Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

A first-line diagnostic assay for limb-girdle muscular dystrophy and other myopathies.

BACKGROUND: Fifty random genetically unstudied families (limb-girdle muscular dystrophy (LGMD)/myopathy) were screened with a gene panel incorporating 759 OMIM genes associated with neurological disorders. Average coverage of the CDS and 10 bp flanking regions of genes was 99 %. All families were referred to the Neurosciences Clinic of King Faisal Specialist Hospital and Research Centre, Saudi Arabia. Patients presented with muscle weakness affecting the pelvic and shoulder girdle. Muscle biopsy in all cases showed dystrophic or myopathic changes. Our main objective was to evaluate a neurological gene panel as a first-line diagnostic test for LGMD/myopathies. RESULTS: Our panel identified the mutation in 76 % of families (38/50; 11 novel). Thirty-four families had mutations in LGMD-related genes with four others having variants not typically associated with LGMD. The majority of cases had recessive inheritance with homoallelic pathogenic variants (97.4 %, 37/38), as expected considering the high rate of consanguinity in the study population. In one case, we detected a heterozygous mutation in DNAJB responsible for LGMD-1E. Our cohort included seven different subtypes of LGMD2. Mutations of DYSF were the most commonly identified cause of disease followed by that in CAPN3 and FKRP. Non-LGMD myopathies were due to mutations in genes associated with congenital disorder of glycosylation (ALG2), rigid spine muscular dystrophy 1 (SEPN1), inclusion body myopathy2/Nonaka myopathy (GNE), and neuropathy (WNK1). Whole exome sequencing (WES) of patients who remained undiagnosed with the neurological panel did not improve our diagnostic yield. CONCLUSIONS: Our neurological panel achieved a high clinical sensitivity (76 %) and is an effective first-line laboratory test in patients with LGMD and other myopathies. This sensitive, cost-effective, and rapid assay significantly assists clinical practice especially in these phenotypically and genetically heterogeneous disorders. Moreover, the application of the American College of Medical Genetics (ACMG) and Association for Molecular Pathology (AMP) guidelines applied in the classification of variant pathogenecity provides a clear interpretation for physicians on the relevance of such findings.

Unbiased targeted next-generation sequencing molecular approach for primary immunodeficiency diseases.

BACKGROUND: Molecular genetics techniques are an essential diagnostic tool for primary immunodeficiency diseases (PIDs). The use of next-generation sequencing (NGS) provides a comprehensive way of concurrently screening a large number of PID genes. However, its validity and cost-effectiveness require verification. OBJECTIVES: We sought to identify and overcome complications associated with the use of NGS in a comprehensive gene panel incorporating 162 PID genes. We aimed to ascertain the specificity, sensitivity, and clinical sensitivity of the gene panel and its utility as a diagnostic tool for PIDs. METHODS: A total of 162 PID genes were screened in 261 patients by using the Ion Torrent Proton NGS sequencing platform. Of the 261 patients, 122 had at least 1 known causal mutation at the onset of the study and were used to assess the specificity and sensitivity of the assay. The remaining samples were from unsolved cases that were biased toward more phenotypically and genotypically complicated cases. RESULTS: The assay was able to detect the mutation in 117 (96%) of 122 positive control subjects with known causal mutations. For the unsolved cases, our assay resulted in a molecular genetic diagnosis for 35 of 139 patients. Interestingly, most of these cases represented atypical clinical presentations of known PIDs. CONCLUSIONS: The targeted NGS PID gene panel is a sensitive and cost-effective diagnostic tool that can be used as a first-line molecular assay in patients with PIDs. The assay is an alternative choice to the complex and costly candidate gene approach, particularly for patients with atypical presentation of known PID genes.

A Web-based interactive diabetes registry for health care management and planning in Saudi Arabia.

