Publications by authors named "Valerie Pelletier"

25 Publications

  • Page 1 of 1

Atypical Retinal Phenotype in a Patient With Alström Syndrome and Biallelic Novel Pathogenic Variants in , Including a Variation.

Front Genet 2020 21;11:938. Epub 2020 Aug 21.

Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Alström syndrome (ALMS) is a rare autosomal recessive multi-organ syndrome considered to date as a ciliopathy and caused by variations in . Phenotypic variability is well-documented, particularly for the systemic disease manifestations; however, early-onset progressive retinal degeneration affecting both cones and rods (cone-rod type) is universal, leading to blindness by the teenage years. Other features include cardiomyopathy, kidney dysfunction, sensorineural deafness, and childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus. Here, we present an unusual and delayed retinal dystrophy phenotype associated with ALMS in a 14-year-old female, with affected cone function and surprising complete preservation of rod function on serial electroretinograms (ERGs). High-throughput sequencing of the affected proband revealed compound heterozygosity with two novel nonsense variations in the gene, including one variant of inheritance, an unusual finding in autosomal recessive diseases. To confirm the diagnosis in the context of an unusually mild phenotype and identification of novel variations, we demonstrated the biallelic status of the compound heterozygous variations (c.[286C > T];[1211C > G], p.[(Gln96)];[(Ser404)]). This unique case extends our knowledge of the phenotypic variability and the pathogenic variation spectrum in ALMS patients.
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http://dx.doi.org/10.3389/fgene.2020.00938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472914PMC
August 2020

Proteasome subunit PSMC3 variants cause neurosensory syndrome combining deafness and cataract due to proteotoxic stress.

EMBO Mol Med 2020 07 5;12(7):e11861. Epub 2020 Jun 5.

Laboratoire de Génétique Médicale, INSERM, UMRS_1112, Institut de Génétique Médicale d'Alsace (IGMA), Université de Strasbourg, Faculté de médecine de Strasbourg, Strasbourg, France.

The ubiquitin-proteasome system degrades ubiquitin-modified proteins to maintain protein homeostasis and to control signalling. Whole-genome sequencing of patients with severe deafness and early-onset cataracts as part of a neurological, sensorial and cutaneous novel syndrome identified a unique deep intronic homozygous variant in the PSMC3 gene, encoding the proteasome ATPase subunit Rpt5, which lead to the transcription of a cryptic exon. The proteasome content and activity in patient's fibroblasts was however unaffected. Nevertheless, patient's cells exhibited impaired protein homeostasis characterized by accumulation of ubiquitinated proteins suggesting severe proteotoxic stress. Indeed, the TCF11/Nrf1 transcriptional pathway allowing proteasome recovery after proteasome inhibition is permanently activated in the patient's fibroblasts. Upon chemical proteasome inhibition, this pathway was however impaired in patient's cells, which were unable to compensate for proteotoxic stress although a higher proteasome content and activity. Zebrafish modelling for knockout in PSMC3 remarkably reproduced the human phenotype with inner ear development anomalies as well as cataracts, suggesting that Rpt5 plays a major role in inner ear, lens and central nervous system development.
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http://dx.doi.org/10.15252/emmm.201911861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338805PMC
July 2020

Mutations in KARS cause a severe neurological and neurosensory disease with optic neuropathy.

Hum Mutat 2019 10 18;40(10):1826-1840. Epub 2019 Jun 18.

Laboratoire de Génétique Médicale, INSERM U1112, Institut de Génétique Médicale d'Alsace, Université de Strasbourg, Strasbourg, France.

Mutations in genes encoding aminoacyl-tRNA synthetases have been reported in several neurological disorders. KARS is a dual localized lysyl-tRNA synthetase and its cytosolic isoform belongs to the multiple aminoacyl-tRNA synthetase complex (MSC). Biallelic mutations in the KARS gene were described in a wide phenotypic spectrum ranging from nonsyndromic deafness to complex impairments. Here, we report on a patient with severe neurological and neurosensory disease investigated by whole-exome sequencing and found to carry biallelic mutations c.683C>T (p.Pro228Leu) and c.871T>G (p.Phe291Val), the second one being novel, in the KARS gene. The patient presented with an atypical clinical presentation with an optic neuropathy not previously reported. At the cellular level, we show that cytoplasmic KARS was expressed at a lower level in patient cells and displayed decreased interaction with MSC. In vitro, these two KARS variants have a decreased aminoacylation activity compared with wild-type KARS, the p.Pro228Leu being the most affected. Our data suggest that dysfunction of cytoplasmic KARS resulted in a decreased level of translation of the nuclear-encoded lysine-rich proteins belonging to the respiratory chain complex, thus impairing mitochondria functions.
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http://dx.doi.org/10.1002/humu.23799DOI Listing
October 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, Paris, France.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

Virologic outcome among patients receiving antiretroviral therapy at five hospitals in Haiti.

