Adi Aran1, Nuphar Rosenfeld1, Ranit Jaron1, Paul Renbaum1, Shachar Zuckerman1, Hila Fridman1, Sharon Zeligson1, Reeval Segel1, Yoav Kohn1, Lara Kamal1, Moien Kanaan1, Yoram Segev1, Eyal Mazaki1, Ron Rabinowitz1, Ori Shen1, Ming Lee1, Tom Walsh1, Mary Claire King1, Suleyman Gulsuner1, Ephrat Levy-Lahad2. 1. From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle. 2. From the Neuropediatric Unit (A.A.), Medical Genetics (N.R., R.J., P.R., S. Zuckerman, H.F., S. Zeligson, R.S., E.L.-L.), MRI Unit (Y.S.), and Obstetrics and Gynecology Department (E.M., R.R., O.S.), Shaare Zedek Medical Center; Hebrew University-Hadassah School of Medicine (A.A., N.R., H.F., R.S., Y.K., R.R., E.L.-L.), Jerusalem; Jerusalem Mental Health Center (Y.K.), Eitanim Psychiatric Hospital, Israel; Hereditary Research Laboratory (L.K., M.K.), Bethlehem University, Palestinian Authority; and Departments of Medicine (Medical Genetics) and Genome Sciences (M.L., T.W., M.C.K., S.G.), University of Washington, Seattle. lahad@szmc.org.il.
Abstract
OBJECTIVE: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability. METHODS: Identification of the responsible gene by whole exome sequencing and homozygosity mapping. RESULTS: Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12 p.R839X is <0.00001 worldwide. Genotyping PCDH12 p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12 p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability. CONCLUSIONS: Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.
OBJECTIVE: To identify the genetic basis of a recessive syndrome characterized by prenatal hyperechogenic brain foci, congenital microcephaly, hypothalamic midbrain dysplasia, epilepsy, and profound global developmental disability. METHODS: Identification of the responsible gene by whole exome sequencing and homozygosity mapping. RESULTS: Ten patients from 4 consanguineous Palestinian families manifested in utero with hyperechogenic brain foci, microcephaly, and intrauterine growth retardation. Postnatally, patients had progressive severe microcephaly, neonatal seizures, and virtually no developmental milestones. Brain imaging revealed dysplastic elongated masses in the midbrain-hypothalamus-optic tract area. Whole exome sequencing of one affected child revealed only PCDH12 c.2515C>T, p.R839X, to be homozygous in the proband and to cosegregate with the condition in her family. The allele frequency of PCDH12p.R839X is <0.00001 worldwide. Genotyping PCDH12p.R839X in 3 other families with affected children yielded perfect cosegregation with the phenotype (probability by chance is 2.0 × 10(-12)). Homozygosity mapping revealed that PCDH12p.R839X lies in the largest homozygous region (11.7 MB) shared by all affected patients. The mutation reduces transcript expression by 84% (p < 2.4 × 10(-13)). PCDH12 is a vascular endothelial protocadherin that promotes cellular adhesion. Endothelial adhesion disruptions due to mutations in OCLN or JAM3 also cause congenital microcephaly, intracranial calcifications, and profound psychomotor disability. CONCLUSIONS: Loss of function of PCDH12 leads to recessive congenital microcephaly with profound developmental disability. The phenotype resembles Aicardi-Goutières syndrome and in utero infections. In cases with similar manifestations but no evidence of infection, our results suggest consideration of an additional, albeit rare, cause of congenital microcephaly.
Authors: Mary C O'Driscoll; Sarah B Daly; Jill E Urquhart; Graeme C M Black; Daniela T Pilz; Knut Brockmann; Meriel McEntagart; Ghada Abdel-Salam; Maha Zaki; Nicole I Wolf; Roger L Ladda; Susan Sell; Stefano D'Arrigo; Waney Squier; William B Dobyns; John H Livingston; Yanick J Crow Journal: Am J Hum Genet Date: 2010-08-19 Impact factor: 11.025
Authors: Ganeshwaran H Mochida; Vijay S Ganesh; Jillian M Felie; Danielle Gleason; R Sean Hill; Katie Rose Clapham; Daniel Rakiec; Wen-Hann Tan; Nadia Akawi; Muna Al-Saffar; Jennifer N Partlow; Sigrid Tinschert; A James Barkovich; Bassam Ali; Lihadh Al-Gazali; Christopher A Walsh Journal: Am J Hum Genet Date: 2010-11-25 Impact factor: 11.025