BACKGROUND: Worldwide, eHealth is a rapidly growing technology. It provides good quality health services at lower cost and increased availability. Diabetes has reached an epidemic stage in Saudi Arabia and has a medical and economic impact at a countrywide level. Data are greatly needed to better understand and plan to prevent and manage this medical problem. OBJECTIVE: The Saudi National Diabetes Registry (SNDR) is an electronic medical file supported by clinical, investigational, and management data. It functions as a monitoring tool for medical, social, and cultural bases for primary and secondary prevention programs. Economic impact, in the form of direct or indirect cost, is part of the registry's scope. The registry's geographic information system (GIS) produces a variety of maps for diabetes and associated diseases. In addition to availability and distribution of health facilities in the Kingdom, GIS data provide health planners with the necessary information to make informed decisions. The electronic data bank serves as a research tool to help researchers for both prospective and retrospective studies. METHODS: A Web-based interactive GIS system was designed to serve as an electronic medical file for diabetic patients retrieving data from medical files by trained registrars. Data was audited and cleaned before it was archived in the electronic filing system. It was then used to produce epidemiologic, economic, and geographic reports. A total of 84,942 patients were registered from 2000 to 2012, growing by 10% annually. RESULTS: The SNDR reporting system for epidemiology data gives better understanding of the disease pattern, types, and gender characteristics. Part of the reporting system is to assess quality of health care using different parameters, such as HbA1c, that gives an impression of good diabetes control for each institute. Economic reports give accurate cost estimation of different services given to diabetic patients, such as the annual insulin cost per patient for type 1, type 2, and gestational diabetes, which are 1155 SR (US $308), 1406 SR (US $375), and 1002 SR (US $267), respectively. Of this, 72.02% of the total insulin cost is spent on type 2 patients and 55.39% is in the form of premixed insulin. The SNDR can provide an accurate assessment of the services provided for research purposes. For example, only 27.00% of registered patients had an ophthalmic examination and only 71.10% of patients with proliferative retinopathy had laser therapy. CONCLUSIONS: The SNDR is an effective electronic medical file that can provide epidemiologic, economic, and geographic reports that can be used for disease management and health care planning. It is a useful tool for research and disease health care quality monitoring.

The clinical utility of rapid exome sequencing in a consanguineous population.

BACKGROUND: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. METHODS: Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. RESULTS: A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. CONCLUSIONS: This work expands the diversity of environments in which RES has a demonstrable clinical utility.

Whole-Genome Sequencing Reveals Exonic Variation of ASIC5 Gene Results in Recurrent Pregnancy Loss.

Family trio next-generation sequencing-based variant analysis was done to identify the genomic reason on unexplained recurrent pregnancy loss (RPL). A family (dead fetus and parents) from Saudi Arabia with an earlier history of three unexplained RPLs at the ninth week of pregnancy was included in the study. Whole-genome sequencing (WGS) of a dead fetus and the parents was done to identify the pathogenic variation and confirmed through Sanger sequencing. WGS of dead fetus identifies a novel homozygous exonic variation (NM_017419.3:c.680G>T) in ASIC5 (acid-sensing ion channel subunit family member 5) gene; the parents are heterozygous. Newly designed ARMS PCR followed by direct sequencing confirms the presence of heterozygous in one subject and absence of homozygous novel mutation among randomly selected healthy Saudis. The second family with heterozygous was confirmed with three unexplained RPLs. Pathogenicity analysis of R227I amino acid substitution in ASIC5 protein through molecular docking and interaction analysis revealed that the mutations are highly pathogenic, decrease the stability of the protein, and prevent binding of amiloride, which is an activator to open the acid-sensing ion channel of ASIC5. The identified rare and novel autosomal recessive mutation, c.680G>T:p.R227I (ASIC5Saudi), in two families confirm the ASIC5 gene association with RPL and can be fatal to the fetus.

Sugar-sweetened carbonated beverage consumption correlates with BMI, waist circumference, and poor dietary choices in school children.