PLoS One 2018 30;13(1):e0192077. Epub 2018 Jan 30.

Centers for Disease Control and Prevention, Port-au-Prince, Haiti.

Introduction: Viral load (VL) assessment is the preferred method for diagnosing and confirming virologic failure for patients on antiretroviral therapy (ART). We conducted a retrospective cross-sectional study to evaluate the virologic suppression rate among patients on ART for ≥6 months in five hospitals around Port-au-Prince, Haiti.

Methods: Plasma VL was measured and patients with VL <1,000 copies/mL were defined as virologically suppressed. A second VL test was performed within at least six months of the first test. Factors associated with virologic suppression were analyzed using logistic regression models accounting for site-level clustering using complex survey procedures.

Results: Data were analyzed for 2,313 patients on ART for six months or longer between July 2013 and February 2015. Among them, 1,563 (67.6%) achieved virologic suppression at the first VL test. A second VL test was performed within at least six months for 718 (31.0%) of the patients. Of the 459 patients with an initial HIV-1 RNA <1,000 copies/mL who had a second VL performed, 394 (85.8%) maintained virologic suppression. Virologic suppression was negatively associated with male gender (adjusted odds ratio [aOR]: 0.80, 95% CI: 0.74-0.0.86), 23 to 35 months on ART (aOR:0.72[0.54-0.96]), baseline CD4 counts of 201-500 cells/mm3 and 200 cells/mm3 or lower (aORs: 0.77 [0.62-0.95] and 0.80 [0.66-0.98], respectively), poor adherence (aOR: 0.69 [0.59-0.81]), and TB co-infection (aOR: 0.73 [0.55-0.97]).

Conclusions: This study showed that over two-thirds of the patients in this evaluation achieved virologic suppression after ≥ six months on ART and the majority of them remained suppressed. These results reinforce the importance of expanding access to HIV-1 viral load testing in Haiti for monitoring ART outcomes.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192077PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5790273PMC
March 2018

Retention Throughout the HIV Care and Treatment Cascade: From Diagnosis to Antiretroviral Treatment of Adults and Children Living with HIV-Haiti, 1985-2015.

Am J Trop Med Hyg 2017 Oct;97(4_Suppl):57-70

Programme National de Lutte contre le VIH/SIDA (National AIDS Program), Ministère de la Sante Publique et de la Population (Ministry of Health), Port au Prince, Haiti.

Monitoring retention of people living with HIV (PLHIV) in the HIV care and treatment cascade is essential to guide program strategy and evaluate progress toward globally-endorsed 90-90-90 targets (i.e., 90% of PLHIV diagnosed, 81% on sustained antiretroviral therapy (ART), and 73% virally suppressed). We describe national retention from diagnosis throughout the cascade for patients receiving HIV services in Haiti during 1985-2015, with a focus on those receiving HIV services during 2008-2015. Among the 266,256 newly diagnosed PLHIV during 1985-2015, 49% were linked-to-care, 30% started ART, and 18% were retained on ART by the time of database closure. Similarly, among the 192,187 newly diagnosed HIV-positive patients during 2008-2015, 50% were linked to care, 31% started ART, and 19% were retained on ART by the time of database closure. Most patients (90-92%) at all cascade steps were adults (≥ 15 years old), among whom the majority (60-61%) were female. During 2008-2015, outcomes varied significantly across 42 administrative districts (arrondissements) of residence; cumulative linkage-to-care ranged from 23% to 69%, cumulative ART initiation among care enrollees ranged from 2% to 80%, and cumulative ART retention among ART enrollees ranged from 30% to 88%. Compared with adults, children had lower cumulative incidence of ART initiation among care enrollees (64% versus 47%) and lower cumulative retention among ART enrollees (64% versus 50%). Cumulative linkage-to-care was low and should be prioritized for improvement. Variations in outcomes by arrondissement and between adults and children require further investigation and programmatic response.
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http://dx.doi.org/10.4269/ajtmh.17-0116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676635PMC
October 2017

Trends in Prevalence of Advanced HIV Disease at Antiretroviral Therapy Enrollment - 10 Countries, 2004-2015.

