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Fetal exome

Magalie S Leduc, Marianne Mcguire, Suneeta Madan-Khetarpal, Damara Ortiz, Susan Hayflick, Kory Keller, Christine M Eng, Yaping Yang, Weimin Bi
PRR12 encodes a proline-rich protein nuclear factor suspected to be involved in neural development. Its nuclear expression in fetal brains and in the vision system supports its role in brain and eye development more specifically. However, its function and potential role in human disease has not been determined. Recently, a de novo t(10;19) (q22.3;q13.33) translocation disrupting the PRR12 gene was detected in a girl with intellectual disability and neuropsychiatric alterations. Here we report on three unrelated patients with heterozygous de novo apparent loss-of-function mutations in PRR12 detected by clinical whole exome sequencing: c...
March 19, 2018: Human Genetics
Daniel Bamborschke, Matthias Pergande, Kerstin Becker, Friederike Körber, Jörg Dötsch, Anne Vierzig, Lutz T Weber, Sebahattin Cirak
INTRODUCTION: Recently recessive mutations in sphingosine-1-phosphate lyase (SGPL1) have been published as a cause of syndromic congenital nephrotic syndrome with adrenal insufficiency. We have identified a case with fetal hydrops and brain malformations due to a mutation in SGPL1. CASE REPORT: We report a patient presenting with severe fetal hydrops, congenital nephrotic syndrome and adrenal calcifications. MRI imaging showed generalized cortical atrophy with simplified gyral pattern and hypoplastic temporal lobes as well as cerebellar hypoplasia and hyperintensity in the pons...
February 28, 2018: Brain & Development
Anu Bashamboo, Caroline Eozenou, Anne Jorgensen, Joelle Bignon-Topalovic, Jean-Pierre Siffroi, Capucine Hyon, Attila Tar, Péter Nagy, Janos Sólyom, Zita Halász, Annnabel Paye-Jaouen, Sophie Lambert, David Rodriguez-Buritica, Rita Bertalan, Laetitia Martinerie, Ewa Rajpert-De Meyts, John C Achermann, Ken McElreavey
Emerging evidence from murine studies suggests that mammalian sex determination is the outcome of an imbalance between mutually antagonistic male and female regulatory networks that canalize development down one pathway while actively repressing the other. However, in contrast to testis formation, the gene regulatory pathways governing mammalian ovary development have remained elusive. We performed exome or Sanger sequencing on 79 46,XX SRY-negative individuals with either unexplained virilization or with testicular/ovotesticular disorders/differences of sex development (TDSD/OTDSD)...
February 16, 2018: American Journal of Human Genetics
Angie C Jelin, Neeta Vora
Prenatal whole exome sequencing (WES) has the potential to increase the ability to provide more diagnostic capabilities in fetuses with sonographic abnormalities, which would then improve the ability to counsel families. It is also often the first step in improving the path toward informed diagnosis and treatment, which is especially important in the era of advancing in utero fetal therapy. This article discusses the current literature regarding prenatal WES, clinical indications for WES, challenges with interpretation/counseling (variants of unknown significance), research priorities, ethical issues, and potential future advances...
March 2018: Obstetrics and Gynecology Clinics of North America
Mahmoud Aarabi, Olivia Sniezek, Huaiyang Jiang, Devereux N Saller, Daniel Bellissimo, Svetlana A Yatsenko, Aleksandar Rajkovic
Whole exome sequencing (WES) is an emerging technique in prenatal diagnosis. In this retrospective study, we examined diagnostic utility and limitations of WES in prenatal cases with structural birth defects. DNA from 20 trios (fetal and parental), with normal karyotype and microarray findings, underwent WES and variant interpretation at a reference laboratory. The WES results were later re-evaluated in our academic center utilizing prenatal and postnatal phenotyping. Initial analysis using only prenatal ultrasound findings revealed no pathogenic or likely pathogenic variants in 20 pregnancies with structural birth defects...