BACKGROUND: The prevalence of obesity and overweight is increasing globally. Frequently coexisting with under-nutrition in developing countries, obesity is a major contributor to chronic disease, and will become a serious healthcare burden especially in countries with a larger percentage of youthful population. 35% of the population of Saudi Arabia are under the age of 16, and adult dietary preferences are often established during early childhood years. Our objective was to examine the dietary habits in relation to body-mass-index (BMI) and waist circumference (W_C), together with exercise and sleep patterns in a cohort of male and female Saudi school children, in order to ascertain whether dietary patterns are associated with obesity phenotypes in this population. METHODS: 5033 boys and 4400 girls aged 10 to 19 years old participated in a designed Food Frequency Questionnaire. BMI and W_C measurements were obtained and correlated with dietary intake. RESULTS: The overall prevalence of overweight and obesity was 12.2% and 27.0% respectively, with boys having higher obesity rates than girls (P

Integrated Analysis of Whole Exome Sequencing and Copy Number Evaluation in Parkinson's Disease.

Genetic studies of the familial forms of Parkinson's disease (PD) have identified a number of causative genes with an established role in its pathogenesis. These genes only explain a fraction of the diagnosed cases. The emergence of Next Generation Sequencing (NGS) expanded the scope of rare variants identification in novel PD related genes. In this study we describe whole exome sequencing (WES) genetic findings of 60 PD patients with 125 variants validated in 51 of these cases. We used strict criteria for variant categorization that generated a list of variants in 20 genes. These variants included loss of function and missense changes in 18 genes that were never previously linked to PD (NOTCH4, BCOR, ITM2B, HRH4, CELSR1, SNAP91, FAM174A, BSN, SPG7, MAGI2, HEPHL1, EPRS, PUM1, CLSTN1, PLCB3, CLSTN3, DNAJB9 and NEFH) and 2 genes that were previously associated with PD (EIF4G1 and ATP13A2). These genes either play a critical role in neuronal function and/or have mouse models with disease related phenotypes. We highlight NOTCH4 as an interesting candidate in which we identified a deleterious truncating and a splice variant in 2 patients. Our combined molecular approach provides a comprehensive strategy applicable for complex genetic disorders.

Maternal obesity and neonatal congenital cardiovascular defects.

OBJECTIVE: To determine whether isolated congenital heart defects (CHDs) were associated with maternal obesity. METHOD: In a retrospective study we compared the incidence and severity of isolated CHDs in the offspring of 428 women divided into 3 groups, one of women of normal weight (n=141), one of obese women (n=228), and one of morbidly obese women (n=59) according to their body mass index. RESULTS: There were 143 mild (66.8%), 44 moderate (20.6%), and 27 complex (12.6%) forms of CHDs in the offspring and septal defects were the most common (61.7%). No significant differences were found among the 3 groups of women regarding the type or severity of CHDs in their respective offspring, or the corrective cardiac surgery required. CONCLUSION: No association was found between maternal weight and isolated CHDs in the offspring.

Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with genetic and clinical heterogeneity. The interplay of de novo and inherited rare variants has been suspected in the development of ASD. Here, we applied whole exome sequencing (WES) on 19 trios from singleton Saudi families with ASD. We developed an analysis pipeline that allows capturing both de novo and inherited rare variants predicted to be deleterious. A total of 47 unique rare variants were detected in 17 trios including 38 which are newly discovered. The majority were either autosomal recessive or X-linked. Our pipeline uncovered variants in 15 ASD-candidate genes, including 5 (GLT8D1, HTATSF1, OR6C65, ITIH6 and DDX26B) that have not been reported in any human condition. The remaining variants occurred in genes formerly associated with ASD or other neurological disorders. Examples include SUMF1, KDM5B and MXRA5 (Known-ASD genes), PRODH2 and KCTD21 (implicated in schizophrenia), as well as USP9X and SMS (implicated in intellectual disability). Consistent with expectation and previous studies, most of the genes implicated herein are enriched for biological processes pertaining to neuronal function. Our findings underscore the private and heterogeneous nature of the genetic architecture of ASD even in a population with high consanguinity rates.

Ischemic Stroke and Its Risk Factors in a Registry-Based Large Cross-Sectional Diabetic Cohort in a Country Facing a Diabetes Epidemic.

