3rd Pan Arab Human Genetics Conference

March 13-14, 2010

Al Bustan Rotana Hotel, Dubai, United Arab Emirates

Profiles and Abstracts

Mohammad Afzal

11.00 – 11.30 > Governance Challenges of Genomic Applications in Healthcare Systems

Dr. Mohammad Afzal
Research Policy and Cooperation, Regional Office for the Eastern Mediterranean, World Health Organization, Cairo, Egypt

Exponentially growing human genomics research and its commercial involvement in the present century has created a significant number of policy challenges, such as patenting, genetic testing and genetic information. The transition of governing via risk to governance by uncertainty is another challenge to contemporary genomics governance. These new topics of genomics governance have not been taken up seriously in the already operating or emerging institutional structures of policy making in the counties of the Eastern Mediterranean. Besides, there exists a gap between policy challenges and institutional responses and even with meager genomic research in the Region that might lead to growing social opposition against genomics. The healthcare systems, therefore, must have institutional basis to determine the clinical parameters and real potential of genetic testing application in the diagnosis and treatment of disease, and priority setting mechanism for scientific and social policy research. In the meantime, research ethics committees and advocates should develop ethical frameworks to encourage innovation, while protecting research participants and patients from potential harm.

Wafa A El-Adhami

11.30 – 12.00 > Regulation of Genomic Research in Abu Dhabi

El-Adhami W, Shafey O, Hajat C, Harrison O
Health Authority – Abu Dhabi (HAAD), Abu Dhabi, United Arab Emirates

The Health Authority – Abu Dhabi (HAAD) is the regulatory authority for health research in Abu Dhabi. HAAD is responsible for regulating all aspects of Human Subjects Research to safeguard human subjects involved in health research, including genomic research. As part of this role, HAAD has developed policies and standards to regulate the conduct of health research. The HAAD Policy Governing the Ethical Conduct of Human Subjects Research and HAAD Standard Operating Procedures for Research Ethics Committees establish the regulatory framework for ethical conduct in genomic research. HAAD policies and standards require that all genomic research receive ethical approval from a Research Ethics Committee (REC). Key internationally accepted research ethics principles guide REC decisions whether to grant authorization to conduct genomic research. Population level genetic research is increasingly seen to play an important role in public health. Whilst historically this has centered around monogenic disorders, there is now recognition of the role of genetics in chronic disease causation, gene-environment interaction, pharmacogenomics and a move towards more personalized healthcare. HAAD are working to incorporate genetics into the puzzle of chronic disease causation and prevention. This field of endeavors is not without challenges. Genetic research involving human subjects raises complex ethical, legal and social issues, such as the potential for misuse of data, stigma attached to genetic disorders and data intellectual property issues to name a few. These concerns require careful and sensitive management to protect the safety, privacy and welfare of human subjects. Informed consent is one of the fundamental principles underpinning the lawful and ethical retention and use of body parts, tissue and organs from the living or the deceased. This presentation discusses in further detail the objectives, ethical principles, regulatory requirements and duties for institutions and researchers seeking to engage in genomics research within the Emirate of Abu Dhabi.

Ghazi O Tadmouri

13.30 – 13.50 > Consanguinity and Reproductive Health among Arabs

Ghazi O Tadmouri, Pratibha Nair, Tasneem Obeid, Mahmoud T Al Ali, Najib Al Khaja, Hanan A Hamamy
Centre for Arab Genomic Studies, Dubai, United Arab Emirates

Consanguineous marriages have been practiced since the early existence of modern humans. Until now consanguinity is widely practiced in several global communities with variable rates depending on religion, culture, and geography. Arab populations have a long tradition of consanguinity due to socio-cultural factors. Many Arab countries display some of the highest rates of consanguineous marriages in the world, and specifically first cousin marriages which may reach 25-30% of all marriages. While in some Arab States frequencies of consanguineous marriages are decreasing (e.g., Bahrain, Jordan, Lebanon, Palestine), in other countries consanguinity rates are increasing in the current generation (e.g., Qatar, UAE, and Yemen). Research among Arabs and worldwide has indicated that consanguinity could have an effect on some reproductive health parameters such as postnatal mortality and rates of congenital malformations. The association of consanguinity with other reproductive health parameters, such as fertility and fetal wastage, is controversial. The main impact of consanguinity, however, is an increase in the rate of homozygotes for autosomal recessive genetic disorders. Worldwide, known dominant disorders are more numerous than known recessive disorders. However, data on genetic disorders in Arab populations as extracted from the Catalogue of Transmission Genetics in Arabs (CTGA) database indicate a relative abundance of recessive disorders (63%) compared to a smaller proportion of dominantly inherited traits (27%). Among the CTGA records of 451 genetic disorders reported in the United Arab Emirates, Bahrain, and Oman, 36.6% document the presence of patients resulting from consanguineous marriages, mostly among first cousins. Research on inbreeding is considered a priority in societies with high consanguinity rates to help understand and prevent the deleterious impact of consanguinity on health, and to provide standardized and evidence-based guidelines for health care providers to assist them in counseling for consanguinity.