February 1, 2018: Human Genetics
Suzanne Chartier, Caroline Alby, Lucile Boutaud, Sophie Thomas, Nadia Elkhartoufi, Jelena Martinovic, Josseline Kaplan, Alexandra Benachi, Didier Lacombe, Pascale Sonigo, Séverine Drunat, Michel Vekemans, Joël Agenor, Férechté Encha Razavi, Tania Attie-Bitach
BACKGROUND: The RTTN gene encodes Rotatin, a large centrosomal protein involved in ciliary functions. RTTN mutations have been reported in seven families and are associated with two phenotypes: polymicrogyria associated with seizures and primary microcephaly associated with primordial dwarfism. CASE: A targeted exome sequencing of morbid genes causing cerebral malformations identified novel RTTN compound heterozygous mutations in a family where three pregnancies were terminated because a severe fetal microcephaly was diagnosed...
January 22, 2018: Birth Defects Research
Maarten P van den Berg, Rowida Almomani, Italo Biaggioni, Martijn van Faassen, Pim van der Harst, Herman H Silljé, Irene Mateo Leach, Marc Hemmelder, Gerjan Navis, Gert-Jan Luijckx, Arjan P de Brouwer, Hanka Venselaar, Marcel M Verbeek, Paul A van der Zwaag, Jan D Jongbloed, J P van Tintelen, Ron A Wevers, Ido P Kema
Rationale: Orthostatic hypotension is a common clinical problem, but the underlying mechanisms have not been fully delineated. Objective: We describe two families, with four patients in total, suffering from severe life-threatening orthostatic hypotension due to a novel cause. Methods and Results: As in dopamine β-hydroxylase deficiency (DβH), concentrations of norepinephrine and epinephrine in the patients were very low. Plasma DβH activity, however, was normal and the DBH gene had no mutations. Molecular genetic analysis was performed to determine the underlying genetic cause...
January 17, 2018: Circulation Research
Susanne E Stalman, Nita Solanky, Miho Ishida, Cristina Alemán-Charlet, Sayeda Abu-Amero, Marielle Alders, Lucas Alvizi, William Baird, Charalambos Demetriou, Peter Henneman, Chela James, Lia C Knegt, Lydia J Leon, Marcel M A M Mannens, Adi N Mul, Nicole A Nibbering, Emma Peskett, Faisal I Rezwan, Carrie Ris-Stalpers, Joris A M van der Post, Gerdine A Kamp, Frans B Plötz, Jan M Wit, Philip Stanier, Gudrun E Moore, Raoul C Hennekam
Context: Small for gestational age (SGA) can be a result of fetal growth restriction, associated with perinatal morbidity and mortality. Mechanisms that control prenatal growth are poorly understood. Objective: The aim of the present study was to gain more insight into prenatal growth failure and determine an effective diagnostic approach in SGA newborns. We hypothesized that one or more CNVs and disturbed methylation and sequence variants may be present in genes known to be associated with fetal growth...
January 12, 2018: Journal of Clinical Endocrinology and Metabolism
Shagun Aggarwal, Ashwani Tandon, Aneek Das Bhowmik, Jamal Mohamed Nurul Jain Safarulla, Ashwin Dalal
BACKGROUND: This retrospective study assesses the contribution of genetic disorders in fetuses undergoing postmortem evaluation and the performance of a clinical dysmorphology based systematic approach toward genetic diagnosis. MATERIALS AND METHODS: Ninety fetuses, including spontaneous losses and terminated pregnancies, underwent a postmortem evaluation including dysmorphological examination, radiological studies, and histopathological examination. Genetic testing including karyotyping, biochemical testing, Sanger sequencing, and exome sequencing were performed selectively...
January 16, 2018: Fetal and Pediatric Pathology
Anthony R Gregg, Steven R Lindheim
Genomic based technologies are firmly implanted into clinical medicine. They arrived rapidly and their uses continue to evolve in both the pre and postconception periods. These technologies migrated from the prenatal arena into the domain of the reproductive endocrinology and infertility specialists in some cases nearly simultaneously (expanded carrier screening), in others more slowly (chromosome microarrays), and for some technologies the ethical and cost concerns have resulted in a slower diffusion across the disciplines...