The main aim of this study is to determine the prevalence and risk factors of ischemic stroke among diabetic patients registered in the Saudi National Diabetes Registry (SNDR) database. A cross-sectional sample of 62,681 diabetic patients aged ≥25 years was used to calculate ischemic stroke prevalence and its risk factors. Univariate and multivariate logistic regression analyses were used to assess the roles of different risk factors. The prevalence of ischemic stroke was 4.42% and was higher in the older age group with longer diabetes duration. Poor glycemic control and the presence of chronic diabetes complications were associated with a high risk of ischemic stroke. History of smoking and type 2 diabetes were more frequent among stroke patients. Obesity significantly decreased the risk for ischemic stroke. Regression analysis for ischemic stroke risk factors proved that age ≥45 years, male gender, hypertension, coronary artery disease (CAD), diabetes duration ≥10 years, insulin use, and hyperlipidemia were significant independent risk factors for ischemic stroke. We conclude that ischemic stroke is prevalent among diabetic individuals, particularly among those with type 2 diabetes. Good glycemic, hypertension, and hyperlipidemia control, in addition to smoking cessation, are the cornerstones to achieve a significant reduction in ischemic stroke risk.

Diabetic foot complications and their risk factors from a large retrospective cohort study.

BACKGROUND: Foot complications are considered to be a serious consequence of diabetes mellitus, posing a major medical and economical threat. Identifying the extent of this problem and its risk factors will enable health providers to set up better prevention programs. Saudi National Diabetes Registry (SNDR), being a large database source, would be the best tool to evaluate this problem. METHODS: This is a cross-sectional study of a cohort of 62,681 patients aged ≥ 25 years from SNDR database, selected for studying foot complications associated with diabetes and related risk factors. RESULTS: The overall prevalence of diabetic foot complications was 3.3% with 95% confidence interval (95% CI) of (3.16%-3.44%), whilst the prevalences of foot ulcer, gangrene, and amputations were 2.05% (1.94%-2.16%), 0.19% (0.16%-0.22%), and 1.06% (0.98%-1.14%), respectively. The prevalence of foot complications increased with age and diabetes duration predominantly amongst the male patients. Diabetic foot is more commonly seen among type 2 patients, although it is more prevalent among type 1 diabetic patients. The Univariate analysis showed Charcot joints, peripheral vascular disease (PVD), neuropathy, diabetes duration ≥ 10 years, insulin use, retinopathy, nephropathy, age ≥ 45 years, cerebral vascular disease (CVD), poor glycemic control, coronary artery disease (CAD), male gender, smoking, and hypertension to be significant risk factors with odds ratio and 95% CI at 42.53 (18.16-99.62), 14.47 (8.99-23.31), 12.06 (10.54-13.80), 7.22 (6.10-8.55), 4.69 (4.28-5.14), 4.45 (4.05-4.89), 2.88 (2.43-3.40), 2.81 (2.31-3.43), 2.24 (1.98-2.45), 2.02 (1.84-2.22), 1.54 (1.29-1.83), and 1.51 (1.38-1.65), respectively. CONCLUSIONS: Risk factors for diabetic foot complications are highly prevalent; they have put these complications at a higher rate and warrant primary and secondary prevention programs to minimize morbidity and mortality in addition to economic impact of the complications. Other measurements, such as decompression of lower extremity nerves, should be considered among diabetic patients.

Diabetic retinopathy and its risk factors in a society with a type 2 diabetes epidemic: a Saudi National Diabetes Registry-based study.