Authors:
Andrew F Auld Ray W Shiraishi Ikwo Oboho Christine Ross Moses Bateganya Valerie Pelletier Jacob Dee Kesner Francois Nirva Duval Mayer Antoine Chris Delcher Gracia Desforges Mark Griswold Jean Wysler Domercant Nadjy Joseph Varough Deyde Yrvel Desir Joelle Deas Van Onacker Ermane Robin Helen Chun Isaac Zulu Ishani Pathmanathan E Kainne Dokubo Spencer Lloyd Rituparna Pati Jonathan Kaplan Elliot Raizes Thomas Spira Kiren Mitruka Aleny Couto Eduardo Samo Gudo Francisco Mbofana Melissa Briggs Charity Alfredo Carla Xavier Alfredo Vergara Ndapewa Hamunime Simon Agolory Gram Mutandi Naemi N Shoopala Souleymane Sawadogo Andrew L Baughman Adebobola Bashorun Ibrahim Dalhatu Mahesh Swaminathan Dennis Onotu Solomon Odafe Oseni Omomo Abiri Henry H Debem Hank Tomlinson Velephi Okello Peter Preko Trong Ao Caroline Ryan George Bicego Peter Ehrenkranz Harrison Kamiru Harriet Nuwagaba-Biribonwoha Gideon Kwesigabo Angela A Ramadhani Kahemele Ng'wangu Patrick Swai Mohamed Mfaume Ramadhani Gongo Deborah Carpenter Timothy D Mastro Carol Hamilton Julie Denison Fred Wabwire-Mangen Olivier Koole Kwasi Torpey Seymour G Williams Robert Colebunders Julius N Kalamya Alice Namale Michelle R Adler Bridget Mugisa Sundeep Gupta Sharon Tsui Eric van Praag Duc B Nguyen Sheryl Lyss Yen Le Abu S Abdul-Quader Nhan T Do Modest Mulenga Sebastian Hachizovu Owen Mugurungi Beth A Tippett Barr Elizabeth Gonese Tsitsi Mutasa-Apollo Shirish Balachandra Stephanie Behel Trista Bingham Duncan Mackellar David Lowrance Tedd V Ellerbrock

MMWR Morb Mortal Wkly Rep 2017 Jun 2;66(21):558-563. Epub 2017 Jun 2.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.* To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence.
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http://dx.doi.org/10.15585/mmwr.mm6621a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5657820PMC
June 2017

Comparison of electromagnetic neuronavigation system and free-hand method for ventricular catheter placement in internal shunt.

Clin Neurol Neurosurg 2017 Jul 8;158:93-97. Epub 2017 May 8.

Department of Neurosurgery, Rouen University Hospital, Rue de Germont, Rouen, France; Department of Radiology, Rouen University Hospital, Rue de Germont, Rouen, France; Microvascular Endothelium and Neonate Brain Lesions Laboratory, INSERM ERI 28, Faculty of medecine, Rouen, France; Department of Pharmacy, Rouen University Hospital, Rue de Germont, Rouen, France; Nutrition, Gut and Brain Laboratory, INSERM UMR1073, Faculty of Medecine, Rouen, France.

Objective: Optimal ventricular catheter positioning is able to reduce the risk of catheter dysfunction, and subsequently the risk of multiple revision surgery. The objective of our study was to compare the proportion of optimal ventricular catheter placements in a cohort of patients operated for ventriculoperitoneal (VP) shunt between a free-hand group and a neuronavigated group.

Patients And Methods: Twenty patients with hydrocephalus requiring VP shunt were prospectively included in this study. Patients were divided into two groups; the ventricular catheter was positioned using free-hand method (n=10) or magnetic navigation system (n=10). For the two groups, clinical baseline characteristics, etiology of hydrocephaly and initial ventricular size were assessed. The main judgment criterion was the proportion of optimal catheter placements defined by the presence of all catheter holes in the ventricle, evaluated on post-operative CT scan.

Results: There was no initial difference between the two groups in terms of hydrocephalus etiology or initial ventricular size. The number of optimal catheter placements was 6/10 in the neuronavigated group versus 1/10 in the free-hand group (p<0.05). There were no complications during post-operative period in either cohort.

Conclusion: In patients suffering from hydrocephaly, the use of an electromagnetic neuronavigation system for ventricular catheter placement significantly improved the proportion of optimal catheter placements. Long-term follow-up is necessary to evaluate the number of revision surgeries and the cost in each group.
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http://dx.doi.org/10.1016/j.clineuro.2017.05.007DOI Listing
July 2017

"This Method, I Think, Can Shed New Light": Haitian-American Women's Reflections on Risk, Culture, and Family Planning Decisions From a Short-Term Trial of a Cervical Barrier (Femcap™).

