Publications by authors named "May Sanyoura"

18 Publications

  • Page 1 of 1

Integrated Analysis of the Pancreas and Islets Reveals Unexpected Findings in Human Male With Type 1 Diabetes.

J Endocr Soc 2021 Dec 29;5(12):bvab162. Epub 2021 Oct 29.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.

Clinical and pathologic heterogeneity in type 1 diabetes is increasingly being recognized. Findings in the islets and pancreas of a 22-year-old male with 8 years of type 1 diabetes were discordant with expected results and clinical history (islet autoantibodies negative, hemoglobin A1c 11.9%) and led to comprehensive investigation to define the functional, molecular, genetic, and architectural features of the islets and pancreas to understand the cause of the donor's diabetes. Examination of the donor's pancreatic tissue found substantial but reduced β-cell mass with some islets devoid of β cells (29.3% of 311 islets) while other islets had many β cells. Surprisingly, isolated islets from the donor pancreas had substantial insulin secretion, which is uncommon for type 1 diabetes of this duration. Targeted and whole-genome sequencing and analysis did not uncover monogenic causes of diabetes but did identify high-risk human leukocyte antigen haplotypes and a genetic risk score suggestive of type 1 diabetes. Further review of pancreatic tissue found islet inflammation and some previously described α-cell molecular features seen in type 1 diabetes. By integrating analysis of isolated islets, histological evaluation of the pancreas, and genetic information, we concluded that the donor's clinical insulin deficiency was most likely the result autoimmune-mediated β-cell loss but that the constellation of findings was not typical for type 1 diabetes. This report highlights the pathologic and functional heterogeneity that can be present in type 1 diabetes.
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http://dx.doi.org/10.1210/jendso/bvab162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8633619PMC
December 2021

Novel compound heterozygous LRBA deletions in a 6-month-old with neonatal diabetes.

Diabetes Res Clin Pract 2021 May 15;175:108798. Epub 2021 Apr 15.

Department of Human Genetics, The University of Chicago, 5841 S. Maryland Ave., G701, Chicago, IL 60637, USA. Electronic address:

We report a 6-month-old boy with antibody-positive insulin-dependent diabetes mellitus. Sequencing identified compound heterozygous deletions of exon 5 and exons 36-37 in LRBA. At three years, he has yet to exhibit any other immune symptoms. Genetic testing of LRBA is warranted in patients with neonatal diabetes, even without immune dysregulation.
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http://dx.doi.org/10.1016/j.diabres.2021.108798DOI Listing
May 2021

Prevalence of -mediated spinocerebellar ataxia in a North American ataxia cohort.

Neurol Genet 2020 Jun 20;6(3):e440. Epub 2020 May 20.

Department of Neurology (D.A.S., D.W., Y.M., S.P., B.L.F.), Program in Neurogenetics, David Geffen School of Medicine, University of California, Los Angeles; Department of Neurology (D.W., B.L.F.), Clinical Neurogenomics Research Center, David Geffen School of Medicine, University of California, Los Angeles; Department of Human Genetics (S.A., M.S., S.D.), University of Chicago, IL; Department of Neurology (C.M.D.G., V.K.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Department of Neurology (G.G., C.M.G.), University of Chicago, IL; Bruce Lefroy Centre (P.J.L.), Murdoch Children's Research Institute; Department of Paediatrics (P.J.L.), University of Melbourne, Parkville, Australia; Sackler Faculty of Medicine (S.H.-B.), Tel-Aviv University, Tel-Aviv, Israel; and Department of Human Genetics (B.L.F.), David Geffen School of Medicine, University of California, Los Angeles.

Objective: We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 () and disabled adaptor protein 1 in an undiagnosed ataxia cohort from North America.

Methods: A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes of cerebellar ataxia. Patients were then screened for the presence of pathogenic repeat expansions in (AAGGG) and (ATTTC) using fluorescent repeat-primed PCR (RP-PCR). Two additional undiagnosed ataxia cohorts from different centers, totaling 302 and 13 patients, respectively, were subsequently screened for , resulting in a combined 911 subjects tested.