PURPOSE: To assess diabetic retinopathy prevalence and its risk factors in a society with type 2 diabetes epidemic using the Saudi National Diabetes Registry (SNDR). METHOD: This is a cross-sectional study using patient's clinical data found in SNDR data base. A cohort of 50,464 Saudi patients with type 2 diabetes aged ≥25 years were selected to assess for the prevalence and risk factors for diabetic retinopathy. RESULTS: The overall prevalence of diabetic retinopathy is 19.7%, where 9.1% have non-proliferative diabetic retinopathy (NPDR), 10.6% have proliferative diabetic retinopathy (PDR) and 5.7% have macular oedema (ME). Duration of diabetes and age are the most significant risk factors for diabetic retinopathy with odds ratio (OR) and 95% confidence interval (95% CI) 8.88 (8.30-9.50) and 5.76 (5.10-6.55), respectively. Nephropathy, neuropathy, insulin use, poor glycemic control, hypertension and male gender significantly increased the risk for diabetic retinopathy. Smoking, hyperlipidemia and obesity significantly reduced the risk for diabetic retinopathy among type 2 Saudi diabetic cohort. CONCLUSION: vThe low prevalence of diabetic retinopathy in our registry may be a result of the shortage or absence of well-structured screening programmes. Therefore, many patients with NPDR might have been missed. A prevention programme is needed to reduce the effect of diabetic retinopathy risk factors in this society.

Diabetic nephropathy and its risk factors in a society with a type 2 diabetes epidemic: a Saudi National Diabetes Registry-based study.

AIMS: The prevalence of diabetic nephropathy and its risk factors have not been studied in a society known to have diabetes epidemic like Saudi Arabia. Using a large data base registry will provide a better understanding and accurate assessment of this chronic complication and its related risk factors. METHODOLOGY: A total of 54,670 patients with type 2 diabetes aged ≥ 25 years were selected from the Saudi National Diabetes Registry (SNDR) and analyzed for the presence of diabetic nephropathy. The American Diabetes Association (ADA) criterion was used to identify cases with microalbuminuria, macroalbuminuria and end stage renal disease (ESRD) for prevalence estimation and risk factor assessment. RESULTS: The overall prevalence of diabetic nephropathy was 10.8%, divided into 1.2% microalbuminuria, 8.1%macroalbuninuria and 1.5% ESRD. Age and diabetes duration as important risk factors have a strong impact on the prevalence of diabetic nephropathy, ranging from 3.7% in patients aged 25-44 years and a duration of >5 years, to 21.8% in patients ≥ 65 years with a diabetes duration of ≥ 15 years. Diabetes duration, retinopathy, neuropathy, hypertension, age >45 years, hyperlipidemia, male gender, smoking, and chronologically, poor glycemic control has a significantly high risk for diabetic nephropathy. CONCLUSION: The prevalence of diabetic nephropathy is underestimated as a result of a shortage of screening programs. Risk factors related to diabetic nephropathy in this society are similar to other societies. There is thus an urgent need for screening and prevention programs for diabetic nephropathy among the Saudi population.

Design and development of a web-based Saudi National Diabetes Registry.

BACKGROUND: Given that diabetes is an extremely common disorder in Saudi Arabia, the National Diabetes Registry was designed by King Saud University Hospital Diabetes Center in collaboration with King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia, in the year 2001. The aim of the registry is to identify risk factors related to diabetes and to provide statistics to public health programs and health care professionals for use in planning and evaluation. The registry was designed to provide information on the extent and nature of specific types of diabetes, diabetes complications, and treatment of diabetes in the Kingdom. The registry has been available since 2001, with major collaborations from 26 hospitals as part of Phase I in which 100,000 patient data is to be collected on a regional level from Ar-Riyadh before extending the program to other regions of Saudi Arabia. METHODS: The web application was designed using relational database techniques along with on-line help topics to assist users to get acquainted with application functionalities. All Internet forms were designed with validation checks and appropriate messages to ensure quality of data. The security measures established within the application ensure that only authorized users can gain access to the functionalities of the registry at allowed times. Administrative features were designed to manage the registry-related operations easily. RESULTS: The diabetes registry has been in operation for almost 10 years, and around 67,000 patients have been registered to date. The Web-application offers an anytime-anywhere access to the registry's data, removing geographical boundaries and allowing the national registry to provide real-time data entry, updates, reporting, and mapping functionalities more easily. CONCLUSION: Merging related information in the form of databases can provide improved health care operations through instant access to data, ease of managing complex data structures, and creation of reports to be used by health care planners and hospital administrators.

