Person: Fahed, Akl
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Fahed
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Akl
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Fahed, Akl
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Publication NKX2-5 Mutations in an Inbred Consanguineous Population: Genetic and Phenotypic Diversity(Nature Publishing Group, 2015) Abou Hassan, Ossama K.; Fahed, Akl; Batrawi, Manal; Arabi, Mariam; Refaat, Marwan M.; DePalma, Steven; Seidman, J. G.; Seidman, Christine; Bitar, Fadi F.; Nemer, Georges M.NKX2-5 mutations are associated with different forms of congenital heart disease. Despite the knowledge gained from molecular and animal studies, genotype-phenotype correlations in humans are limited by the lack of large cohorts and the incomplete assessment of family members. We hypothesized that studying the role of NKX2-5 in inbred populations with homogeneous genetic backgrounds and high consanguinity rates such as Lebanon could help closing this gap. We sequenced NKX2-5 in 188 index CHD cases (25 with ASD). Five variants (three segregated in families) were detected in eleven families including the previously documented p.R25C variant, which was found in seven patients from different families, and in one healthy individual. In 3/5 familial dominant ASD cases, we identified an NKX2-5 mutation. In addition to the heterogeneity of NKX2-5 mutations, a diversity of phenotypes occurred within the families with predominant ASD and AV block. We did in fact identify a large prevalence of Sudden Cardiac Death (SCD) in families with truncating mutations, and two patients with coronary sinus disease. NKX2-5 is thus responsible for dominant familial ASD even in consanguineous populations, and a wide genetic and phenotypic diversity is characteristic of NKX2-5 mutations in the Lebanese population.Publication A Novel Role for CSRP1 in a Lebanese Family with Congenital Cardiac Defects(Frontiers Media S.A., 2017) Kamar, Amina; Fahed, Akl; Shibbani, Kamel; El-Hachem, Nehme; Bou-Slaiman, Salim; Arabi, Mariam; Kurban, Mazen; Seidman, Jonathan; Seidman, Christine; Haidar, Rachid; Baydoun, Elias; Nemer, Georges; Bitar, FadiDespite an obvious role for consanguinity in congenital heart disease (CHD), most studies fail to document a monogenic model of inheritance except for few cases. We hereby describe a first-degree cousins consanguineous Lebanese family with 7 conceived children: 2 died in utero of unknown causes, 3 have CHD, and 4 have polydactyly. The aim of the study is to unveil the genetic variant(s) causing these phenotypes using next generation sequencing (NGS) technology. Targeted exome sequencing identified a heterozygous duplication in CSRP1 which leads to a potential frameshift mutation at position 154 of the protein. This mutation is inherited from the father, and segregates only with the CHD phenotype. The in vitro characterization demonstrates that the mutation dramatically abrogates its transcriptional activity over cardiac promoters like NPPA. In addition, it differentially inhibits the physical association of CSRP1 with SRF, GATA4, and with the newly described partner herein TBX5. Whole exome sequencing failed to show any potential variant linked to polydactyly, but revealed a novel missense mutation in TRPS1. This mutation is inherited from the healthy mother, and segregating only with the cardiac phenotype. Both TRPS1 and CSRP1 physically interact, and the mutations in each abrogate their partnership. Our findings add fundamental knowledge into the molecular basis of CHD, and propose the di-genic model of inheritance as responsible for such malformations.Publication Pregnancy in a Woman with Homozygous Familial Hypercholesterolemia Not on Low-Density Lipoprotein Apheresis(Thieme Medical Publishers, 2012) Fahed, Akl; Nassar, Anwar H.Pregnancy in women with homozygous familial hypercholesterolemia (FH) has been rarely reported and might pose risks on the mother and her fetus. Although most reported cases remained on low-density lipoprotein (LDL) apheresis, there are no clear guidelines regarding the management of this entity. We report the first case of an uncomplicated pregnancy in a 24-year-old homozygous FH woman who was not maintained on LDL apheresis. FH expresses a wide variability in the phenotype, and management of homozygous FH cases who desire to become pregnant should be individualized based on preconceptional assessment with frequent antenatal follow-up. Decisions on management should be made after weighing the risks versus benefits of LDL apheresis.Publication Variable expressivity and co‐occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy(John Wiley