Repository of mutations from Oman: The entry point to a national mutation database

Introduction

Oman is situated in the South East of the Arabian Peninsula along the East coast of the Arabian Gulf (Figure 1). It has its borders with United Arab Emirates to the North, Saudi Arabia to the West and Yemen to the South West. Oman is the second largest territory in the Arabian Peninsula with an area of 82,000 square miles and a coastline length of 1,300 miles. The native Omani population comprises around 2.2 million inhabitants, and the rate of annual population increase is approximately 25 per 1000. Oman has a young population with nearly half of the population being under 15 years. The Omani population is characterized by a high growth rate, large family size, consanguineous marriages, and the presence of genetic isolates.

Figure 1. Oman is situated in the South East of the Arabian Peninsula along the East coast of the Arabian Gulf.

Clinical genetic services were introduced in the Sultanate of Oman in the past decade and they have become an important component of health care. This greatly facilitated the systematic collection of data on genetic diseases and birth defects in the past few decades. With the inauguration of the National Genetic Center in 2013, the existing clinical genetic services were supplemented by sophisticated genetic laboratory services.

The amount of published data available on genetic disorders in the Sultanate is considerable. There were a few previous attempts to list the genetic diseases reported in Oman^1–4 and to link them to specific population groups and geographic locations^5,6, analyze population structure⁷, and to estimate the impact of genetic disorders and birth defects on the community⁴ and summarize the genetic services available⁸. The advances in bioinformatics required to annotate human genomic variants and to place them in public data repositories have not kept pace with their discovery. The deposition of such data in the public domain is essential to maximize both their scientific and clinical utility⁹.

Hence, in the current study we present a comprehensive compilation of germline mutations in nuclear genes associated with human disease in the Omani population.

Materials and methods

The wealth of genetic variant data in Omani nationals was collected from multiple sources which form a basis for research into genetic conditions reported from Oman. Multiple sources of data were reviewed to form repository of mutations in Omani nationals introduced in this paper. The sources of data included:

(1) 1993–2015 records of patients consulted by clinical geneticists of the Royal Hospital, the largest tertiary hospital in Oman;

(2) 2008–2015 publications curated from PUBMED on birth defects and genetic conditions in Omani nationals. The keywords used were: “Oman”, “Genetic disorders”, “Birth defects”, “mutations”;

(3) 2012–2014 commercial laboratories referral registry at the Royal Hospital for the samples tested overseas.

(4) The internal genetic variant repository of the National Genetic Center <<HTTP://ogvd.net>>;

The data presented in this article was manually curated. The OMIM identifiers, Phenotype MIM accession numbers, Phenotype name (OMIM), mutation descriptions, and relevant publications with PMID numbers were all collected from the NCBI database repository. All unavailable through PubMed mutation details were checked with ClinVar, LOVD and CentoMD. The details of unpublished mutations are not included in the present study and feature in Table 2 as “Novel mutations”.

Results

In this study, a wide range of genetic conditions with known mutations collected in Omani nationals were analysed. The disease classifications are comprised of 44 gene variants causing neurodevelopmental disorders, 21 inborn errors of metabolism, 13 endocrinopathies, 15 skeletal dysplasias, nine disorders of the immune system, four hereditary blood disorders as well as other National groups (Table 1).

In total more than 150 rare genetic disorders were listed in Table 2 and Table 3 with relevant OMIM numbers, PubMed ID (PMID), Gene/Locus name, nucleotide(s) change(s) and the source of the data (PubMed ID Number/ OMIM/ClinVar/LOVD/CentoMD). The names of genetic conditions in Table 2 are stated as found in OMIM “Phenotype-Gene Relationships” table as “Phenotype” arranged in alphabetical order. In Table 3, we present a separate list of 69 known mutations (11–15) that were collected through service provision at the Hemoglobinopathy Laboratory at the National Genetic Center in Oman.

For the majority (85%) of rare disorders presented in Table 2, data was derived from publications. The original mutations identified for the first time in Omani population constitute more than half of rare disease data presented in Table 2.

Discussion

Soon after the completion of the Human Genome Project in 2003, it was clear that the genetic data collected until then presented only a glimpse of the complexity of the human genome and the significance of genetic variants in human disease. Since then, genetic researchers have unearthed innumerable variants that are not only individual-specific; but also ethnicity-, population- and country-specific. Human genetic variation databases have significant implications for both diagnostic and predictive medicine. Often, the pathogenicity of rare mutations is primarily assessed through multiple reports of occurrence in diseased patients that are documented and routinely updated in mutation databases. Given the fact that gene mutations and their frequencies in many Mendelian disorders differ widely between different ethnic groups, even within a country, national databases are highly valuable resources for studies on disease-gene associations, population diversity and genetic history¹⁰.