Results: In the initial cohort, 41 samples were identified with 1 expanded allele in the gene (6.9%), and 9 had 2 expanded alleles (1.5%). For the additional cohorts, we found 20 heterozygous samples (6.6%) and 17 biallelic samples (5.6%) in the larger cohort and 1 heterozygous sample (7.7%) and 3 biallelic samples (23%) in the second. In total, 29 patients were identified with biallelic repeat expansions in (3.2%). Of these 29 patients, 8 (28%) had a clinical diagnosis of cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), 14 had cerebellar ataxia with neuropathy (48%), 4 had pure cerebellar ataxia (14%), and 3 had spinocerebellar ataxia (10%). No patients were identified with expansions in the gene (spinocerebellar ataxia type 37).

Conclusions: In a large undiagnosed ataxia cohort from North America, biallelic pathogenic repeat expansion in was observed in 3.2%. Testing should be strongly considered in patients with ataxia, especially those with CANVAS or neuropathy.
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http://dx.doi.org/10.1212/NXG.0000000000000440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274910PMC
June 2020

A Non-Coding Disease Modifier of Pancreatic Agenesis Identified by Genetic Correction in a Patient-Derived iPSC Line.

Cell Stem Cell 2020 07 21;27(1):137-146.e6. Epub 2020 May 21.

Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. Electronic address:

GATA6 is a critical regulator of pancreatic development, with heterozygous mutations in this transcription factor being the most common cause of pancreatic agenesis. To study the variability in disease phenotype among individuals harboring these mutations, a patient-induced pluripotent stem cell model was used. Interestingly, GATA6 protein expression remained depressed in pancreatic progenitor cells even after correction of the coding mutation. Screening the regulatory regions of the GATA6 gene in these patient cells and 32 additional agenesis patients revealed a higher minor allele frequency of a SNP 3' of the GATA6 coding sequence. Introduction of this minor allele SNP by genome editing confirmed its functionality in depressing GATA6 expression and the efficiency of pancreas differentiation. This work highlights a possible genetic modifier contributing to pancreatic agenesis and demonstrates the usefulness of using patient-induced pluripotent stem cells for targeted discovery and validation of non-coding gene variants affecting gene expression and disease penetrance.
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http://dx.doi.org/10.1016/j.stem.2020.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335348PMC
July 2020

Update of variants identified in the pancreatic β-cell K channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes.

Hum Mutat 2020 05 17;41(5):884-905. Epub 2020 Feb 17.

Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.

The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
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http://dx.doi.org/10.1002/humu.23995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187370PMC
May 2020

GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants.

Diabetes Res Clin Pract 2019 May 4;151:231-236. Epub 2019 May 4.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA.

We report on 134 unique GCK variants in 217 families, including 27 unpublished variants, identified in the US Monogenic Diabetes Registry in the last decade. Using ACMG guidelines, 26% were pathogenic, 56% likely pathogenic and 18% were of uncertain significance. Those with pathogenic variants had clinical features consistent with GCK-MODY.
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http://dx.doi.org/10.1016/j.diabres.2019.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544496PMC
May 2019

Management and pregnancy outcomes of women with GCK-MODY enrolled in the US Monogenic Diabetes Registry.

Acta Diabetol 2019 Apr 11;56(4):405-411. Epub 2018 Dec 11.

Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center, University of Chicago, 5841 South Maryland Ave., MC 1027, Chicago, IL, 60637, USA.

Aims: GCK-MODY is characterized by mild hyperglycemia. Treatment is not required outside of pregnancy. During pregnancy, insulin treatment is recommended if second trimester fetal ultrasound monitoring shows macrosomia, suggesting the fetus has not inherited the GCK gene. There are limited data about GCK-MODY management in pregnancy. The aim of this study was to examine clinical management and pregnancy outcomes amongst women with a known diagnosis of GCK-MODY.