Moien Kanaan

13.50 – 14.10 > Population Genomics of Hearing Loss in the Palestinian Population: A Model for Genetic Heterogeneity

Hashem Shahin*, Tom Walsh**, Amal Abu Rayyan*, Ming K Lee**, Jake Higgins**, Mary-Claire King**, Moien Kanaan*
*Department of Life Sciences, Bethlehem University, Palestine; **Departments of Medicine and Genome Sciences, University of Washington, Seattle, USA

Recessively inherited phenotypes are frequent in the Palestinian population as the result of a long historical tradition of marriages within extended families. Traditionally, gene localization in these families has been achieved with microsatellite linkage mapping. We demonstrate that genome wide screening with high density SNP arrays is an effective method for pinpointing causative genes and novel loci in consanguineous Palestinian families. In total, we genotyped 84 deaf and 84 hearing sibs or parents, from 21 families, on Affymetrix 250K SNP arrays. We generated deafness-associated homozygosity profiles from the SNP data in each family. We defined a peak of homozygosity as a contiguous region greater than 2MB where SNPs were homozygous for one allele among affected members but discordant (heterozygous or homozygous for the complement allele) from unaffected relatives in the pedigree, either parents or sibs. For 15/21 families the longest homozygous peak mapped to a genomic region that included a known deafness gene. Sequencing the relevant gene from each peak region identified 12 deleterious alleles, 10 of which were novel. They included premature truncations of OTOF, PEJK, TECTA, and TMPRSS3, and a large genomic deletion of OTOA that was mediated by a segmental duplication. The mutational spectrum also included novel missense alleles of LHFPL5, MYO15A, MYO7A and CDH23, which were determined to be pathogenic based on molecular modeling tools. Six of the 21 families harbor mutations in as-yet-unknown genes for inherited hearing loss. SNP-based homozygosity mapping defines the genomic locales of these novel loci with considerable precision.

Habiba Al Safar

14.10 – 14.30 > The EFR Project: A Collaborative Network to Establish an Arabian Biobank Resource to Identify Disease Genes of Indigenous Populations

Al Safar H*,**,***, Jamieson S****, Cordell H*****, Blackwell J****,******, Hassoun A*******, Hui J********, Khazanehdari Ki*********, Ridha A*********, Tay G***
*Dubai Police General Head Quarters, Dubai, United Arab Emirates; **School of Biomedical, Biomolecular and Chemical Sciences, University of Western Australia, Crawley Western Australia; ***Centre for Forensic Science, The University of Western Australia, Crawley Western Australia; ****Telethon Institute for Child Health Research, Centre for Child Health Research, The University of Western Australia, Subiaco, Western Australia; *****Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, United Kingdom; ******Cambridge Institute for Medical Research and Department of Medicine, School of Clinical, Medicine University of Cambridge, Cambridge, United Kingdom; *******Joslin Diabetes Centre, Rashed Hospital, Dubai, United Arab Emirates; ********Pathwest, QEII Medical Centre, Nedlands, Western Australia; *********Molecular Biology and Genetics, Central Veterinary Research Laboratory, Dubai, United Arab Emirates

The "EFR Project" or Emirates Family Registry was established as part of a collaborative effort to develop the capabilities of a bio-specimen repository, the associated database resources, high-throughput genotyping capabilities and skills in medical bioinformatics for the UAE. Towards demonstrating its feasibility, a pilot project since 2007 has recruited volunteers from 3 local hospitals and 9 primary care centres. Through this network, 23,064 volunteers provided consent to allow their clinical data to be stored in EFR's database. DNA samples from Bedouins with Type 2 Diabetes (T2D) were collected from 1,766 donors. Due to an increasing prevalence of T2D in the region, lifestyle management strategies with an emphasis on prevention are required. Consequently, understanding the environmental factors and genetic predispositions were important aims of this study to ensure successful implementation of future public awareness programs. Diet and lifestyle factors (smoking, exercise, and others) are known to play a role. Assessment of the quantitative traits collected in this study showed significant contributions by factors such as Body Mass Index (BMI) and waist circumference (p < 1x10-6). There were other suggestive traits (cholesterol, creatinine levels; p < 0.05). Although phenotype studies provide some insight, matching genetic studies will augment the understanding of disease mechanisms. Towards this, the first Genome Wide Association Study in Bedouins was performed on 178 volunteers from the EFR project's DNA repository using Illumina's Human 660W-Quad-BeadChip. Work in Caucasians have defined genetic susceptibility regions on Chromosomes 3, 6, 8, 9, 10, 11, 16, and 17. Preliminary analysis of data from this study has revealed potential candidate genes on Chromosome 14 and 10. Work continues to assess if shared regions could explain common clinical manifestations and whether differences are responsible for phenotypes that are unique to Arabs. As Phase One of the EFR project draws to a close, the collaborations established with regional and international partners will see the expansion of the project to other GCC countries. The assortment of ethnic groups in the region covers a diverse array of different populations (e.g., Arabs, Bedouins, Persians, Kurds, Lebanese, Palestinians, Turks, and others). An understanding of the genetic diversity in the region will provide an insight into mechanisms that cause disease. These developments could possibly lead to improved intervention and prevention programs to improve the quality of life throughout Arab nations.