Int Q Community Health Educ 2016 Jul 19;36(4):253-263. Epub 2016 Sep 19.

4 Department of Epidemiology, Stempel College of Public Health and Social Work, Florida International University, Miami, FL, USA.

Improving the reproductive health of immigrant populations requires understanding the specific context of risk and need. As part of a field trial of the FemCap™, a woman-initiated cervical barrier contraceptive, we conducted postintervention focus group discussions (FGDs) with 20 women (five FGDs) of Haitian background, the majority of whom were born in Haiti and spoke Haitian Créole at home, at a community health center in south Florida. Participants discussed the role of religion and inequitable gender norms in Haitian traditions about family planning decisions and provided important insights into the gender-power nuances of their partnership dynamics vis à vis the use of female barrier methods. Encouraged by more equitable gender norms in the United States, participants were eager to serve as health education agents, with strong altruistic sentiments toward other Haitian girls and women who they felt could be encouraged to negotiate for greater reproductive decision-making power.
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http://dx.doi.org/10.1177/0272684X16666432DOI Listing
July 2016

Lower Levels of Antiretroviral Therapy Enrollment Among Men with HIV Compared with Women - 12 Countries, 2002-2013.

MMWR Morb Mortal Wkly Rep 2015 Nov 27;64(46):1281-6. Epub 2015 Nov 27.

Equitable access to antiretroviral therapy (ART) for men and women with human immunodeficiency virus (HIV) infection is a principle endorsed by most countries and funding bodies, including the U.S. President's Emergency Plan for AIDS (acquired immunodeficiency syndrome) Relief (PEPFAR) (1). To evaluate gender equity in ART access among adults (defined for this report as persons aged ≥15 years), 765,087 adult ART patient medical records from 12 countries in five geographic regions* were analyzed to estimate the ratio of women to men among new ART enrollees for each calendar year during 2002-2013. This annual ratio was compared with estimates from the Joint United Nations Programme on HIV/AIDS (UNAIDS)(†) of the ratio of HIV-infected adult women to men in the general population. In all 10 African countries and Haiti, the most recent estimates of the ratio of adult women to men among new ART enrollees significantly exceeded the UNAIDS estimates for the female-to-male ratio among HIV-infected adults by 23%-83%. In six African countries and Haiti, the ratio of women to men among new adult ART enrollees increased more sharply over time than the estimated UNAIDS female-to-male ratio among adults with HIV in the general population. Increased ART coverage among men is needed to decrease their morbidity and mortality and to reduce HIV incidence among their sexual partners. Reaching more men with HIV testing and linkage-to-care services and adoption of test-and-treat ART eligibility guidelines (i.e., regular testing of adults, and offering treatment to all infected persons with ART, regardless of CD4 cell test results) could reduce gender inequity in ART coverage.
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http://dx.doi.org/10.15585/mmwr.mm6446a2DOI Listing
November 2015

Albinism in a patient with mutations at both the OA1 and OCA3 loci.

Pigment Cell Melanoma Res 2016 Jan 24;29(1):107-9. Epub 2015 Oct 24.

Maladies Rares: Génétique et Métabolisme (MRGM) EA4576, University Bordeaux, Bordeaux, France.

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http://dx.doi.org/10.1111/pcmr.12408DOI Listing
January 2016

Long term follow up of two independent patients with Schinzel-Giedion carrying SETBP1 mutations.

Eur J Med Genet 2015 Sep 15;58(9):479-87. Epub 2015 Jul 15.

Laboratoire de Génétique Médicale INSERM U1112, Institut de Génétique Médicale d'Alsace (IGMA), Faculté de Médecine de Strasbourg, Université De Strasbourg, Strasbourg, France; Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpitaux Universitaires de Strasbourg, Strasbourg, France; Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Strasbourg, France. Electronic address:

