The Israeli National Genetic database: a 10-year experience

BACKGROUND: The Israeli National and Ethnic Mutation database ( http://server.goldenhelix.org/israeli ) was launched in September 2006 on the ETHNOS software to include clinically relevant genomic variants reported among Jewish and Arab Israeli patients. In 2016, the database was reviewed and corrected according to ClinVar ( https://www.ncbi.nlm.nih.gov/clinvar ) and ExAC ( http://exac.broadinstitute.org ) database entries. The present article summarizes some key aspects from the development and continuous update of the database over a 10-year period, which could serve as a paradigm of successful database curation for other similar resources.RESULTS: In September 2016, there were 2444 entries in the database, 890 among Jews, 1376 among Israeli Arabs, and 178 entries among Palestinian Arabs, corresponding to an ~4× data content increase compared to when originally launched. While the Israeli Arab population is much smaller than the Jewish population, the number of pathogenic variants causing recessive disorders reported in the database is higher among Arabs (934) than among Jews (648). Nevertheless, the number of pathogenic variants classified as founder mutations in the database is smaller among Arabs (175) than among Jews (192). In 2016, the entire database content was compared to that of other databases such as ClinVar and ExAC. We show that a significant difference in the percentage of pathogenic variants from the Israeli genetic database that were present in ExAC was observed between the Jewish population (31.8%) and the Israeli Arab population (20.6%).CONCLUSIONS: The Israeli genetic database was launched in 2006 on the ETHNOS software and is available online ever since. It allows querying the database according to the disorder and the ethnicity; however, many other features are not available, in particular the possibility to search according to the name of the gene. In addition, due to the technical limitations of the previous ETHNOS software, new features and data are not included in the present online version of the database and upgrade is currently ongoing

A novel BRCA-1 mutation in Arab kindred from east Jerusalem with breast and ovarian cancer

BACKGROUND: The incidence of breast cancer (BC) in Arab women is lower compared to the incidence in the Jewish population in Israel; still, it is the most common malignancy among Arab women. There is a steep rise in breast cancer incidence in the Arab population in Israel over the last 10 years that can be attributed to life style changes. But, the younger age of BC onset in Arab women compared with that of the Jewish population is suggestive of a genetic component in BC occurrence in that population. METHODS: We studied the family history of 31 women of Palestinian Arab (PA) origin affected with breast (n = 28), ovarian (n = 3) cancer. We used denaturing high performance liquid chromatography (DHPLC) to screen for mutations of BRCA1/2 in 4 women with a personal and family history highly suggestive of genetic predisposition. RESULTS: A novel BRCA1 mutation, E1373X in exon 12, was found in a patient affected with ovarian cancer. Four of her family members, 3 BC patients and a healthy individual were consequently also found to carry this mutation. Of the other 27 patients, which were screened for this specific mutation none was found to carry it. CONCLUSION: We found a novel BRCA1 mutation in a family of PA origin with a history highly compatible with BRCA1 phenotype. This mutation was not found in additional 30 PA women affected with BC or OC. Therefore full BRCA1/2 screening should be offered to patients with characteristic family history. The significance of the novel BRCA1 mutation we identified should be studied in larger population. However, it is likely that the E1373X mutation is not a founder frequent mutation in the PA population

ETHNOS: A versatile electronic tool for the development and curation of national genetic databases

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available softw

ETHNOS : A versatile electronic tool for the development and curation of national genetic databases.