Bassam Ali

14.30 – 14.50 > Cellular Organelle Disease Genomics: The ER-Associated Protein Degradation (ERAD) is a Major Mechanism Underlying Numerous Human Genetic Disorders

Ali BR*, Akawi NA*, John A*, Al-Gazali L**
Departments of *Pathology and **Paediatrics, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates

More than a third of all cellular proteins are targeted to the endoplasmic reticulum (ER) as a first step in their trafficking routes along the secretory pathway to their final cellular destinations. The processes of protein folding, assembly into multi-subunit complexes and export out of the ER are subjected to a stringent quality control system to ensure that only properly folded and assembled proteins exit the ER. Malfolded proteins and unassembled subunits of protein complexes are rejected by this ER quality control system and re-translocated to the cytosol for degradation by the ubiquitin/proteasome. This process has been named ERAD (ER-Associated protein Degradation) and has been implicated in the cellular mechanisms of at least 50 human monogenic diseases including cystic fibrosis. Due to the high stringency of ERAD and the large number of cellular proteins that has to pass through the secretory pathway (~8,000), we reasoned that ERAD should be implicated in the mechanisms of many more human monogenic conditions. We therefore, utilized bioinformatics and data mining approaches and found that at least 45% of all known human disease genes have an ER-targeting signal and consequently we identified many ERAD disease candidates. We validated our predictive approach experimentally by establishing that ERAD is indeed responsible for most of the loss-of-function missense mutations in the genes involved in a number of the identified ERAD disease candidates including Robinow syndrome and Acromesomelic Dysplasia type Maroteaux.

Rami A Jarjour

14.50 – 15.10 > Genetic Disorders in Syria

Jarjour RA
Clinical Genetics Unit, Molecular Biology and Biotechnology Department, Atomic Energy Commission of Syria (AECS), P.O. Box 6091, Damascus, Syria

In Syria, several genetic disorders, including beta-thalassemia, familial Mediterranean fever (FMF), glucose-6-phosphate dehydrogenase deficiency, sickle-cell disease, hemophilia, inborn errors of metabolism, are common. Familial Mediterranean fever (MEFV) gene mutations and the genotype–phenotype correlation were investigated. The carrier rate in the Syrian population for MEFV mutations is 17.5%. The most frequent mutation was M694V, followed by V726A, E148Q, M680I (G/C), and M694I mutations. Rare mutations (R761H, A744S, M680I (G/A), K695R, P369S, F479L and I692del) were also detected in the patients. M694V was associated with the severe form of the disease. beta-Thalassemia is endemic in Syria. The prevalence rate of beta-thalassemia trait in high risk groups is 7% (1-1.5 million carriers) and the estimated number of affected patients is 7785. The various beta-thalassemia mutations are being characterized. Moreover, rare genetic disorders (such as cystic fibrosis) are also being investigated. Premarital carrier screening and prenatal diagnosis is offered to the affected families in order to prevent those genetic disorders.

Suzanne Giesebrecht

15.10 – 15.30 > Linkage Mapping and Mutation Screening in Two Families with Autosomal Recessive, Non-Syndromic Mental Retardation

Giesebrecht S*, Kluck N*, Lippke B*, Schumacher J*, Propping P*, Haug K**, Nothen M*, Abou Jamra R***
*Institute of Human Genetics, Bonn, Germany; **Praenatal-Medizin und Genetik, Düsseldorf, Germany; ***Institute of Human Genetics, Erlangen, Germany

Because of common consanguineous marriages, autosomal recessive gene defects may be the most important, but least studied genetic cause of severe cognitive dysfunction in the Middle East. Studies of consanguineous families with affected children represent the best available strategy for the identification of causative genes. Two consanguineous families of Kuwaiti and Turkish descent had 2 and 3 children, respectively, with severe, non-syndromic mental retardation. Routine analyses did not enable us to establish a diagnosis. We thus ran a genome wide linkage analysis using SNP-chips and revealed in each of the families one homozygote region on 13q13.2-q21.3 (29Mb, Kuwaiti family) and 8p12-q12.3 (22Mb, Turkish family). None of the regions have been described in association with mental retardation before. So far, we have sequenced 102 genes (out of 105) in the linkage region in the Kuwaiti family and 38 genes (out of 91) in the Turkish family. Taken together, we sequenced over 1500 exons and identified 426 variants, 9 of them are potentially causative. Ongoing work includes the genotyping of the 9 potentially causing variants in control samples and the sequencing the rest of the candidate genes in the linkage regions.

