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      The phenotypic spectrum of Schaaf-Yang syndrome – 18 new affected individuals from 14 families

      research-article
      1 , 2 , 3 , , MD, PhD 4 , , ScM, CGC 10 , , PhD 10 , , PhD 2 , , MD 5 , 7 , , PhD 2 , , PhD 2 , , MD, PhD 2 , 6 , , MD 2 , 6 , , MD 2 , 6 , , MD 4 , , PhD 4 , , MD 7 , , MD 7 , , MD 8 , , MD 9 , , MD, PhD 11 , , MD 12 , , MD, PhD 13 , , MD 14 , , MS, CGC 2 , , MS, CGC 14 , , MD, MPH 15 , , MD 16 , , MS, CGC 16 , , MD 17 , , MD 18 , , MS, CGC 2 , 6 , , PhD 19 , 19 , , MD 20 , , MD, PhD 21 , , MD 22 , , MD PhD 23 , , PhD 23 , , MD 24 , , MD, PhD 4 , ** , , MD, PhD 1 , 2 , 3 , *
      Genetics in medicine : official journal of the American College of Medical Genetics
      Schaaf-Yang syndrome, Prader-Willi syndrome, MAGEL2, neurodevelopment

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          Abstract

          Purpose

          Truncating mutations in the maternally imprinted, paternally expressed gene MAGEL2, which is located in the Prader-Willi critical region 15q11-13, have recently been reported to cause Schaaf-Yang syndrome, a Prader-Willi-like disease, manifesting developmental delay/intellectual disability, hypotonia, feeding difficulties, and autism spectrum disorder. The causality of the reported variants in the context of the patients’ phenotypes was questioned, as MAGEL2 whole gene deletions appear to cause little to no clinical phenotype.

          Methods

          Here we report a total of 18 new individuals with Schaaf-Yang syndrome from 14 families, including one family with three individuals found to be affected with a truncating variant of MAGEL2, 11 individuals clinically affected, but not tested molecularly, and a presymptomatic fetal sibling with carrying the pathogenic MAGEL2 variant.

          Results

          All cases harbor truncating mutations of MAGEL2, and nucleotides c.1990-1996 arise as a mutational hotspot, with 10 individuals and one fetus harboring a c.1996dupC (p.Q666fs) mutation and two fetuses harboring a c.1996delC (p.Q666fs). The phenotypic spectrum of Schaaf-Yang syndrome ranges from fetal akinesia to individuals with neurobehavioral disease and contractures of the small finger joints.

          Conclusion

          This study provides strong evidence for the pathogenicity of truncating mutations of the paternal allele of MAGEL2, refines the associated clinical phenotypes, and highlights implications for genetic counseling of affected families.

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          Most cited references18

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          Nutritional phases in Prader-Willi syndrome.

          Prader-Willi syndrome (PWS) is a complex neurobehavioral condition which has been classically described as having two nutritional stages: poor feeding, frequently with failure to thrive (FTT) in infancy (Stage 1), followed by hyperphagia leading to obesity in later childhood (Stage 2). We have longitudinally followed the feeding behaviors of individuals with PWS and found a much more gradual and complex progression of the nutritional phases than the traditional two stages described in the literature. Therefore, this study characterizes the growth, metabolic, and laboratory changes associated with the various nutritional phases of PWS in a large cohort of subjects. We have identified a total of seven different nutritional phases, with five main phases and sub-phases in phases 1 and 2. Phase 0 occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In phase 1 the infant is hypotonic and not obese, with sub-phase 1a characterized by difficulty feeding with or without FTT (ages birth-15 months; median age at completion: 9 months). This phase is followed by sub-phase 1b when the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months; age quartiles 5-15 months). Phase 2 is associated with weight gain-in sub-phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset 2.08 years; age quartiles 20-31 months;), while in sub-phase 2b the weight gain is associated with a concomitant increased interest in food (median age of onset: 4.5 years; quartiles 3-5.25 years). Phase 3 is characterized by hyperphagia, typically accompanied by food-seeking and lack of satiety (median age of onset: 8 years; quartiles 5-13 years). Some adults progress to phase 4 which is when an individual who was previously in phase 3 no longer has an insatiable appetite and is able to feel full. Therefore, the progression of the nutritional phases in PWS is much more complex than previously recognized. Awareness of the various phases will aid researchers in unraveling the pathophysiology of each phase and provide a foundation for developing rational therapies. Counseling parents of newly diagnosed infants with PWS as to what to expect with regard to these nutritional phases may help prevent or slow the early-onset of obesity in this syndrome. Copyright © 2011 Wiley-Liss, Inc.
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            Truncating mutations of MAGEL2cause Prader-Willi phenotypes and autism