Schinzel-Giedion syndrome (SGS, MIM #269150) is a rare syndrome characterized by severe intellectual disability, typical facial gestalt, hypertrichosis and multiple congenital malformations including skeletal, genitourinary, renal and cardiac abnormalities. The prognosis of SGS is very severe and death occurs generally within a few years after birth. In 2002, we reported 2 children with SGS with a follow-up of 3 years. They presented a very similar and particular phenotype associating distinctive facial gestalt, severe developmental delay, megacalycosis, progressive neurodegeneration, alacrimi, corneal hypoesthesia and deafness. Furthermore, temporal bone imaging revealed a tuning-fork malformation of the stapes. In 2010, Hoischen et al. identified in SGS patients pathogenic heterozygous de novo mutations in SETBP1. We sequenced SETBP1 in our patients and found the previously reported c.2608G>A (p.Gly870Ser) mutation in both children. Since 2002, one of our patients died at 6 years old and the other patient is still alive at 15 years old. Such a life expectancy has never been reported so far. We describe herein the follow up of the 2 children during 6 and 15 years respectively. This article gives further evidence of the implication of SETBP1 as the major gene of SGS, and reports the previously unseen natural evolution of the disease in a 15 years old patient.
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http://dx.doi.org/10.1016/j.ejmg.2015.07.004DOI Listing
September 2015

Predominantly Cone-System Dysfunction as Rare Form of Retinal Degeneration in Patients With Molecularly Confirmed Bardet-Biedl Syndrome.

Am J Ophthalmol 2015 Aug 15;160(2):364-372.e1. Epub 2015 May 15.

Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace, Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Strasbourg, France; Laboratoire de Génétique Médicale, Institut de Génétique Médicale d'Alsace, INSERM U1112, Faculté de Médecine, Université de Strasbourg, Strasbourg, France. Electronic address:

Purpose: To describe a series of patients with Bardet-Biedl syndrome (BBS) and predominantly retinal cone dysfunction, a previously only rarely reported association.

Design: Retrospective observational case series.

Methods: Seven patients with clinically proven Bardet-Biedl syndrome had undergone detailed ocular phenotyping, which included fundus examination, Goldmann visual fields, fundus autofluorescence imaging (FAF), optical coherence tomography (OCT), and electroretinography (ERG). Mutational screening in the BBS genes was performed either by direct Sanger sequencing or targeted next-generation sequencing.

Results: All 7 patients had proven BBS mutations; 1 had a cone dystrophy phenotype on ERG and 6 had a cone-rod pattern of dysfunction. Macular atrophy was present in all patients, usually with central hypofluorescence surrounded by a continuous hyperfluorescent ring on fundus autofluorescence imaging. OCT confirmed loss of outer retinal structure within the atrophic areas. No clear genotype-phenotype relationship was evident.

Conclusions: Patients with Bardet-Biedl syndrome usually develop early-onset retinitis pigmentosa. In contrast, the patients described herein, with molecularly confirmed Bardet-Biedl syndrome, developed early cone dysfunction, including the first reported case of a cone dystrophy phenotype associated with the disorder. The findings significantly expand the phenotype associated with Bardet-Biedl syndrome.
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http://dx.doi.org/10.1016/j.ajo.2015.05.007DOI Listing
August 2015

'Men don't need to know everything': a field trial of a discreet, female-initiated, contraceptive barrier method (FemCap™) among Haitian-American women.

Cult Health Sex 2015 23;17(7):842-58. Epub 2015 Feb 23.

a Department of Epidemiology , Stempel College of Public Health and Social Work, Florida International University , Miami , USA.

Worldwide, women report the need for safe, non-hormonal, woman-initiated methods of family planning. Cervical barriers provide such technology but are under-researched and under-promoted. In the USA, there are few studies of cervical barriers among women at high unmet need for contraception. A feasibility study of the FemCap™ was conducted among US women of Haitian origin. Participants were heterosexual and seeking to avoid pregnancy. At first visit, participants completed baseline assessments, underwent group counselling and were fitted with FemCap™. Women were asked to insert or use the cap at home. The second visit (2-3 weeks) included an interviewer-administered questionnaire and a focus-group discussion. Participants (n  =  20) were Haitian-born (70%), married (55%) and parous (85%). Their mean age was 32.6 years. Seventy percent reported recent unprotected sex. All women inserted the device at home and 9 women used it during intercourse, including 5 without prior partner negotiation. Of 20 women, 11 liked FemCap™ very much or somewhat; 7 considered it 'OK'; 2 disliked it. Best-liked attributes were comfort, discreet wear and reusability. Difficulties with removal abated over time. Qualitative data revealed a high value placed on lack of systemic side effects. Use of FemCap™ was feasible and acceptable, supporting expansion of research, particularly among relevant populations with unmet need.
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http://dx.doi.org/10.1080/13691058.2015.1005672DOI Listing
April 2016

Development of an electronic medical record based alert for risk of HIV treatment failure in a low-resource setting.

PLoS One 2014 12;9(11):e112261. Epub 2014 Nov 12.

International Training and Education Center for Health, Department of Global Health, University of Washington, Seattle, Washington, United States of America; Department of Medicine, University of Washington, Seattle, Washington, United States of America.