Fahd Al-Mulla

16.00 – 16.20 > Novel Insight into Genomic Medicine: From Diagnosis to Tailored Therapy

Fahd Al-Mulla
Molecular Pathology Unit, Department of Pathology, Faculty of Medicine, Kuwait University, Kuwait

Before the birth of modern medicine, it has been known that similar diseases behave differently and respond variably to treatment in different patients. Perhaps the most important milestone of recent time is the deciphering of the human genome and the realization of its complexity. The utilization of high throughput technologies, such as microarrays, proteomics and complex functional techniques has allowed us to explore reasons behind the variations we see in disease expressivity and treatment responses. Moreover these technologies and advances are allowing us to identify genetic and epigenetic causes of complex diseases in an impressive speed and ingenuity. We gained complex tools to match and decipher complex disorders and diagnose them quickly and more accurately. For example, we now know that cancer is not one disease, but a spectrum of diseases that have different prognosis and treatment responses depending on their transcriptome and proteome. However, we have to move forward with humility and the realization that we have barely “scratched the surface” of this black box we call disease. In my talk, I will introduce recent advances in the “OMICS” field and explore how our laboratory in Kuwait University is utilizing these techniques for better translational medicine.

Chaker Adra

16.20 – 16.40 > The Application of Proteomics for Kidney Disease Diagnostics: Global Differential Protein Expression Profiling of Serum in FSGS Families

Al-Romaih K*,****, Shinwari Z*, Al-Mojalli H**, Al-Manea H***, Atallah N*, Al-Rodayan M*, Alaiya A*, Pollak M****,*****, Adra C*,*****
*Stem Cell Therapy Program, **Pediatrics Department, and ***Laboratory Medicine and Pathology, King Faisal Hospital & Research Centre, Riyadh, Saudi Arabia; ****Renal Divisions, Brigham & Women’s Hospital, and Harvard Medical School, Boston, MA, USA; *****Transplantation Center, Children’s Hospital Boston, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA

Focal and Segmental Glomerulosclerosis (FSGS) is a kidney disorder caused in part by mutations in genes encoding proteins involved in cytoskeleton processes, cell adhesion, and signal transduction. The mechanisms involved in the development of FSGS remain poorly understood and some of the challenges that are faced in the clinic include the lack of early diagnosis of FSGS and inability to determine the mechanisms underlying kidney failure as a result of FSGS and treatment failure in children with FSGS. The focus of this collaborative research is on glomerular diseases, with a particular interest in the study of FSGS. We are recruiting FSGS patients and their unaffected family members to perform global proteomic expression profiling on serum samples. In this study, serum from six FSGS patients and six unaffected relatives were analyzed. Two-dimensional gel electrophoresis (2-DE) coupled with tandem mass spectrometry was used to identify proteins. Image analysis was performed using PDQuest Software. A total of 21 proteins with at least a twofold change in the FSGS patients were identified based on Mann-Whitney Signed-rank test (CI = 98%). Hierarchical Cluster analysis using the proteome expression patterns showed distinct segregation of FSGS patients from unaffected individuals based on the differential expression of the 21 protein spots. This study presents the first attempt to utilize serum proteomics as a tool for biomarker discovery in chronic kidney disease and will contribute to identification of early diagnostic biomarkers, improving the accuracy of diagnosis, and to providing prevention strategies. In addition, our data highlights the potential role of serum proteomic profiling for mapping proteins, which may be critical in FSGS development and progression to kidney failure in FSGS patients.

Abdel Halim A Salem Deifalla

16.40 – 17.00 > Mobile Elements Create Structural Variation: Analysis of a Complete Human Genome

Salem A-H*, Xing J**, Han K***, Batzer M***, Jorde L**
*Department of Anatomy, CMMS, Arabian Gulf University, Manama, Bahrain; **Department of Human Genetics, University of Utah, Salt Lake City, UT, USA; ***Department of Biological Sciences, LSU, Baton Rouge, LA, USA