National and ethnic mutation databases (NEMDBs) are emerging online repositories, recording extensive information about the described genetic heterogeneity of an ethnic group or population. These resources facilitate the provision of genetic services and provide a comprehensive list of genomic variations among different populations. As such, they enhance awareness of the various genetic disorders. Here, we describe the features of the ETHNOS software, a simple but versatile tool based on a flat-file database that is specifically designed for the development and curation of NEMDBs. ETHNOS is a freely available software which runs more than half of the NEMDBs currently available. Given the emerging need for NEMDB in genetic testing services and the fact that ETHNOS is the only off-the-shelf software available for NEMDB development and curation, its adoption in subsequent NEMDB development would contribute towards data content uniformity, unlike the diverse contents and quality of the available gene (locus)-specific databases. Finally, we allude to the potential applications of NEMDBs, not only as worldwide central allele frequency repositories, but also, and most importantly, as data warehouses of individual-level genomic data, hence allowing for a comprehensive ethnicity-specific documentation of genomic variation

The crystal structure of human Rogdi provides insight into the causes of Kohlschutter-Tonz Syndrome

Kohlschutter-Tönz syndrome (KTS) is a rare autosomal-recessive disorder of childhood onset characterized by global developmental delay, spasticity, epilepsy, and amelogenesis imperfecta. Rogdi, an essential protein, is highly conserved across metazoans, and mutations in Rogdi are linked to KTS. However, how certain mutations in Rogdi abolish its physiological functions and cause KTS is not known. In this study, we determined the crystal structure of human Rogdi protein at atomic resolution. Rogdi forms a novel elongated curved structure comprising the ?? domain, a leucine-zipper-like four-helix bundle, and a characteristic ??-sheet domain. Within the ?? domain, the N-terminal H1 helix (residues 19-45) pairs with the C-terminal H6 helix (residues 252-287) in an antiparallel manner, indicating that the integrity of the four-helix bundle requires both N- and C-terminal residues. The crystal structure, in conjunction with biochemical data, indicates that the ?? domain might undergo a conformational change and provide a structural platform for protein-protein interactions. Disruption of the four-helix bundle by mutation results in significant destabilization of the structure. This study provides structural insights into how certain mutations in Rogdi affect its structure and cause KTS, which has important implications for the development of pharmaceutical agents against this debilitating neurological disease

Reconstructing Druze population history

The Druze are an aggregate of communities in the Levant and Near East living almost exclusively in the mountains of Syria, Lebanon and Israel whose ~1000 year old religion formally opposes mixed marriages and conversions. Despite increasing interest in genetics of the population structure of the Druze, their population history remains unknown. We investigated the genetic relationships between Israeli Druze and both modern and ancient populations. We evaluated our findings in light of three hypotheses purporting to explain Druze history that posit Arabian, Persian or mixed Near Eastern-Levantine roots. The biogeographical analysis localised proto-Druze to the mountainous regions of southeastern Turkey, northern Iraq and southeast Syria and their descendants clustered along a trajectory between these two regions. The mixed Near Eastern-Middle Eastern localisation of the Druze, shown using both modern and ancient DNA data, is distinct from that of neighbouring Syrians, Palestinians and most of the Lebanese, who exhibit a high affinity to the Levant. Druze biogeographic affinity, migration patterns, time of emergence and genetic similarity to Near Eastern populations are highly suggestive of Armenian-Turkish ancestries for the proto-Druze

Folic acid to reduce neonatal mortality from neural tube disorders

Background Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear

Economic burden of neural tube defects and impact of prevention with folic acid: a literature review

Neural tube defects (NTDs) are the second most common group of serious birth defects. Although folic acid has been shown to reduce effectively the risk of NTDs and measures have been taken to increase the awareness, knowledge, and consumption of folic acid, the full potential of folic acid to reduce the risk of NTDs has not been realized in most countries. To understand the economic burden of NTDs and the economic impact of preventing NTDs with folic acid, a systematic review was performed on relevant studies. A total of 14 cost of illness studies and 10 economic evaluations on prevention of NTDs with folic acid were identified. Consistent findings were reported across all of the cost of illness studies. The lifetime direct medical cost for patients with NTDs is significant, with the majority of cost being for inpatient care, for treatment at initial diagnosis in childhood, and for comorbidities in adult life. The lifetime indirect cost for patients with spina bifida is even greater due to increased morbidity and premature mortality. Caregiver time costs are also significant. The results from the economic evaluations demonstrate that folic acid fortification in food and preconception folic acid consumption are cost-effective ways to reduce the incidence and prevalence of NTDs. This review highlights the significant cost burden that NTDs pose to healthcare systems, various healthcare payers, and society and concludes that the benefits of prevention of NTDs with folic acid far outweigh the cost. Further intervention with folic acid is justified in countries where the full potential of folic acid to reduce the risk of NTDs has not been realized

