Anna Maria Pinto1, Laura Bianciardi2, Maria Antonietta Mencarelli3, Valentina Imperatore2, Chiara Di Marco1, Simone Furini4, Agnese Suppiej5, Leonardo Salviati6, Romano Tenconi7, Francesca Ariani1, Francesca Mari1, Alessandra Renieri8. 1. Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 2. Medical Genetics, University of Siena, Siena, Italy. 3. Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. 4. Department of Medical Biotechnologies, University of Siena, Siena, Italy. 5. Child Neurology Unit, Department of Woman's and Child's Health, University Hospital of Padova, Padova, Italy. 6. Clinical Genetics Unit, Department of Woman and Child Health, University of Padova, Italy. 7. University of Padova, Padova, Italy. 8. Medical Genetics, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. Electronic address: alessandra.renieri@unisi.it.
Abstract
BACKGROUND: Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders. CASE: We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype. CONCLUSIONS: This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.
BACKGROUND:Neurodevelopmental disorders include a broad spectrum of conditions, which are characterized by delayed motor and/or cognitive milestones and by a variable range of intellectual disability with or without an autistic behavior. Several genetic factors have been implicated in intellectual disability onset and exome sequencing studies have recently identified new inherited or de novo mutations in patients with neurodevelopmental disorders. CASE: We report the case of two monozygotic twins who came for the first time to our attention at the age of 20months for a global neurodevelopmental delay associated with an autism spectrum disorder, hypotonia, postnatal microcephaly, stereotypic movements and circadian rhythm alterations in association with late-onset epilepsy. MECP2 sequence was normal. A CGH-array analysis revealed in both twins two maternally inherited duplications on chromosomes 8p22 and 16p13.11. The latter has been previously associated with neurodevelopmental disorders. We performed an exome sequencing analysis on one twin and her parents and identified a CHD2 mutation, previously described in association with a phenotypic spectrum overlapping our patients' phenotype. CONCLUSIONS: This work underlines the importance to consider a CHD2 involvement in children with intellectual disability and autism spectrum disorder even in the absence of epilepsy at an early age. It also highlights the necessity to re-evaluate inherited copy number variants with low penetrance and/or high phenotypic variability because an underlying de novo molecular event can be the major cause of the phenotype. This is essential in order to reach a correct diagnosis and provide the couple with a proper recurrence risk.
Authors: Hadley Stevens Smith; J Michael Swint; Seema R Lalani; Jose-Miguel Yamal; Marcia C de Oliveira Otto; Stephan Castellanos; Amy Taylor; Brendan H Lee; Heidi V Russell Journal: Genet Med Date: 2018-05-14 Impact factor: 8.822