Bader Alhaddad1, Anna Schossig2, Tobias B Haack1,3,4, Reka Kovács-Nagy1, Matthias C Braunisch1,5, Christine Makowski6, Jan Senderek7, Katharina Vill8, Wolfgang Müller-Felber8, Tim M Strom1,3, Birgit Krabichler2, Peter Freisinger9, Charu Deshpande10, Tilman Polster11, Nicole I Wolf12, Isabelle Desguerre13, Friedrich Wörmann11, Agnès Rötig14, Uwe Ahting1, Robert Kopajtich1,3, Holger Prokisch1,3, Thomas Meitinger1,3, René G Feichtinger15, Johannes A Mayr15, Heinz Jungbluth16,17,18, Michael Hubmann19, Johannes Zschocke2, Felix Distelmaier20, Johannes Koch15. 1. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 2. Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria. 3. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 4. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Germany. 5. Department of Nephrology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. 6. Department of Pediatrics, Technische Universität München (TUM), Munich, Germany. 7. Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University Munich, Munich, Germany. 8. Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-Universität München, Munich, Germany. 9. Department of Pediatrics, Kreisklinken Reutlingen, Reutlingen, Germany. 10. Department of Clinical Genetics, Guy's Hospital, London, United Kingdom. 11. Department of Pediatric Epileptology, Bethel Epilepsy Centre, Bielefeld, Germany. 12. Department of Child Neurology and Amsterdam Neuroscience, VU University Medical Centre, Amsterdam, The Netherlands. 13. Department of Pediatric Neurology, Necker Enfants Malades Hospital, Paris, France. 14. INSERM U1163, Institut Imagine, Université Paris Descartes, Paris, France. 15. Department of Pediatrics, Salzburger Landeskliniken (SALK) and Paracelsus Medical University (PMU), Salzburg, Austria. 16. Department of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, United Kingdom. 17. Randall Division of Cell and Molecular Biophysics, Muscle Signalling Section, King's College, London, United Kingdom. 18. Department of Basic and Clinical Neuroscience, IoPPN, King's College London, London, United Kingdom. 19. Department of Neuropediatrics, Kinderärzte Zirndorf, Zirndorf, Germany. 20. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
Abstract
BACKGROUND: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. METHODS: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. RESULTS: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. CONCLUSIONS: PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature. Georg Thieme Verlag KG Stuttgart · New York.
BACKGROUND: Primary microcephaly and profound global developmental delay have been considered the core clinical phenotype in patients with bi-allelic PRUNE1 mutations. METHODS: Linkage analysis and whole-exome sequencing (WES) in a multiplex family and extraction of further cases from a WES repository containing 571 children with severe developmental disabilities and neurologic symptoms. RESULTS: We identified bi-allelic PRUNE1 mutations in twelve children from six unrelated families. All patients who survived beyond the first 6 months of life had early-onset global developmental delay, bilateral spastic paresis, dysphagia and difficult-to-treat seizures, while congenital or later-evolving microcephaly was not a consistent finding. Brain MRI showed variable anomalies with progressive cerebral and cerebellar atrophies and T2-hyperintense brain stem lesions. Peripheral neuropathy was documented in five cases. Disease course was progressive in all patients and eight children died in the first or early second decade of life. In addition to the previously reported missense mutation p.(Asp106Asn), we observed a novel homozygous missense variant p.(Leu172Pro) and a homozygous contiguous gene deletion encompassing most of the PRUNE1 gene and part of the neighboring BNIPL gene. CONCLUSIONS:PRUNE1 deficiency causes severe early-onset disease affecting the central and peripheral nervous systems. Microcephaly is probably not a universal feature. Georg Thieme Verlag KG Stuttgart · New York.
Authors: Harikiran Nistala; John Dronzek; Claudia Gonzaga-Jauregui; Shek Man Chim; Saathyaki Rajamani; Samer Nuwayhid; Dennis Delgado; Elizabeth Burke; Ender Karaca; Matthew C Franklin; Prasad Sarangapani; Michael Podgorski; Yajun Tang; Melissa G Dominguez; Marjorie Withers; Ron A Deckelbaum; Christopher J Scheonherr; William A Gahl; May C Malicdan; Brian Zambrowicz; Nicholas W Gale; Richard A Gibbs; Wendy K Chung; James R Lupski; Aris N Economides Journal: Hum Mol Genet Date: 2021-01-06 Impact factor: 6.150