            Prader-Willi Syndrome (PWS) is caused by the absence of paternally expressed, maternally silenced genes at 15q11-q13. We report four individuals with truncating mutations on the paternal allele of MAGEL2, a gene within the PWS domain. The first subject was ascertained by whole genome sequencing analysis for PWS features. Three additional subjects were identified by reviewing results of exome sequencing of 1248 cases in a clinical laboratory. All four subjects had autism spectrum disorder (ASD), intellectual disability (ID), and a varying degree of clinical and behavioral features of PWS. These findings suggest MAGEL2 is a novel gene causing complex ASDs, and MAGEL2loss of function can contribute to several aspects of the PWS phenotype.
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              An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

              Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth.
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                Author and article information

                Journal
                9815831
                22061
                Genet Med
                Genet. Med.
                Genetics in medicine : official journal of the American College of Medical Genetics
                1098-3600
                1530-0366
                8 April 2016
                19 May 2016
                21 November 2016
                Affiliations
                [1 ]Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
                [2 ]Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA
                [3 ]Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston TX, 77030, USA
                [4 ]Department of Clinical Genetics, Leiden University Medical Center, Leiden, 2333 ZA, Netherlands
                [5 ]Division of Medical Genetics, University of Texas Medical Branch, Galveston, TX, 77555 USA
                [6 ]Texas Children’s Hospital, Houston, TX, 77030, USA
                [7 ]Department of Pediatrics, The University of Texas Medical School at Houston, Houston, TX, 77030, USA
                [8 ]Genetic Services, Cook Children’s Health Care System, Fort Worth, TX, 76102, USA
                [9 ]Clinical Genetics, VU University Medical Center, Amsterdam, 1081 HZ, Netherlands
                [10 ]GeneDX, Gaithersburg, MD, 20877, USA
                [11 ]Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, 9700 RB, Netherlands
                [12 ]Department of Clinical Genetics, Academic Medical Center, Amsterdam, 1105 AZ, Netherlands
                [13 ]Département de pédiatrie, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, J1H 5N4, Canada
                [14 ]Children’s Hospital Colorado, Aurora, CO, 80045, USA
                [15 ]McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287
                [16 ]Department of Medical Genetics, BC Children’s and Women’s Health Center of British Columbia, The University of British Columbia, Vancouver, B.C., Canada
                [17 ]Department of Pediatrics, BC Children’s and Women’s Health Center of British Columbia, The University of British Columbia, Vancouver, B.C., Canada
                [18 ]Division of Genetics, UMass Memorial Children’s Medical Center, University of Massachusetts Medical School, Worcester, MA 01655, USA
                [19 ]Department of Molecular Neuroscience, UCL Institute of Neurology, London, WC1N 3BG, UK
                [20 ]Centro Hospitalar de Trás-os-Montes e Alto Douro, Unidade Hospital de Vila Real, 5000-508 Vila Real
                [21 ]Department of Pediatrics, Juliana Children’s Hospital-Haga Teaching Hospital, The Hague, the Netherlands
                [22 ]Department of Child Neurology, Juliana Children's Hospital–Haga Teaching Hospital, The Hague, The Netherlands
                [23 ]Department of Clinical Genetics and School for Oncology and Developmental Biology, Maastricht UMC+, Maastricht, The Netherlands
                [24 ]Department of Pediatrics, Máxima Medical Center, Veldhoven, the Netherlands
                Author notes
                [25]

                Co-first authors

                [* ]Correspondence: schaaf@ 123456bcm.edu , 1250 Moursund St., Suite 1325, Houston, Texas 77030, Office: 832-824-8787, Fax: 713-798-8728
                Article
                NIHMS775009
                10.1038/gim.2016.53
                5116288
                27195816
                dd5ee68f-137f-4017-8873-62b58dd3fcf0

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                Categories
                Article

                Genetics
                schaaf-yang syndrome,prader-willi syndrome,magel2,neurodevelopment
                Genetics
                schaaf-yang syndrome, prader-willi syndrome, magel2, neurodevelopment

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