The catalog of Omani mutations presented here will therefore represent a valuable resource that may guide mutation analysis in Omanis suspected of having genetic disease. Unique circumstances in Oman with government-funded comprehensive healthcare throughout the country, and the national coverage for clinical genetics has made the present study possible. Future efforts will be required to extend this database to cover the full spectrum of mutations and population specific variants.

The disease-associated mutation data presented (Table 1, Table 2, Table 3) show a considerable proportion of novel disease genes as well as novel genetic variants within the Omani population. This was expected due to the presence of inbred and geographically isolated communities, the practice of consanguineous marriages, all of which have tended to skew the allelic spectrum toward rare and private variants within the Omani population. In addition to this, the list of genetic variants also reveals known mutations that were previously reported in certain non-Omani populations, thereby reflecting the historic genetic admixture that occurred in Oman, along the trade routes of a once powerful Omani empire and its foreign colonies. Many of the mutations reported are unique to the Omani population, suggesting a founder effect.

The interest in genetic testing is growing among physicians aiming to provide better medical care and genetic disease prevention. The data collected largely represent mutations of rare autosomal recessively inherited disorders in Oman. The mutation data in Table 2 can be searched by OMIM number, or by disease name. The names of diseases in Table 2 were chosen as described in OMIM in “Phenotype-Gene Relationships” table as “Phenotype” in order to ease finding specific genetic disorders by name.

The number of collected mutations among different disease groups (Table 1) reflect the frequency of disorders in the Omani population, the burden caused by genetic diseases⁴, and the interests of individual clinicians in genetic testing.

The knowledge of the genetics of Hemoglobin disorders is among the best in Oman due to national preventive programs and research starting from the 1990s. It is not surprising that around a third of all mutations known in Omani population to date are in four genes causing Hemoglobin disorders (Table 1, Table 3). The birth prevalence of infants with a hemoglobin disorder was recorded as 3.5–4.7/1,000^7,11. The frequency of hemoglobin disorders in Oman is among the highest in the world, and may reflect natural selection due to advantage for survival, in the heterozygous state, against malaria. Around 10% of Omani nationals are carriers of the allele for sickle cell anemia, 2–3% carry an allele for Beta-thalassemia and 45% are carriers of an alpha-thalassemia allele^12–15.

Genetic disorders causing disabilities and handicap are of great concern. These are different groups of rare disorders leading to intellectual disability or physical handicap requiring detailed clinical classification, genetic testing, research and preventive measures. The high prevalence of birth defects and genetic conditions in Omani communities causes social, psychological and financial difficulties⁴. The development and use of national mutation data is of importance to Omani medical care because it not only allows the genetic burden of disease to be quantified, but also provides diagnosticians and researchers access to an up-to-date resource that will assist them in their daily clinical practice and biomedical research⁹. National databases for genetic variants are also significant from the perspective of preventive healthcare. There is a significant correlation between the occurrence of rare genetic variants associated with Mendelian disease and the burden of morbidity from complex diseases within a population. Heterozygous carriers for recessive disease genes do not manifest the recessive disease but may be at risk of developing complex trait conditions with some similarity in phenotype. For example, heterozygote carriers of mutations in the ataxia telangiectasia gene locus are reportedly susceptible to breast cancer¹⁶, and heterozygote carriers of mutations in the glucocerebrosidase (GBA) gene causing Gaucher disease are at an increased risk for Parkinson disease^17,18. Hence, the collection of genetic variant data in national databases will contribute significantly to the prevention of genetic diseases in the population and might greatly impact the management of complex trait diseases in the future. Genetic scientists and international consortiums studying human genetic variation are increasingly interested in dissecting the interplay between genetic makeup and environmental influences on the pattern of diseases worldwide. Current research is expected to create a foundation for the national data online for the benefit of Oman Healthcare.

Data availability

This article was prepared to introduce the first Omani genetic variation database. This data is available online at HTTP://ogvd.net; raw datasets are not available for Royal Hospital laboratory and clinical data, as the registry contains confidential information that could not be deidentified.