and Sons Inc., 2016) Fahed, Akl; Khalaf, Ruby; Salloum, Rony; Andary, Rabih R.; Safa, Raya; El‐Rassy, Inaam; Moubarak, Elie; Azar, Sami T.; Bitar, Fadi F.; Nemer, GeorgesAbstract Background: The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low‐density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype. Methods: We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR‐associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype‐phenotype correlation in our previous screening. Results: We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLR and LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes. Conclusion: The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.Publication GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient(John Wiley and Sons Inc., 2015) Kassab, Kameel; Hariri, Hadla; Gharibeh, Lara; Fahed, Akl; Zein, Manal; El‐Rassy, Inaam; Nemer, Mona; El‐Rassi, Issam; Bitar, Fadi; Nemer, GeorgesAbstract Background: GATA transcription factors are evolutionary conserved zinc finger proteins with multiple roles in cell differentiation/proliferation and organogenesis. GATA5 is only transiently expressed in the embryonic heart, and the inactivation of both Gata5 alleles results in a partially penetrant bicuspid aortic valve (BAV) phenotype in mice. We hypothesized that only biallelic mutations in GATA5 could be disease causing. Methods: A total of 185 patients with different forms of congenital heart disease (CHD) were screened along 150 healthy individuals for GATA4, 5, and 6. All patients' phenotypes were diagnosed with echocardiography. Results: Sequencing results revealed eight missense variants (three of which are novel) in cases with various conotruncal and septal defects. Out of these, two were inherited in recessive forms: the p.T67P variant, which was found both in patients and in healthy individuals, and the previously described p.Y142H variant which was only found in a patient with a double outlet right ventricle (DORV). We characterized the p.Y142H variant and showed that it significantly reduced the transcriptional activity of the protein over cardiac promoters by 30–40%. Conclusion: Our results do prove that p.Y142H is associated with DORV and suggests including GATA5 as a potential gene to be screened in patients with this phenotype.Publication Diet, Genetics, and Disease: A Focus on the Middle East and North Africa Region(Hindawi Publishing Corporation, 2012) Fahed, Akl; El-Hage-Sleiman, Abdul-Karim M.; Farhat, Theresa I.; Nemer, Georges M.The Middle East and North Africa (MENA) region suffers a drastic change from a traditional diet to an industrialized diet. This has led to an unparalleled increase in the prevalence of chronic diseases. This review discusses the role of nutritional genomics, or the dietary signature, in these dietary and disease changes in the MENA. The diet-genetics-disease relation is discussed in detail. Selected disease categories in the MENA are discussed starting with a review of their epidemiology in the different MENA countries, followed by an examination of the known genetic factors that have been reported in the disease discussed, whether inside or outside the MENA. Several diet-genetics-disease relationships in the MENA may be contributing to the increased prevalence of civilization disorders of metabolism and micronutrient deficiencies. Future research in the field of nutritional genomics in the MENA is needed to better define these relationships.Publication Connecting the Lines between Hypogonadism and Atherosclerosis(Hindawi Publishing Corporation, 2012) Fahed, Akl; Gholmieh, Joanna M.; Azar, Sami T.Epidemiological studies show that atherosclerotic cardiovascular disease is a leading cause of morbidity and mortality worldwide and point to gender differences with ageing males being at highest risk. Atherosclerosis is a complex process that has several risk factors and mediators. Hypogonadism is a commonly undiagnosed disease that has been associated with many of the events, and risk factors leading to atherosclerosis. The mechanistic relations between testosterone levels, atherosclerotic events, and risk factors are poorly understood in many instances, but the links are clear. In this paper, we summarize the research journey that explains the link between hypogonadism, each of the atherosclerotic events, and risk factors. We look into the different areas from which lessons could be learned, including epidemiological studies, animal and laboratory experiments, studies on androgen deprivation therapy patients, and studies on testosterone-treated patients. We finish by providing recommendations for the clinician and needs for future research.