Estimation of modified concordance ratio in sib-pairs: effect of consanguinity on the risk of congenital heart diseases.

Family studies are widely used for research into genetic and environmental influences on human traits. In this paper, we establish statistical methodology for the estimation of a new measure of sib similarity with respect to dichotomous traits measured on each member of within family sib-pair. We call this parameter "excess risk." For inference problems involving a single sample, we construct a large sample confidence interval on the concerned parameter. It has long been suspected that consanguinity is a risk factor for many genetic defects. Therefore, we establish a procedure to test the significance of the difference between excess risk parameters in a sample of consanguineous marriages and another sample of non-consanguineous marriages. We apply the methodology to data from a hospital-based congenital heart defects registry in Saudi Arabia, a population in which consanguinity is quite common.

Pattern of cleft lip and palate in hospital-based population in Saudi Arabia: retrospective study.

OBJECTIVE: To report the patterns of cleft lip and/or cleft palate in Saudi Arabia from data collected at a tertiary care hospital. DESIGN AND SETTING: King Faisal Specialist Hospital and Research Center, Riyadh. PATIENTS: All the cleft lip and/or cleft palate patients registered in the Cleft Lip/Palate and Craniofacial Anomalies Registry from June 1999 to December 2005. RESULTS: Retrospectively, 807 cases of cleft lip and/or palate were registered. There were 451 boys and 356 girls. Cleft lip and palate was more common (387) than isolated cleft palate (294) and isolated cleft lip (122). Boys predominated in cleft lip and palate and cleft lip; whereas, girls predominated in isolated cleft palate, with boy to girl ratios of 1.6:1, 1.2:1, and 0.9:1 for cleft lip and/or palate, isolated cleft lip, and isolated cleft palate, respectively. The Riyadh region had more cases (32.0%) than the Asir (15.6%) and Eastern (14.6%) regions. Parents of 439 individuals had consanguineous marriages. A positive family history of cleft was seen in 224 cases. Of 238 cases with associated anomalies, 91 had congenital heart disease. Of the children with isolated cleft palate, 40.5% had associated anomalies, whereas only 23.0% of the children with isolated cleft lip or cleft lip and palate had associated malformations. CONCLUSION: The pattern of cleft observed in this study does not differ significantly from those reported in the literature for Arab populations.

Design and development of an Internet registry for congenital heart defects.

BACKGROUND: Congenital Heart Defects (CHD) are conditions that encompass more than 50 diagnoses and are due to developmental abnormalities early in fetal life. The King Faisal Specialist Hospital and Research Centre in the Kingdom of Saudi Arabia treats approximately 100 new cases per month. We recently developed a new CHD Registry that captures, stores and processes our data via the Internet. METHODS: The Registry was developed using Hypertext Markup Language (HTML), Microsoft Active Server Pages and Microsoft Structured Query Language (SQL). RESULTS: Details of CHD cases are captured in a World Wide Web (WWW) Registry, permitting any browser-enabled PC or Mac to participate fully in all registry functions, including data-entry, viewing, editing, searching, reporting, validating, charting, and exporting data subsets to statistics packages. It includes "administrative" features and an active security system. The paper forms have been designed to reflect the "look and feel" of the Web pages. Automatic validation procedures are also included. CONCLUSIONS: Our Registry has been in operation for 3 years. It serves 10 PCs and contains more than 3,000 registered cases of CHD. It is the first CHD Registry to be fully functional on the Internet. It is also the first dedicated CHD registry, and the first to routinely report on the full spectrum of CHD diagnoses. The WWW offers several logistical advantages to disease registries, especially those that represent large regions. It also offers the possibility of sharing resources between registries, facilitating the aggregation and analysis of disease data on a world-wide scale. This is useful for rare diseases such as CHD (see http://rc.kfshrc.edu.sa/chdr/demo/).