title: Tentative clinical diagnosis of Lujan-Fryns syndrome--A conglomeration of different genetic entities?
abstract: The clinical diagnosis of Lujan-Fryns syndrome (LFS) comprises X-linked intellectual disability (XLID) with marfanoid habitus, distinct combination of minor facial anomalies and nasal speech. However the definition of syndrome was significantly broadened since the original report and implies ID with marfanoid habitus. Mutations of three genes (MED12, UPF3B, and ZDHHC9) have been reported in "broadly defined" LFS. We examined these genes in 28 individuals with a tentative clinical diagnosis of LFS but we did not identify any causative mutation. By molecular karyotyping we detected other disorders, i.e., Phelan-McDermid syndrome and 16p11.2 microduplication, each in one patient. One affected individual was carrier of a different recurrent duplication on 16p11.2 that has been reported several times to the DECIPHER and ISCA databases in individuals with autism, intellectual disability (ID), and developmental delay. It may represent a new duplication syndrome. We also identified previously unreported de novo duplication on chromosome 12p13.31 which we considered to be disease-causing. X-exome sequencing of four individuals revealed private or non-recurrent mutations in NKAP and LAS1L in one patient each. While LFS is defined as a form of XLID, there seem to be various conditions that have rather similar phenotypes. Therefore, the combination of ID and marfanoid habitus in a male patient is not sufficient for the diagnosis of LFS. We suggest that the diagnosis of LFS in patients with ID and marfanoid habitus should be made only in presence of specific facial features, nasal speech and obvious X-linked segregation of the disorder or an unambiguously pathogenic mutation in the MED12.
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Karl
authors.initials: K
authors.lastname: Hackmann
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rump
authors.affiliation: Department of Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Haas
authors.affiliation: Division of Human Genetics, University Children's Hospital Inselspital, Bern, Switzerland.
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.affiliation: Centre for Human Genetics, KU Leuven/University Hospital Leuven, Leuven, Belgium.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.affiliation: Institut fuer Medizinische Genetik und Angewandte Genomik, Universitaetsklinikum, Tuebingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universitaet Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universitaet Duisburg-Essen, Essen, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Albrecht
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universitaet Duisburg-Essen, Essen, Germany.
authors.forename: Alma
authors.initials: A
authors.lastname: Kuechler
authors.affiliation: Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Ripperger
authors.affiliation: Zentrum fuer Diagnostik GmbH MVZ, Praxis fuer Humangenetik, Klinikum Chemnitz, Chemnitz, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Kobelt
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Konrad
authors.initials: K
authors.lastname: Oexle
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schrock
authors.affiliation: Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Vera M
authors.initials: VM
authors.lastname: Kalscheuer
authors.affiliation: Institut fuer Klinische Genetik, Medizinische Fakultaet Carl Gustav Carus, Technische Universitaet Dresden, Dresden, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D000217:Acyltransferases / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000175:diagnosis* / Q000235:genetics; D005260:Female; D050172:Genes, X-Linked / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis* / Q000235:genetics; D056892:Mediator Complex / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D016601:RNA-Binding Proteins / Q000235:genetics
chemical_list: C460107:MED12 protein, human; D056892:Mediator Complex; D016601:RNA-Binding Proteins; C435488:UPF3B protein, human; D000217:Acyltransferases; C504825:ZDHHC9 protein, human
keywords: 16p11.2; 18p11.32; Lujan-Fryns syndrome; X-exome; X-linked intellectual disability; clinical heterogeneity