Background: The adoption of electronic medical record systems in resource-limited settings can help clinicians monitor patients' adherence to HIV antiretroviral therapy (ART) and identify patients at risk of future ART failure, allowing resources to be targeted to those most at risk.

Methods: Among adult patients enrolled on ART from 2005-2013 at two large, public-sector hospitals in Haiti, ART failure was assessed after 6-12 months on treatment, based on the World Health Organization's immunologic and clinical criteria. We identified models for predicting ART failure based on ART adherence measures and other patient characteristics. We assessed performance of candidate models using area under the receiver operating curve, and validated results using a randomly-split data sample. The selected prediction model was used to generate a risk score, and its ability to differentiate ART failure risk over a 42-month follow-up period was tested using stratified Kaplan Meier survival curves.

Results: Among 923 patients with CD4 results available during the period 6-12 months after ART initiation, 196 (21.2%) met ART failure criteria. The pharmacy-based proportion of days covered (PDC) measure performed best among five possible ART adherence measures at predicting ART failure. Average PDC during the first 6 months on ART was 79.0% among cases of ART failure and 88.6% among cases of non-failure (p<0.01). When additional information including sex, baseline CD4, and duration of enrollment in HIV care prior to ART initiation were added to PDC, the risk score differentiated between those who did and did not meet failure criteria over 42 months following ART initiation.

Conclusions: Pharmacy data are most useful for new ART adherence alerts within iSanté. Such alerts offer potential to help clinicians identify patients at high risk of ART failure so that they can be targeted with adherence support interventions, before ART failure occurs.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0112261PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4229190PMC
July 2015

Migration patterns among Floridians with AIDS, 1993-2007: implications for HIV prevention and care.

South Med J 2014 Sep;107(9):531-9

From the Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, the AIDS Institute/Florida Consortium for HIV/AIDS Research, Tampa, and the HIV/AIDS and Hepatitis Section, Florida Department of Health, Tallahassee.

Objectives: To characterize migration patterns among people diagnosed as having and who died of acquired immunodeficiency syndrome (AIDS) from 1993 to 2007 because migrating to a new community can disrupt human immunodeficiency virus/AIDS care delivery and patients' adherence to care and affect migrants' social services and healthcare needs.

Methods: Florida AIDS surveillance data were used to describe patterns of migration among people diagnosed as having and who died of AIDS from 1993 to 2007. Individual and community characteristics were compared between residence at the time of AIDS diagnosis and residence at the time of death by type of migration.

Results: Of 31,816 people in the cohort, 2510 (7.9%) migrated to another county in Florida and 1306 (4.1%) migrated to another state. Interstate migrants were more likely to be men, 20 to 39 years old, non-Hispanic white, and born in the United States, to have had a transmission mode of injection drug use (IDU) or men who have sex with men with IDU (MSM&IDU), and to have been diagnosed before 1999. Intercounty migrants were more likely to be non-Hispanic white, younger than 60 years, have had a transmission mode of MSM, IDU, or MSM&IDU, have higher CD4 counts/percentages, and to have lived in areas with low levels of poverty or low physician density. There was a small net movement from urban to rural areas within the state.

Conclusions: A sizable percentage of people, particularly younger people and people with a transmission mode of IDU and IDU&MSM, migrated at least once between the time of their AIDS diagnosis and death. This has important implications for care and treatment, as well as efforts to prevent the disease. Further research is needed to explore barriers and facilitators to access to care upon migration and to assess the need for programs to help people transfer their human immunodeficiency virus/AIDS care, ensuring continuity of care and adherence.
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http://dx.doi.org/10.14423/SMJ.0000000000000155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155510PMC
September 2014

MSX2 Gene Duplication in a Patient with Eye Development Defects.

Ophthalmic Genet 2015 25;36(4):353-8. Epub 2014 Mar 25.

a Centre de référence pour les Affections Rares en Génétique Ophtalmologique (CARGO), Hôpital Civil , Strasbourg , France .

Background: MSX2 mutations are a very rare cause of craniosynostosis. Gain-of-function mutations may lead to the Boston-type craniosynostosis with limb defects and refraction errors, whereas loss-of-function mutations causes primary osseous defects such as enlarged parietal foramina.

Materials And Methods: Herein we report the case of a child with bicoronal synostosis and cutaneous syndactylies, who presented iridal and chorioretinal colobomas. Due to the craniofacial features that were prominent in the clinical picture, the genes involved in craniosynostosis were explored.