Approximately half of the human genome consists of repetitive, transposable DNA sequences. These elements play an important role in generating structural variants (SVs) in humans. We assessed, for the first time, the impact of mobile elements on SVs in an individual (HuRef), and evaluated more than 8,000 SVs to identify mobile element-associated SVs as small as 100 bp, specific to the HuRef genome. Combining both computational and experimental analyses, we identified and validated 706 mobile element insertion events, which added ~305 kb of new DNA sequence to the HuRef genome compared to the Human Genome Project (HGP) reference sequence. We also identified 140 mobile element-associated deletions, which removed ~126 kb of sequence from the HuRef genome. Overall, ~10% of the HuRef specific indels that are larger than 100 bp are caused by mobile element-associated events. More than one-third of the indels events occurred in genic regions, and new Alu insertions occurred in exons of three human genes. We estimated the Alu, L1, and SVA retrotransposition rates to be one in 21 births, 212 births, and 916 births, respectively. This study presents the first comprehensive analysis of mobile element-related SVs in the complete DNA sequence of an individual and demonstrates that mobile elements play an important role in generating inter-individual structural variation.

Safa MH Taha

17.00 – 17.20 > A Novel Immune System Mediator

Bakhiet M, Taha S
Department of Molecular Medicine, HH Princess Al-Jawhara Center for Genetics and Inherited Diseases, College of Medicine and Medical Sciences, AGU, P.O. BOX 26671, Bahrain

The present work relates to a novel immune system mediator signaling between the immune system and the nervous system following an immune challenge. Supernatants of 48h cultured splenocytes prepared from subcutaneously trypanosome-inoculated rats and mice spleens obtained directly after inoculation and added to naïve cells showed increased IFN-? production and cell proliferation. This action was significantly blocked by surgical denervation of the spleen. To identify genes differentially expressed in this process, the florescent differential display technique was used. A new gene in mouse splenocytes was identified and sequenced. The full length mRNA was cloned into a mammalian expression vector and the library was screened by specific primers, and the full-length sequence of a novel gene was obtained and found to be located in chromosome 14 (GenBank accession number: EU552928). Protein expression was done and the recombinant protein was purified. Western blot analysis using rabbit polyclonal antibody against the protein demonstrated a ~15 kDa molecular mass band. The recombinant protein showed similar biological activities as the cultured supernatants. Furthermore, the protein was able to reactivate experimentally immunosuppressed cells by regaining their ability to proliferate, suggesting that such a nervous system-induced immune system-released activating agent (ISRAA) may have a potential therapeutic benefit in immunocompromised situations and in further understanding the mechanism for innate immunity commencement and action.

Mohamed Salah El-Din Riad

09.00 – 09.20 > United Arab Emirates National Newborn Screening Program: An Evaluation (1995 – 2009)

Al Hosani H, Salah El-Den M, Osman H, Saada D, Khalfan A
National Screening Program for Woman and Child Health, Central Department of Maternal and Child Health, P.O. Box 848, Ministry of Health, Abu Dhabi, United Arab Emirates

In UAE, the program started by screening for PKU in January 1995 and then congenital hypothyroidism and sickle cell diseases were introduced in January 1998 and January 2002, respectively. Congenital adrenal hyperplasia screening program was started as a pilot study in January 2005 and expanded at the national level in 2007. Blood is collected on the third day (? 48 hours) by heel prick onto the filter paper S & S 903. TSH, phenylalanine and 17-OHP are assayed by Delfia Fluorometric method and the same filter papers are tested for sickle cell disease by High Performance Liquid Chromatography (HPLC). There is UK NEQAS (United Kingdom National External Quality Assessment Schemes) for quality assessment of laboratory results. For the evaluation, we used the coverage (% uptake), timeliness of the screening program indicators, the indicators of validity of test (recall rate, sensitivity, specificity and positive predictive values), follow up results and determine the relative incidence rates for PKU, congenital hypothyroidism, sickle cell diseases and congenital adrenal hyperplasia cases. Since the implementation of the program (from January 1995 until DEC 2009): more than 650,000 infants were screened with 95% uptake and more than 500 cases were prevented from mental retardation and decrease morbidity and mortality. The coverage is good for all medical districts and the indicators of program quality currently approximate international standards .Future Plans include additional of others tests to the program in 2010 as Biotinidase deficiency and tandem mass spectrometry (MS/MS).

Shaikha S. Al-Arrayed

09.20 – 09.40 > The Bahrain Program to Control Genetic Blood Diseases: 1984-2010

Al Arrayed S
Genetic Department, Salmaniya Medical Complex, Manama, Kingdom of Bahrain

The goals of this campaign were to reduce the incidence of hereditary diseases in Bahrain, and to improve the standard of management for patients suffering from these diseases. The campaign to control genetic disease in Bahrain‏ was organized in the period 1984-2010. The prevention strategy depended on health education, screening and counseling. A comprehensive health education program has been launched to increase public awareness of the diseases and methods to avoid them. This program used the media, and targeted key opinion leaders in society and the community, in schools and other public places. Screening for hemoglobinopathies included sickle cell disease, thalassemia, was undertaken on the following categories of the population: antenatal mothers, premarital couples, newborns, and school students, followed by counseling of families. The campaign was supported by both the policy makers and the community. These efforts continued for more than 25 years. It had tremendous effects in reducing the prevalence of Genetic Blood Diseases (GBD) among the newborns, in 1984 the incidence of SCD among newborn was 20 per thousand, now it is 6 per thousand with 70% decline. Consanguinity rate also declined gradually due to increase awareness about genetic diseases. The total consanguinity rate in 1990 was 40%, while in 2007 it became 20% with 66% decline. During this campaign, the ethical, legal, and social issues were taken care of, such as: equity, informed consent, privacy, confidentiality and prevention of stigmatization and discrimination.