February 2018: Fertility and Sterility
Séverine Bacrot, Charlotte Mechler, Naima Talhi, Dominique Martin-Coignard, Philippe Roth, Caroline Michot, Amale Ichkou, Olivier Alibeu, Patrick Nitschke, Sophie Thomas, Michel Vekemans, Férechté Razavi, Lucile Boutaud, Tania Attie-Bitach
BACKGROUND: Bainbridge-Ropers syndrome (BRPS) is a recently identified severe disorder characterized by failure to thrive, facial dysmorphism, and severe developmental delay, caused by de novo dominant loss of function mutation in the ASXL3 gene. CASE: We report here the first case of prenatal BRPS in a fetus presenting with arthrogryposis on ultrasound and for pontocerebellar hypoplasia type 1 (PCH1) following neuropathological examination. The diagnosis was done by whole exome sequencing that identified a novel de novo ASXL3 mutation...
January 8, 2018: Birth Defects Research
Jane Hayward, Lyn S Chitty
Emerging genomic technologies, largely based around next generation sequencing (NGS), are offering new promise for safer prenatal genetic diagnosis. These innovative approaches will improve screening for fetal aneuploidy, allow definitive non-invasive prenatal diagnosis (NIPD) of single gene disorders at an early gestational stage without the need for invasive testing, and improve our ability to detect monogenic disorders as the aetiology of fetal abnormalities. This presents clinicians and scientists with novel challenges as well as opportunities...
January 2, 2018: Seminars in Fetal & Neonatal Medicine
Sarah Boissel, Catherine Fallet-Bianco, David Chitayat, Valérie Kremer, Christina Nassif, Françoise Rypens, Marie-Ange Delrue, Dorothée Dal Soglio, Luc L Oligny, Natalie Patey, Elisabeth Flori, Mireille Cloutier, David Dyment, Philippe Campeau, Aspasia Karalis, Sonia Nizard, William D Fraser, François Audibert, Emmanuelle Lemyre, Guy A Rouleau, Fadi F Hamdan, Zoha Kibar, Jacques L Michaud
PurposeFetal anomalies represent a poorly studied group of developmental disorders. Our objective was to assess the impact of whole-exome sequencing (WES) on the investigation of these anomalies.MethodsWe performed WES in 101 fetuses or stillborns who presented prenatally with severe anomalies, including renal a/dysgenesis, VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula, renal anomalies, and limb abnormalities), brain anomalies, suspected ciliopathies, multiple major malformations, and akinesia...
October 26, 2017: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Jan Hodgson, Belinda J McClaren
For many pregnant women, prenatal testing is a routine component of contemporary pregnancy care. Receiving a prenatal diagnosis is frequently associated with intense feelings of shock and grief; the extent of which may be unrelated to the pregnancy gestation or the condition diagnosed. During this time of crisis, parents are often faced with important choices about their pregnancy. Levels of understanding and experiences of professional support throughout this time likely impact decisions that are made and how they are subsequently perceived...
December 16, 2017: Seminars in Fetal & Neonatal Medicine
Jerome F Strauss, Roberto Romero, Nardhy Gomez-Lopez, Hannah Haymond-Thornburg, Bhavi P Modi, Maria E Teves, Laurel N Pearson, Timothy P York, Harvey A Schenkein
Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has been only modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence that suggests that the nature and intensity of an inflammatory response in adults and children are under genetic control...
March 2018: American Journal of Obstetrics and Gynecology
Baptiste Fouquet, Patrycja Pawlikowska, Sandrine Caburet, Celine Guigon, Marika Mäkinen, Laura Tanner, Marja Hietala, Kaja Urbanska, Laura Bellutti, Bérangère Legois, Bettina Bessieres, Alain Gougeon, Alexandra Benachi, Gabriel Livera, Filippo Rosselli, Reiner A Veitia, Micheline Misrahi
Primary Ovarian Insufficiency (POI) affects ~1% of women under forty. Exome sequencing of two Finnish sisters with non-syndromic POI revealed a homozygous mutation in FANCM, leading to a truncated protein (p.Gln1701*). FANCM is a DNA-damage response gene whose heterozygous mutations predispose to breast cancer. Compared to the mother's cells, the patients' lymphocytes displayed higher levels of basal and mitomycin C (MMC)-induced chromosomal abnormalities. Their lymphoblasts were hypersensitive to MMC and MMC-induced monoubiquitination of FANCD2 was impaired...