Methods: In this observational, cross-sectional study, a survey was distributed via Redcap to women ≥ 18 years enrolled in the University of Chicago Monogenic Diabetes Registry (n = 94). All or part of the survey was completed by 54 women (128 pregnancies).

Results: There were 78 term births (61%), 15 pre-term births (12%), and 24 miscarriages (19%). Of the 39 pregnancies where insulin was given, 22 (56%) had occasional or frequent hypoglycemia including 9 with severe hypoglycemia. Average birth weight for full-term GCK-affected infants was significantly less in cases of maternal insulin treatment versus no treatment (2967 and 3725 g, p = 0.005). For GCK-unaffected infants, conclusions are limited by small sample size but large for gestational age (LGA) was common with maternal insulin treatment (56%) and no treatment (33%), p = 0.590.

Conclusions: The observed miscarriage rate was comparable to the background US population rate (15-20%). Patients treated with insulin experienced a 23% incidence of severe hypoglycemia and lower birth weights were observed in the insulin-treated, GCK-affected neonates. These data support published guidelines of no treatment if the fetus is suspected to have inherited GCK-MODY and highlight the importance of additional studies to determine optimal pregnancy management for GCK-MODY, particularly among unaffected fetuses.
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http://dx.doi.org/10.1007/s00592-018-1267-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468988PMC
April 2019

Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks.

J Clin Invest 2019 01 3;129(1):246-251. Epub 2018 Dec 3.

Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, USA.

Using an integrated approach to characterize the pancreatic tissue and isolated islets from a 33-year-old with 17 years of type 1 diabetes (T1D), we found that donor islets contained β cells without insulitis and lacked glucose-stimulated insulin secretion despite a normal insulin response to cAMP-evoked stimulation. With these unexpected findings for T1D, we sequenced the donor DNA and found a pathogenic heterozygous variant in the gene encoding hepatocyte nuclear factor-1α (HNF1A). In one of the first studies of human pancreatic islets with a disease-causing HNF1A variant associated with the most common form of monogenic diabetes, we found that HNF1A dysfunction leads to insulin-insufficient diabetes reminiscent of T1D by impacting the regulatory processes critical for glucose-stimulated insulin secretion and suggest a rationale for a therapeutic alternative to current treatment.
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http://dx.doi.org/10.1172/JCI121994DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6307934PMC
January 2019

Monogenic Diabetes in Children and Adolescents: Recognition and Treatment Options.

Curr Diab Rep 2018 06 22;18(8):58. Epub 2018 Jun 22.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL, 60637, USA.

Purpose Of Review: We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment.

Recent Findings: Monogenic forms of diabetes account for approximately 1-2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether. Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.
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http://dx.doi.org/10.1007/s11892-018-1024-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312113PMC
June 2018

α Cell Function and Gene Expression Are Compromised in Type 1 Diabetes.

Cell Rep 2018 03;22(10):2667-2676

Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University Medical Center, Nashville, TN, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA; Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. Electronic address:

Many patients with type 1 diabetes (T1D) have residual β cells producing small amounts of C-peptide long after disease onset but develop an inadequate glucagon response to hypoglycemia following T1D diagnosis. The features of these residual β cells and α cells in the islet endocrine compartment are largely unknown, due to the difficulty of comprehensive investigation. By studying the T1D pancreas and isolated islets, we show that remnant β cells appeared to maintain several aspects of regulated insulin secretion. However, the function of T1D α cells was markedly reduced, and these cells had alterations in transcription factors constituting α and β cell identity. In the native pancreas and after placing the T1D islets into a non-autoimmune, normoglycemic in vivo environment, there was no evidence of α-to-β cell conversion. These results suggest an explanation for the disordered T1D counterregulatory glucagon response to hypoglycemia.
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http://dx.doi.org/10.1016/j.celrep.2018.02.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368357PMC
March 2018

FOXP3 mutations causing early-onset insulin-requiring diabetes but without other features of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

Pediatr Diabetes 2018 05 29;19(3):388-392. Epub 2017 Nov 29.

Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism and Kovler Diabetes Center, The University of Chicago, Chicago, Illinois.

Diabetes occurs in 1/90 000 to 1/160 000 births and when diagnosed under 6 months of age is very likely to have a primary genetic cause. FOXP3 encodes a transcription factor critical for T regulatory cell function and mutations are known to cause "immune dysregulation, polyendocrinopathy (including insulin-requiring diabetes), enteropathy, X-linked" (IPEX) syndrome. This condition is often fatal unless patients receive a bone-marrow transplant. Here we describe the phenotype of male neonates and infants who had insulin-requiring diabetes without other features of IPEX syndrome and were found to have mutations in FOXP3. Whole-exome or next generation sequencing of genes of interest was carried out in subjects with isolated neonatal diabetes without a known genetic cause. RT-PCR was carried out to investigate the effects on RNA splicing of a novel intronic splice-site variant. Four male subjects were found to have FOXP3 variants in the hemizygous state: p.Arg114Trp, p.Arg347His, p.Lys393Met, and c.1044+5G>A which was detected in 2 unrelated probands and in a brother diagnosed with diabetes at 2.1 years of age. Of these, p.Arg114Trp is likely a benign rare variant found in individuals of Ashkenazi Jewish ancestry and p.Arg347His has been previously described in patients with classic IPEX syndrome. The p.Lys393Met and c.1044+5G>A variants are novel to this study. RT-PCR studies of the c.1044+5G>A splice variant confirmed it affected RNA splicing by generating both a wild type and truncated transcript. We conclude that FOXP3 mutations can cause early-onset insulin-requiring diabetes with or without other features of IPEX syndrome.
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http://dx.doi.org/10.1111/pedi.12612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918222PMC
May 2018

Pancreatic Histopathology of Human Monogenic Diabetes Due to Causal Variants in KCNJ11, HNF1A, GATA6, and LMNA.

J Clin Endocrinol Metab 2018 01;103(1):35-45

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois.

Context: Monogenic diabetes is thought to account for 2% of all diabetes cases, but most patients receive misdiagnoses of type 1 or type 2 diabetes. To date, little is known about the histopathological features of pancreata from patients with monogenic diabetes.

Objective: Retrospective study of the JDRF Network for Pancreatic Organ Donors with Diabetes biorepository to identify possible cases of monogenic diabetes and to compare effects of genetic variants on pancreas histology.

Methods: We selected cases of diabetes for genetic testing on the basis of criteria that included young age at diagnosis, low body mass index, negative autoantibody status, and/or detectable C-peptide level. Samples underwent next-generation-targeted sequencing of 140 diabetes/diabetes-related genes. Pancreas weight and histopathology were reviewed.

Results: Forty-one of 140 cases of diabetes met the clinical inclusion criteria, with 38 DNA samples available. Genetic variants of probable clinical significance were found in four cases: one each in KCNJ11, HNF1A, GATA6, and LMNA. The KCNJ11 and HNF1A samples had significantly decreased pancreas weight and insulin mass similar to that of type 1 diabetes but had no insulitis. The GATA6 sample had severe pancreatic atrophy but with abundant β cells and severe amyloidosis similar to type 2 diabetes. The LMNA sample had preserved pancreas weight and insulin mass but abnormal islet architecture and exocrine fatty infiltrates.

Conclusions: Four cases of diabetes had putative causal variants in monogenic diabetes genes. This study provides further insight into the heterogeneous nature of monogenic diabetes cases that exhibited clinical and pathophysiological features that overlap with type 1/type 2 diabetes.
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http://dx.doi.org/10.1210/jc.2017-01159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5761488PMC
January 2018

Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis.