Sadika A. Al-Awadi

09.40 – 10.00 > Modern Approaches in the Genetic Diagnostics in Kuwait

Sadika A Al-Awadi
Kuwait Medical Genetics Center, Kuwait

Genetic diagnostic approaches differ from one center to another according to the facilities of each center and the experiences of its medical staff. The objective of this study is to present the experience of Kuwait Medical Genetics Center in diagnosis of common and rare genetic disorders. One of these disorders, which have different approaches for diagnosis, is Prader-Willi/Angelman (PWS/AS) syndrome complex. PWS is caused by lack of the paternal contribution of 15q11.2-q12, through loss of the entire paternal chromosome 15, with presence of uniparental maternal disomy or through imprinting defects of paternal SNRPN gene in this locus. On the other hand, Angelman syndrome results from a lack of maternal contribution from chromosome 15q11-q13, arising from de novo deletion in most cases, from unipaternal isodisomy or a mutation in UBE3A gene. These two syndromes are distinct entities and have different clinical criteria. We developed a cost/efective time consuming approach for the diagnosis of the syndrome complex which will be discussed in this presentation.

Hanan Hamamy

10.00 – 10.20 > Childhood Short Stature: Approach to Evalutation and Diagnosis in a Genetic Counseling Clinic

Hanan Hamamy
Department of Genetic Medicine and Development, Geneva University Hospital, Geneva, Switzerland

Parents who bring their child to a genetic counseling clinic with the main presentation of short stature usually have high hopes that an accurate diagnosis will be reached and that management will eventually add some centimeters to the final height. Childhood short stature is broadly classified into familial, constitutional growth delay (CGD) and pathologic. The first two categories should be ruled out before further evaluation for genetic causes. Pathologic childhood short stature is etiologically heterogeneous, necessitating a step by step evaluation of the affected child. The differentiation between proportionate and disproportianate short stature which is mainly related to skeletal dysplasias is crucial. Proportionate short stature could be of prenatal or postnatal onset. In «Smith’s recognizable patterns of human malformations», some syndromes are categorised as ‘very small stature, not skeletal dysplasia, while others as «moderate short stature». Management depends on the underlying etiology and could be markedly rewarding in some cases such as in isolated growth hormone deficiency, or slightly rewarding as in Turner and Noonan syndromes. Rare syndromes need detailed investigations to reach the accurate diagnosis: a model case from presentation to clinical and molecular diagnosis will be presented.

Fatma Al-Jasmi

10.20 – 10.40 > Mild Phenotype of Mucolipidosis Type III

Fatma Al-Jasmi
Department of Pediatrics, Faculty of Medicine and Health Science, UAE University, Al Ain, United Arab Emirates

Mucolipidosis type III (ML III; pseudo Hurler polydystrophy) is a genetically heterogenous progressive lysosomal disorder mainly involving the skeletal system. It is an autosomal recessive inherited disorder caused by a defective N-acetylglucosamin 1-phosphotransferase (phosphotransferase). Phosphotransferase deficiency is caused by mutation in GNPTA and GNPTG encoding phosphotransferase subunits. Here we report a mild phenotype of MLIII on two siblings from consanginous Pakistani family with positive family history. The younger sibling presented with mild joint stiffness of the hand, while the older sibling have more joint involvement illustrating the natural progressive course of the disease. Urinary mucopolysaccharide excretion was abnormal with elevated dermatan and heparan sulfate. ?-hexosamindiase enzyme activities were significantly elevated in the serum.