Authors: Marco Henneke; Simone Diekmann; Andreas Ohlenbusch; Jens Kaiser; Volkher Engelbrecht; Alfried Kohlschütter; Ralph Krätzner; Marcos Madruga-Garrido; Michèle Mayer; Lennart Opitz; Diana Rodriguez; Franz Rüschendorf; Johannes Schumacher; Holger Thiele; Sven Thoms; Robert Steinfeld; Peter Nürnberg; Jutta Gärtner Journal: Nat Genet Date: 2009-06-14 Impact factor: 38.330
Authors: Yanick J Crow; Diana S Chase; Johanna Lowenstein Schmidt; Marcin Szynkiewicz; Gabriella M A Forte; Hannah L Gornall; Anthony Oojageer; Beverley Anderson; Amy Pizzino; Guy Helman; Mohamed S Abdel-Hamid; Ghada M Abdel-Salam; Sam Ackroyd; Alec Aeby; Guillermo Agosta; Catherine Albin; Stavit Allon-Shalev; Montse Arellano; Giada Ariaudo; Vijay Aswani; Riyana Babul-Hirji; Eileen M Baildam; Nadia Bahi-Buisson; Kathryn M Bailey; Christine Barnerias; Magalie Barth; Roberta Battini; Michael W Beresford; Geneviève Bernard; Marika Bianchi; Thierry Billette de Villemeur; Edward M Blair; Miriam Bloom; Alberto B Burlina; Maria Luisa Carpanelli; Daniel R Carvalho; Manuel Castro-Gago; Anna Cavallini; Cristina Cereda; Kate E Chandler; David A Chitayat; Abigail E Collins; Concepcion Sierra Corcoles; Nuno J V Cordeiro; Giovanni Crichiutti; Lyvia Dabydeen; Russell C Dale; Stefano D'Arrigo; Christian G E L De Goede; Corinne De Laet; Liesbeth M H De Waele; Ines Denzler; Isabelle Desguerre; Koenraad Devriendt; Maja Di Rocco; Michael C Fahey; Elisa Fazzi; Colin D Ferrie; António Figueiredo; Blanca Gener; Cyril Goizet; Nirmala R Gowrinathan; Kalpana Gowrishankar; Donncha Hanrahan; Bertrand Isidor; Bülent Kara; Nasaim Khan; Mary D King; Edwin P Kirk; Ram Kumar; Lieven Lagae; Pierre Landrieu; Heinz Lauffer; Vincent Laugel; Roberta La Piana; Ming J Lim; Jean-Pierre S-M Lin; Tarja Linnankivi; Mark T Mackay; Daphna R Marom; Charles Marques Lourenço; Shane A McKee; Isabella Moroni; Jenny E V Morton; Marie-Laure Moutard; Kevin Murray; Rima Nabbout; Sheela Nampoothiri; Noemi Nunez-Enamorado; Patrick J Oades; Ivana Olivieri; John R Ostergaard; Belén Pérez-Dueñas; Julie S Prendiville; Venkateswaran Ramesh; Magnhild Rasmussen; Luc Régal; Federica Ricci; Marlène Rio; Diana Rodriguez; Agathe Roubertie; Elisabetta Salvatici; Karin A Segers; Gyanranjan P Sinha; Doriette Soler; Ronen Spiegel; Tommy I Stödberg; Rachel Straussberg; Kathryn J Swoboda; Mohnish Suri; Uta Tacke; Tiong Y Tan; Johann te Water Naude; Keng Wee Teik; Maya Mary Thomas; Marianne Till; Davide Tonduti; Enza Maria Valente; Rudy Noel Van Coster; Marjo S van der Knaap; Grace Vassallo; Raymon Vijzelaar; Julie Vogt; Geoffrey B Wallace; Evangeline Wassmer; Hannah J Webb; William P Whitehouse; Robyn N Whitney; Maha S Zaki; Sameer M Zuberi; John H Livingston; Flore Rozenberg; Pierre Lebon; Adeline Vanderver; Simona Orcesi; Gillian I Rice Journal: Am J Med Genet A Date: 2015-01-16 Impact factor: 2.802
Authors: Alicia Guemez-Gamboa; Ahmet Okay Çağlayan; Valentina Stanley; Anne Gregor; Maha S Zaki; Sahar N Saleem; Damir Musaev; Jennifer McEvoy-Venneri; Denice Belandres; Naiara Akizu; Jennifer L Silhavy; Jana Schroth; Rasim Ozgur Rosti; Brett Copeland; Steven M Lewis; Rebecca Fang; Mahmoud Y Issa; Huseyin Per; Hakan Gumus; Ayse Kacar Bayram; Sefer Kumandas; Gozde Tugce Akgumus; Emine Z Erson-Omay; Katsuhito Yasuno; Kaya Bilguvar; Gali Heimer; Nir Pillar; Noam Shomron; Daphna Weissglas-Volkov; Yuval Porat; Yaron Einhorn; Stacey Gabriel; Bruria Ben-Zeev; Murat Gunel; Joseph G Gleeson Journal: Ann Neurol Date: 2018-10-04 Impact factor: 10.422
Authors: Mohamed S Abdel-Hamid; Ghada M H Abdel-Salam; Mahmoud Y Issa; Bayoumi A Emam; Maha S Zaki Journal: J Hum Genet Date: 2017-02-09 Impact factor: 3.172
Authors: Gaël Nicolas; Monica Sanchez-Contreras; Eliana Marisa Ramos; Roberta R Lemos; Joana Ferreira; Denis Moura; Maria J Sobrido; Anne-Claire Richard; Alma Rosa Lopez; Andrea Legati; Jean-François Deleuze; Anne Boland; Olivier Quenez; Pierre Krystkowiak; Pascal Favrole; Daniel H Geschwind; Adi Aran; Reeval Segel; Ephrat Levy-Lahad; Dennis W Dickson; Giovanni Coppola; Rosa Rademakers; João R M de Oliveira Journal: Neurol Genet Date: 2017-07-26