December 12, 2017: ELife
Francesca Cristofoli, Bart De Keersmaecker, Luc De Catte, Joris R Vermeesch, Hilde Van Esch
STIL (SCL/TAL1 interrupting locus) is a core component of the centriole duplication process. STIL mutations have been associated with both autosomal recessive primary microcephaly (MCPH) and holoprosencephaly. In this report, we describe a family with multiple miscarriages and 2 terminations of pregnancy due to marked fetal microcephaly, delayed cortical gyrification, and dysgenesis of the corpus callosum. Whole exome sequencing allowed us to identify novel compound heterozygous mutations in STIL. The mutations lie, respectively, in the CPAP/CENPJ and the hsSAS6 interacting domains of STIL...
November 2017: Molecular Syndromology
M Rasmussen, L Sunde, M L Nielsen, M Ramsing, A Petersen, T D Hjortshøj, T E Olsen, A Tabor, J M Hertz, I Johnsen, L Sperling, O B Petersen, U B Jensen, F G Møller, M B Petersen, D L Lildballe
Identification of fetal kidney anomalies invites questions about underlying causes and recurrence risk in future pregnancies. We therefore investigated the diagnostic yield of next-generation sequencing in fetuses with bilateral kidney anomalies and the correlation between disrupted genes and fetal phenotypes. Fetuses with bilateral kidney anomalies were screened using an in-house-designed kidney-gene panel. In families where candidate variants were not identified, whole-exome sequencing was performed. Genes uncovered by this analysis were added to our kidney panel...
November 30, 2017: Clinical Genetics
Bhavi P Modi, Maria E Teves, Laurel N Pearson, Hardik I Parikh, Hannah Haymond-Thornburg, John L Tucker, Piya Chaemsaithong, Nardhy Gomez-Lopez, Timothy P York, Roberto Romero, Jerome F Strauss
BACKGROUND: Twin studies have revealed a significant contribution of the fetal genome to risk of preterm birth. Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of preterm delivery. Infection and inflammation of the fetal membranes is commonly found associated with PPROM. METHODS: We carried out whole exome sequencing (WES) of genomic DNA from neonates born of African-American mothers whose pregnancies were complicated by PPROM (76) or were normal term pregnancies (N = 43) to identify mutations in 35 candidate genes involved in innate immunity and host defenses against microbes...
November 2017: Molecular Genetics & Genomic Medicine
Karen L Stals, Matthew Wakeling, Júlia Baptista, Richard Caswell, Andrew Parrish, Julia Rankin, Carolyn Tysoe, Garan Jones, Adam C Gunning, Hana Lango Allen, Lisa Bradley, Angela F Brady, Helena Carley, Jenny Carmichael, Bruce Castle, Deirdre Cilliers, Helen Cox, Charu Deshpande, Abhijit Dixit, Jacqueline Eason, Frances Elmslie, Andrew E Fry, Alan Fryer, Muriel Holder, Tessa Homfray, Emma Kivuva, Victoria McKay, Ruth Newbury-Ecob, Michael Parker, Ravi Savarirayan, Claire Searle, Nora Shannon, Deborah Shears, Sarah Smithson, Ellen Thomas, Peter D Turnpenny, Vinod Varghese, Pradeep Vasudevan, Emma Wakeling, Emma L Baple, Sian Ellard
OBJECTIVE: Rare genetic disorders resulting in prenatal or neonatal death are genetically heterogeneous, but testing is often limited by the availability of fetal DNA, leaving couples without a potential prenatal test for future pregnancies. We describe our novel strategy of exome sequencing parental DNA samples to diagnose recessive monogenic disorders in an audit of the first 50 couples referred. METHOD: Exome sequencing was carried out in a consecutive series of 50 couples who had 1 or more pregnancies affected with a lethal or prenatal-onset disorder...
January 2018: Prenatal Diagnosis
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