Twin Town in South Brazil: A Nazi's Experiment or a Genetic Founder Effect?

Cândido Godói (CG) is a small municipality in South Brazil with approximately 6,000 inhabitants. It is known as the “Twins' Town” due to its high rate of twin births. Recently it was claimed that such high frequency of twinning would be connected to experiments performed by the German Nazi doctor Joseph Mengele. It is known, however, that this town was founded by a small number of families and therefore a genetic founder effect may represent an alternatively explanation for the high twinning prevalence in CG. In this study, we tested specific predictions of the “Nazi's experiment” and of the “founder effect” hypotheses. We surveyed a total of 6,262 baptism records from 1959–2008 in CG catholic churches, and identified 91 twin pairs and one triplet. Contrary to the “Nazi's experiment hypothesis”, there is no spurt in twinning between the years (1964–1968) when Mengele allegedly was in CG (P = 0.482). Moreover, there is no temporal trend for a declining rate of twinning since the 1960s (P = 0.351), and no difference in twinning among CG districts considering two different periods: 1927–1958 and 1959–2008 (P = 0.638). On the other hand, the “founder effect hypothesis” is supported by an isonymy analysis that shows that women who gave birth to twins have a higher inbreeding coefficient when compared to women who never had twins (0.0148, 0.0081, respectively, P = 0.019). In summary, our results show no evidence for the “Nazi's experiment hypothesis” and strongly suggest that the “founder effect hypothesis” is a much more likely alternative for explaining the high prevalence of twinning in CG. If this hypothesis is correct, then this community represents a valuable population where genetic factors linked to twinning may be identified

Public perceptions and attitudes toward thalassaemia: Influencing factors in a multi-racial population

<p>Abstract</p> <p>Background</p> <p>Thalassaemia is a common public health problem in Malaysia and about 4.5 to 6% of the Malays and Chinese are carriers of this genetic disorder. The major forms of thalassaemia result in death <it>in utero </it>of affected foetuses (α-thalassaemia) or life-long blood transfusions for survival in β-thalassaemia. This study, the first nationwide population based survey of thalassaemia in Malaysia, aimed to determine differences in public awareness, perceptions and attitudes toward thalassaemia in the multi-racial population in Malaysia.</p> <p>Methods</p> <p>A cross-sectional computer-assisted telephone interview survey of a representative sample of multi-racial Malaysians aged 18 years and above was conducted between July and December 2009.</p> <p>Results</p> <p>Of a total of 3723 responding households, 2846 (76.4%) have heard of thalassaemia. Mean knowledge score was 11.85 (SD ± 4.03), out of a maximum of 21, with higher scores indicating better knowledge. Statistically significant differences (<it>P </it>< 0.05) in total knowledge score by age groups, education attainment, employment status, and average household income were observed. Although the majority expressed very positive attitudes toward screening for thalassaemia, only 13.6% of married participants interviewed have been screened for thalassaemia. The majority (63.4%) were unsupportive of selective termination of foetuses diagnosed with thalassaemia major.</p> <p>Conclusion</p> <p>Study shows that carrier and premarital screening programs for thalassaemia may be more effective and culturally acceptable in the reduction of pregnancies with thalassaemia major. The findings provide insights into culturally congruent educational interventions to reach out diverse socio-demographic and ethnic communities to increase knowledge and cultivate positive attitudes toward prevention of thalassaemia.</p