Results: The patient disclosed an intragenic duplication of the entire MSX2 gene whereas no mutation was identified in any major genes known to be involved in craniosynostosis.

Conclusion: This is the first report of an eye development defect due to an increase in the MSX2 copy number in a human being. The implication of this gene in eye development has already been shown in several animal models. Indeed, overexpression of the Msx2 gene in a mouse model resulted also in optic nerve aplasia and microphthalmia. This report expands the phenotypic spectrum of the MSX2 mutations impacting early ocular development knowledge.
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http://dx.doi.org/10.3109/13816810.2014.886270DOI Listing
July 2016

Exome sequencing of Bardet-Biedl syndrome patient identifies a null mutation in the BBSome subunit BBIP1 (BBS18).

J Med Genet 2014 Feb 11;51(2):132-6. Epub 2013 Sep 11.

Laboratoire de Génétique Médicale, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg, Strasbourg, France.

Background: Bardet-Biedl syndrome (BBS) is a recessive and genetically heterogeneous ciliopathy characterised by retinitis pigmentosa, obesity, kidney dysfunction, postaxial polydactyly, behavioural dysfunction and hypogonadism. 7 of the 17 BBS gene products identified to date assemble together with the protein BBIP1/BBIP10 into the BBSome, a protein complex that ferries signalling receptors to and from cilia.

Methods And Results: Exome sequencing performed on a sporadic BBS case revealed for the first time a homozygous stop mutation (NM_001195306: c.173T>G, p.Leu58*) in the BBIP1 gene. This mutation is pathogenic since no BBIP1 protein could be detected in fibroblasts from the patient, and BBIP1[Leu58*] is unable to associate with the BBSome subunit BBS4.

Conclusions: These findings identify BBIP1 as the 18th BBS gene (BBS18) and suggest that BBSome assembly may represent a unifying pathomechanism for BBS.
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http://dx.doi.org/10.1136/jmedgenet-2013-101785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3966300PMC
February 2014

Sequencing analysis of the ATOH7 gene in individuals with optic nerve hypoplasia.

Ophthalmic Genet 2014 Mar 26;35(1):1-6. Epub 2013 Jun 26.

The Center for Human Genetics, Duke University Medical Center , Durham, NC , USA.

Background: The Atonal Homolog 7 (ATOH7) gene has been implicated in association studies with optic nerve head diameter size. Hence, we screened optic nerve hypoplasia (ONH) patient DNA samples from Australia, France, and the United States for sequence variants in theATOH7 gene using Sanger sequencing.

Methods: Sanger sequencing of theATOH7 gene was performed on 34 affected individual DNA samples. Sequencing was also carried out in three unaffected family members to confirm segregation of identified single nucleotide variations.

Results: Seven sequence variations were identified in ATOH7. No disease-causing sequence changes in the ATOH7 gene was discovered in the ONH patient samples.

Conclusions: Mutations within the ATOH7 gene are not implicated in the pathogenesis of optic nerve hypoplasia in our patient cohort.
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http://dx.doi.org/10.3109/13816810.2012.752017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159081PMC
March 2014

Factors explaining racial/ethnic disparities in rates of physician recommendation for colorectal cancer screening.

Am J Public Health 2013 Jul 16;103(7):e91-9. Epub 2013 May 16.

Department of Epidemiology, Robert Stempel College of Public Health and Social Work, Florida International University, Miami, FL 33199, USA.

Objectives: Physician recommendation plays a crucial role in receiving endoscopic screening for colorectal cancer (CRC). This study explored factors associated with racial/ethnic differences in rates of screening recommendation.

Methods: Data on 5900 adults eligible for endoscopic screening were obtained from the National Health Interview Survey. Odds ratios of receiving an endoscopy recommendation were calculated for selected variables. Planned, sequenced logistic regressions were conducted to examine the extent to which socioeconomic and health care variables account for racial/ethnic disparities in recommendation rates.

Results: Differential rates were observed for CRC screening and screening recommendations among racial/ethnic groups. Compared with Whites, Hispanics were 34% less likely (P < .01) and Blacks were 26% less likely (P < .05) to receive this recommendation. The main predictors that emerged in sequenced analysis were education for Hispanics and Blacks and income for Blacks. After accounting for the effects of usual source of care, insurance coverage, and education, the disparity reduced and became statistically insignificant.

Conclusions: Socioeconomic status and access to health care may explain major racial/ethnic disparities in CRC screening recommendation rates.
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http://dx.doi.org/10.2105/AJPH.2012.301034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3682597PMC
July 2013

Homozygosity mapping and candidate prioritization identify mutations, missed by whole-exome sequencing, in SMOC2, causing major dental developmental defects.