Diabetes Care 2017 10 4;40(10):e147-e148. Epub 2017 Aug 4.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL

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http://dx.doi.org/10.2337/dc17-1145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606305PMC
October 2017

A novel ALMS1 splice mutation in a non-obese juvenile-onset insulin-dependent syndromic diabetic patient.

Eur J Hum Genet 2014 Jan 8;22(1):140-3. Epub 2013 May 8.

1] Inserm UMR-S958, Medical Faculty Paris 7, site Villemin, Paris, France [2] University Paris 7 Denis-Diderot, Paris, France.

Insulin-dependent juvenile-onset diabetes may occur in the context of rare syndromic presentations suggesting monogenic inheritance rather than common multifactorial autoimmune type 1 diabetes. Here, we report the case of a Lebanese patient diagnosed with juvenile-onset insulin-dependent diabetes presenting ketoacidosis, early-onset retinopathy with optic atrophy, hearing loss, diabetes insipidus, epilepsy, and normal weight and stature, who later developed insulin resistance. Despite similarities with Wolfram syndrome, we excluded the WFS1 gene as responsible for this disease. Using combined linkage and candidate gene study, we selected ALMS1, responsible for Alström syndrome, as a candidate gene. We identified a novel splice mutation in intron 18 located 3 bp before the intron-exon junction (IVS18-3T>G), resulting in exon 19 skipping and consequent frameshift generating a truncated protein (V3958fs3964X). The clinical presentation of the patient significantly differed from typical Alström syndrome by the absence of truncal obesity and short stature, and by the presence of ketoacidotic insulin-dependent diabetes, optic atrophy and diabetes insipidus. Our observation broadens the clinical spectrum of Alström syndrome and suggests that ALMS1 mutations may be considered in patients who initially present with an acute onset of insulin-dependent diabetes.
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http://dx.doi.org/10.1038/ejhg.2013.87DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865412PMC
January 2014

Relaxin polymorphisms associated with metabolic disturbance in patients treated with antipsychotics.

J Psychopharmacol 2012 Mar 21;26(3):374-9. Epub 2011 Jun 21.

Optimal Medicine Ltd., Warwick Enterprise Park, Wellesbourne, Warwick, UK.

People with schizophrenia have an increased risk of metabolic syndrome, with consequent elevated morbidity and mortality, largely due to cardiovascular disease. Metabolic disorders comprise obesity, dyslipidemia and elevated levels of triglycerides, hypertension, and disturbed insulin and glucose metabolism. The elevated risk of metabolic syndrome in individuals suffering from schizophrenia is believed to be multifactorial, related to a genetic predisposition, lifestyle characteristics and treatment with antipsychotic medications. Relaxin 3 (RLN3, also known as INSL7) is a recently identified member of the insulin/relaxin superfamily that plays a role in the regulation of appetite and body weight control. RLN3 stimulates relaxin-3 receptor 1 (relaxin/insulin-like family peptide receptor 3, RXFP3) and relaxin receptor 2 (relaxin/insulin-like family peptide receptor 4, RXFP4). We have investigated the role of ten polymorphisms in these genes (RLN3 rs12327666, rs1982632, and rs7249702, RLN3R1 rs42868, rs6861957, rs7702361, and rs35399, and RLN3R2 rs11264422, rs1018730 and rs12124383) in the occurrence of metabolic syndrome phenotypes (obesity, diabetes, hypercholesterolemia, hypertrigyceridemia, and hypertension) in a cross-sectional cohort of 419 US Caucasian patients treated with antipsychotic drugs. We found several associations between relaxin polymorphisms and hypecholesterolemia, obesity and diabetes, suggesting a role for the relaxin/insulin pathway in the development of metabolic disturbance observed in patients treated with antipsychotics.
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http://dx.doi.org/10.1177/0269881111408965DOI Listing
March 2012

Prenatal and neonatal Group B Streptococcus screening and serotyping in Lebanon: incidence and implications.

Acta Obstet Gynecol Scand 2010 Mar;89(3):399-403

Department of Obstetrics & Gynecology, American University of Beirut-Medical Center, Beirut, Lebanon.