Mohammed AbdulAziz AlOwain

10.40 – 11.00 > An Autosomal Recessive Syndrome of Severe Mental Retardation, Dysmorphic Facies and Skeletal Abnormalities Maps to the Long Arm of Chromosome 17

Al-Owain M*,**, Alazami A***, Alkuraya F**,***,****
*Department of Medical Genetics, KFSHRC, P.O. BOX 3354, Riyadh-11211, Saudi Arabia; **College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; ***Department of Genetics, KFSHRC, Riyadh, Saudi Arabia; ****Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia

Mental retardation (MR) is one of the most challenging referrals to the clinical genetics service. The different algorithms proposed to assist in the molecular diagnosis of MR rest largely on the distinction between syndromic and non-syndromic forms. We have identified what appears to be a novel syndromic form of MR, the variable phenotype of which comprises severe mental retardation, hirsutism, dysmorphic facies and skeletal abnormalities, and have mapped it to a single locus 17q21.31-17q22 with a minimal linkage interval of 12.2 Mb. Two candidate genes, HOXB6 and PPP1R9B were sequenced but no pathogenic alterations were identified. While the dysmorphology profile in the family we report is not striking, we believe it is distinctive enough to warrant its classification as a syndrome. The remote resemblance to Cornelia de Lange syndrome may aid in the dysmorphology recognition of this syndrome but it is not yet clear if the two are related pathoetiologically since no components of the cohesin complex are known to reside in the minimal linkage interval. This report adds to the growing list of autosomal recessive syndromic MR conditions and defines a linkage interval harboring a gene which likely plays a vital role in brain development.

Mona Abdel Razek El Gammal

11.30 – 11.50 > A Novel Homozygous Missense Mutation of the Leptin Gene (N103K) in an Obese Egyptian Patient

Mazen I*, El-Gammal M*, Abdel-Hamid M**, Amr K**
*Clinical Genetics Department, **Medical Molecular Genetics Department, National Research Centre, 33 El-Behoos Street, Doki, Cairo, Egypt

Congenital leptin deficiency is a rare recessive genetic disorder resulting in severe hyperphagia and early onset obesity. It is caused by mutations in the LEP gene encoding leptin. To date, only two mutations have been identified in the LEP gene, D133G and R105W. We present the third reported mutation identified in an Egyptian patient with very low serum leptin levels and severe early onset obesity (BMI = 51). Direct sequencing of the coding region of the LEP gene revealed a novel homozygous missense mutation, N103K. The N103K mutation was not found in 100 alleles from 50 unrelated Egyptian normal-weight control subjects using polymerase chain reaction and restriction fragment length polymorphism analysis. In conclusion, this study presents the third reported mutation of the LEP gene and will provide further insight into the physiologic role of leptin in human obesity.

Faouzi Maazoul

11.50 – 12.10 > Baraitser Syndrome: A New Case

Maazoul F, Chaabouni M, Ksantini MA, Euchi L, Ben Jemaa L, M’rad R, Chaabouni-Bouhamed H
Department of Congenital and Hereditary Disorders, Charles Nicolle Hospital, Tunis, Tunisia

Baraitser syndrome, or syndrome of brachyphalangy, polydactyly, and absent tibia (OMIM: 609945) was first described in 1997. It is a very rare syndrome, to date 10 cases have been reported (7 males and 3 females). We report a new case; a Tunisian female aged nine months. She was born from healthy consanguineous parents. She has no sibling. She had intrauterine growth retardation, congenital microcephaly, facial dysmorphism, short neck, limb anomalies and hypoplasia of external genitalia. The patient had flat face, flat occiput and temporal depression. She had hypotelorism, ptosis of left eyelid, blepharophimosis, microtia with dysplastic and low set ears, flat nasal bridge with broad nose, long philtrum, and microrethrognatism. Limb anomalies were characterized by limited joints extension, broad fingers and toes, nail dysplasia, preaxial polydactyly of feet, brachyphalangy, right fibula agenesis, tibia hypoplasia and club foot varus. She had horse kidney and sacral dimple. The heart and the brain were normal. There was no family history. The karyotype was normal: 46,XX. The syndrome is probably due to gene mutation. The inheritance pattern is still unclear due to small number of cases. There are two probable candidate genes ALX3 and ALX4 that were demonstrated to be involved in mice limbs anomalies. ALX4 haploinsufficiency in humans causes parietal foramina, which one patient with this syndrome was reported to have. Sequencing of coding exons of ALX4 and its related homologue, ALX3, in a reported case, failed to reveal coding sequence alterations. New documented cases will be very useful to complete clinical and genetic characteristics of the syndrome.

Jamil Alami

12.10 – 12.30 > Delineation of De Novo Copy-Number Variations in a Number of Cases with Genetic Disorders

Al-Alami J, Tolefat M, Al-Sarraj Y, Hamed Z, Saleh B, El-Shanti H
Shaffallah Medical Genetics Center, Doha, Qatar

Copy-number variations (CNV) are responsible for several genetic disorders. However, CNVs represent polymorphisms. We report on the phenotypic and genotypic delineation of de novo CNVs in a number of cases with genetic disorders. Methods: Affected individuals underwent a rigorously phenotypic evaluation by a Clinical geneticist. DNA was extracted from blood using standard methods. CNVs and break point region were identified using Illumina Infinium Bead Chip Human CNV370 and Human 1M. Analyses of the Illumina results were carried out using bead studio v3.2 from Illumina. A 20 year old male with severe intellectual disability and Marfanoid habitus, cleft palate, facial dysmorphism and microphthalmia and hypermetropia. Cytogenetic investigation showed an additional un-identified chromosome piece attached to the short arm of chromosome 14. A DNA sample run on Illumina whole genome revealed a duplication of the terminal piece of the long arm of chromosome 10 (30.1 Mb). The break point region was identified to be within a 5.33 Kbp segment between rs 4307650 & rs7920251. Other cases will be presented. The cases included demonstrate that CNVs play a role in genetic disorders. This study provides a proof of principle that the Illumina whole genome chips are a good screening tool for the delineation of CNVs.