Am J Hum Genet 2011 Dec;89(6):773-81

Faculty of Dentistry, University of Strasbourg, 1 place de l'Hôpital, Strasbourg, France.

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2.
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http://dx.doi.org/10.1016/j.ajhg.2011.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3234372PMC
December 2011

A novel TFAP2A mutation in familial Branchio-Oculo-Facial Syndrome with predominant ocular phenotype.

Ophthalmic Genet 2011 Nov 5;32(4):250-5. Epub 2011 Jul 5.

Centre de Référence pour les Affections Rares en Génétique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.

Introduction: Branchio-Oculo-Facial Syndrome (BOFS) is a rare autosomal dominant congenital disorder defined by branchial defects, ocular anomalies and craniofacial malformations, including variable degrees of cleft lip with or without cleft palate. In addition, temporal bone anomalies, renal and ectodermal manifestations can be present. Mutations in the TFAP2A gene have been reported in patients with BOFS, prompting phenotype-genotype studies because of the variable clinical spectrum.

Materials And Methods: We report on a family (a mother, her daughter and son) with BOFS and significant variability in clinical expression. The daughter presents predominantly with an ocular phenotype of unilateral microphthalmia and bilateral chorioretinal colobomas, whereas her brother is more severely affected contrasting with the paucisymptomatic mother. TFAP2A molecular analysis revealed a novel frameshift mutation.

Discussion: We confirm the wide clinical spectrum of BOFS. The importance of upper lip examination in mild and paucisymptomatic cases is underlined. TFAP2A mutation spectrum is discussed and broadened by the report of the second frameshift mutation in this gene.

Conclusion: Patients with BOFS and predominant ocular phenotypes can be underdiagnosed. In such cases, upper lip examination can be of important diagnostic value. TFAP2A analysis provides diagnostic confirmation and improves genetic counselling.
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http://dx.doi.org/10.3109/13816810.2011.592176DOI Listing
November 2011

Spectrum of SPATA7 mutations in Leber congenital amaurosis and delineation of the associated phenotype.

Hum Mutat 2010 Mar;31(3):E1241-50

Unité de Recherches Génétique et Epigénétique des Maladies Métaboliques, Neurosensorielles et du Développement, INSERM U781 and Université Paris Descartes, CHU Necker Enfants Malades, Paris, France.

Leber congenital amaurosis (LCA) is the earliest and most severe retinal degeneration. It may present as a congenital stationary cone-rod dystrophy (LCA type I) or a progressive yet severe rod-cone dystrophy (LCA type II). Twelve LCA genes have been identified, three of which account for Type I and nine for LCA type II. All proteins encoded by these genes but two are preferentially expressed in the retina and are responsible for non-syndromic LCA only. By contrast LCA5 and CEP290 are widely expressed and mutations in this latter result in a variety of phenotypes from non-syndromic retinal degeneration to pleiotropic disorders including senior-Loken (SNLS) and Joubert syndromes (JBTS). Recently, mutations in the widely expressed gene SPATA7 were reported to cause LCA or juvenile retinitis pigmentosa. The purpose of this study was i) to determine the level of expression of two major alternative SPATA7 transcripts in a large range of tissues and ii) to assess the involvement of this novel gene in a large cohort of unrelated patients affected with LCA (n = 134). Here, we report high SPATA7expression levels in retina, brain and testis with differential expression of the two transcripts. SPATA7 mutations were identified in few families segregating non-syndromic LCA (n = 4/134). Six different mutations were identified, four of which are novel; All affected both SPATA7 transcripts. The clinical evaluation of patients suggested that SPATA7 mutations account for the rod-cone dystrophy type of the disease.
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http://dx.doi.org/10.1002/humu.21203DOI Listing
March 2010

[Vision disorders in children: what type of genetic counseling?].

Rev Prat 2007 Nov;57(18):2000-1

Centre de reference pour les Affections rares en genetique ophtalmologique(Cargo), hopitaux universitaires de Strasbourg, 67000 Strasbourg.

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November 2007

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling.

Hum Mutat 2007 Jan;28(1):81-91

Unité de Recherches Génétique et Epigénétique des Maladies Métaboliques, Neurosensorielles et du Développement, Institut Nationale de la Santé et de la Recherche Médicale (INSERM) U781, Hôpital Necker-Enfants Malades, Paris, France.

X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6-20%; RPGR: 78.4% vs. 55-90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.
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http://dx.doi.org/10.1002/humu.20417DOI Listing
January 2007