocranial dysplasia. These findings broaden our understanding
of the physical and genetic features RUNX2.
3) Five novel variants in genes BMP1, CRTAP, and SERPINF1 causes extremely rare
forms of osteogenesis imperfecta.
4) A study identifying genes associated with severe COVID-19. Genes identified are
linked to blood clotting, immune response, and intensity of inflammation.
5) Sudden death following covid-19 vaccination was found to be associated with
variants in the SCN5A gene that causes Brugada syndrome.
6) This report identifies genes associated with Covid-19 severity in Thai population
and other races.
7) A pre-implantation genetic testing using mini-sequencing method for Marfan
syndrome is used to identify mutation identification and help facilitate normal
embryo transfer for in vitro fertilization. This method can be easily applied to
other genetic diseases.
8) Novel variants in gene SMAD6 and SMARCA4 causes severe coarctation of aorta,
developmental delay, and multiple dysmorphic features.
9) Identified a novel variant in the LILB1 gene causing autoimmune diseases.
10) Novel variants of NEUROG3 causing kidney dysfunctions in patients, a new
phenotype that has never been reported.
11) A new disease gene, TIGIT, was identified in a Thai patient with severe COVID-19.
This study provides new information to support that TIGIT could contribute to
COVID-19 severity.
12) The usefulness of exome sequencing as a first-tier genetic testing for infantileonset pharmacoresistant epilepsy in Thai population.
13) A novel gain-of-function variant in the STAT6 gene is associated with early-onset
allergies.
14) A novel and rare deleterious variant in the X chromosome toll-like receptor 7
(TLR7) is associated with a five times greater risk of developing severe COVID-19.
15) A novel CNNM4 variant that causes new features the Jalili syndrome, including
advanced dental age and crossbite. This report expands the genotypic and
phenotypic spectra of Jalili syndrome.
16) A novel homozygous 1 base-pair duplication causing new features of ACBD6-
associated NDDs. This report expands the mutational spectrum of ACBD6-
associated NDDs.
17) Through whole genome exome sequencing, novel variants in the COL4A4 and
MAFB gene have been identified in Thai patients with FSGS.
18) Identified novel variants in the FAM20A gene, and for the first time, observed
defective mineral composition as well as physical and mechanical properties in
the dentition of patients with AI1G.
19) Exome sequencing identified genetic variations in Thai pediatric patients for
diagnosing congenital myopathies and muscular dystrophy with overlapping
phenotypes. This led to precise treatment and genetic counseling.
20) Two novel loss-of-function variants in the KCNQ2 gene, p.N258K and p.G279D
causing KCNQ2‑ related epilepsy.