Hans Peter Arnold

11.15 – 12.15 > Illumina Sequencing Technology in Molecular Genetics and Cytogenetics

Hans Peter Arnold
Illumina, Germany

In addition to SNPs, structural variability is now recognized as a substantial source of genetic variation that has a major influence on phenotypic variation. Thus, genome-wide profiling for chromosomal aberrations—such as amplifications, deletions, and rearrangements—is crucial for both the study of cancer and congenital disorders. Illumina offers a broad portfolio of products on two different platforms—based on BeadArray or sequencing technologies—to cater to cytogenetics. Both platforms provide substantially better resolution to detect smaller regions than conventional cytogenetic methods like karyotyping, FISH, or CGH. In general, array technology is rapidly taking over the cytogenetics laboratory, resulting in greatly improved detection capabilities. While CGH (comparative genomic hybridization) array platforms have been the most widely used to date, SNP technology is rapidly becoming accepted as the future of cytogenetics because of its ability to detect more relevant aberrations. The unique ability of SNP genotyping arrays to simultaneously measure intensity differences and allelic ratios allows for the profiling of both aneuploidy and copy-neutral loss of heterozygosity (CN-LOH). The analysis of CN-LOH is of relevance for the detection of uniparental disomy (UPD) and consanguinity. Since many tumor suppressor genes have been identified by CN-LOH, SNP arrays are also a valuable tool to cancer cytogeneticists. The simultaneous and integrated analysis of genotypes (b-allele frequency) allows a better analysis of complex genetic arrangements and a higher resolution in the detection of mosaic samples. Illumina sequencing technology is the ultimate molecular karyotype and generates up to 50 gigabases of sequence data per week, to quickly provide sufficient genomic coverage for the study of nearly all point mutations, structural variants, translocations, inversions, insertions, and deletions, with base-pair resolution breakpoint identification. In research settings, Illumina sequencing technology has been successfully used for the non-invasive detection of fetal aneuploidy by sequencing maternal blood plasma.

Hatem El-Shanti

10.45 – 11.15 > The Utilization of High Through-put SNP Genotyping for Gene Discovery in Genetic Disorders

Hatem El-Shanti
Shafallah Medical Genetics Center, Qatar

The Shafallah Medical Genetics Center has taken advantage of the prevalent consanguinity in our populations, the advances in genotyping and sequencing technology and the robust available analytic tools to launch several gene discovery projects. The high though-put SNP genotyping chip technology provided by the Illumina platform is applied in three approaches to facilitate gene discovery in genetic disorders. The first approach is tracing recent ancestry to identify genes and loci implicated in complex disorders such as epilepsy and autism spectrum disorders through family genotyping studies. Association studies require a large sample size and are thus performed in parallel with the recent ancestry tracing but analyzed in the context of larger sample size contributed by collaborative teams. The second approach is the utilization of homozygosity mapping to identify genes and loci implicated in rare autosomal recessive disorders. Collaboration with other teams from Qatar and other Arabic countries has lead to the mapping of five rare autosomal recessive disorder genes. Gene identification by Sanger and Next Generation sequencing is currently ongoing for these five disorders. The third approach is the utilization of the copy number variations (CNV) utility imbedded into the Illumina chips to identify deletions or duplication that is involved in a genetic disorder. Examples from unbalanced gross chromosomal rearrangements, as well as, cryptic rearrangements will be discussed.

Kamal Khazanehdari

10.45 – 11.15 > Application of High Throughput SNP Array (Illumina) in Animal and Human Genome-Wide Asssociation Studies

Kamal Khazanehdari
Molecular Biology Laboratory, Central Veterinary and Research Lab, Dubai

Sequencing the Equine genome by the Broad Institute provided the opportunity for the International Equine Genome Consortium to benefit from high throughput genotyping technologies. Collaboration of IEGCC as an iSelect with Illumina provided the opportunity for developing the equine SNP array. Consequently, the MBG lab considered the Illumina platform for part of its research work. In addition, as part of MBG effort to support Emirati student in their higher education, the Human SNP array was also used for genome-wide association studies of Type II diabetes in a complex and extended Arab family. Examples of the two studies will be discussed.