The study aimed at determining the prevalence, risk factors, perinatal transmission, and serotypes of Group B Streptococcus (GBS) among pregnant women and their newborns in Beirut, Lebanon. This was a cross-sectional study of all pregnant women admitted from February to September 2006 to three major hospitals. Overall, 137 of 775 (17.7%) mothers and 50 of 682 newborns (7.3%) tested positive for GBS. Maternal colonization was not associated with maternal age, household income, gravidity, intrapartum fever, preterm labor, or premature rupture of membrane. Transmission rate was 40/120 (30%). Serotype 5 (24.1%) was the most common followed by serotype 1a (15.0%), 3 (14.4%), 2 (11.8%) and 1b (7.5%). Pregnant women in Lebanon appear to have a relatively high prevalence of GBS colonization with no identifiable risk factors for its acquisition. These results could provide basis for the institution of a national policy for universal maternal GBS screening to reduce neonatal morbidity and mortality.
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http://dx.doi.org/10.3109/00016340903560008DOI Listing
March 2010

Geographical structure of the Y-chromosomal genetic landscape of the Levant: a coastal-inland contrast.

Ann Hum Genet 2009 Nov 16;73(Pt 6):568-81. Epub 2009 Aug 16.

The Lebanese American University, Chouran, Beirut 1102 2801, Lebanon.

We have examined the male-specific phylogeography of the Levant and its surroundings by analyzing Y-chromosomal haplogroup distributions using 5874 samples (885 new) from 23 countries. The diversity within some of these haplogroups was also examined. The Levantine populations showed clustering in SNP and STR analyses when considered against a broad Middle-East and North African background. However, we also found a coastal-inland, east-west pattern of diversity and frequency distribution in several haplogroups within the small region of the Levant. Since estimates of effective population size are similar in the two regions, this strong pattern is likely to have arisen mainly from differential migrations, with different lineages introduced from the east and west.
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http://dx.doi.org/10.1111/j.1469-1809.2009.00538.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312577PMC
November 2009

WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon.

Hum Mol Genet 2008 Dec 20;17(24):4012-21. Epub 2008 Sep 20.

Lebanese American University, School of Medicine, Chouran, Beirut 1102 2801, Lebanon.

Most cases of juvenile-onset diabetes (JOD) are diagnosed as type 1 diabetes (T1D), for which genetic studies conducted in outbred Caucasian populations support the concept of multifactorial inheritance. However, this view may be partly challenged in particular population settings. In view of the suggestive evidence for a high prevalence of Wolfram syndrome (WFS) in Lebanon, the phenotypic variability associated with WFS1 mutations, and the high consanguinity rate in Lebanon, we aimed to evaluate the contribution of WFS1 mutations as monogenic determinants to JOD in Lebanon. We performed a family-based genetic study, with linkage analysis followed by systematic mutation screening of WFS1 exons in all JOD probands. The study population consisted of an unbiased recruitment of all juvenile-onset insulin-dependent diabetic patients from a specialized diabetes pediatric clinic in Beirut, Lebanon. Homozygous or compound heterozygous WFS1 mutations were found in 22 of the 399 JOD probands (5.5%), resulting in WFS (17 probands) or in non-syndromic non-autoimmune diabetes mellitus (DM, five probands). These accounted for 12.1% (21/174) of probands in consanguineous families, compared with 0.4% (1/225) in non-consanguineous families. Of the 38 patients identified with homozygous or compound heterozygous WFS1 mutations, 11 (29%) had non-syndromic DM, all of whom carried a particular WFS1 mutation, WFS1(LIB), encoding a protein with an extended C-terminal domain. This mutation resulted in a delayed onset or absence of extrapancreatic features. These results underscore the major impact of population-specific factors, such as population-specific mutations and founder effects, and family structure in the genetic determinism of JOD.
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http://dx.doi.org/10.1093/hmg/ddn304DOI Listing
December 2008
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