title: KBG syndrome involving a single-nucleotide duplication inANKRD11.
abstract: KBG syndrome is a rare autosomal dominant genetic condition characterized by neurological involvement and distinct facial, hand, and skeletal features. More than 70 cases have been reported; however, it is likely that KBG syndrome is underdiagnosed because of lack of comprehensive characterization of the heterogeneous phenotypic features. We describe the clinical manifestations in a male currently 13 years of age, who exhibited symptoms including epilepsy, severe developmental delay, distinct facial features, and hand anomalies, without a positive genetic diagnosis. Subsequent exome sequencing identified a novel de novo heterozygous single base pair duplication (c.6015dupA) inANKRD11,which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function inANKRD11,thereby implicating it as contributing to the proband's symptoms and yielding a molecular diagnosis of KBG syndrome. Before molecular diagnosis, this syndrome was not recognized in the proband, as several key features of the disorder were mild and were not recognized by clinicians, further supporting the concept of variable expressivity in many disorders. Although a diagnosis of cerebral folate deficiency has also been given, its significance for the proband's condition remains uncertain.
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleyner
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;; Genetic Counseling Graduate Program, Long Island University (LIU), Brookville, New York 11548, USA.
authors.forename: Janet
authors.initials: J
authors.lastname: Malcolmson
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tegay
authors.affiliation: Affiliated Genetics, Inc., Salt Lake City, Utah 84109, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Ward
authors.affiliation: Epilepsy Association of Utah, West Jordan, Utah 84088, USA.
authors.forename: Annette
authors.initials: A
authors.lastname: Maughan
authors.affiliation: KBG Syndrome Foundation, West Jordan, Utah 84088, USA.
authors.forename: Glenn
authors.initials: G
authors.lastname: Maughan
authors.affiliation: Affiliated Genetics, Inc., Salt Lake City, Utah 84109, USA.
authors.forename: Lesa
authors.initials: L
authors.lastname: Nelson
authors.affiliation: Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90089, USA;; Department of Psychiatry & Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA;; Utah Foundation for Biomedical Research, Salt Lake City, Utah 84107, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Utah Foundation for Biomedical Research, Salt Lake City, Utah 84107, USA.
authors.forename: Reid
authors.initials: R
authors.lastname: Robison
authors.affiliation: Stanley Institute for Cognitive Genomics, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA;; Utah Foundation for Biomedical Research, Salt Lake City, Utah 84107, USA.
authors.forename: Gholson J
authors.initials: GJ
authors.lastname: Lyon
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D001848:Bone Diseases, Developmental / Q000235:genetics*; D002872:Chromosome Deletion; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics; D019066:Facies; D006579:Heterozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009711:Nucleotides / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D014071:Tooth Abnormalities / Q000235:genetics*; D000073359:Exome Sequencing / Q000379:methods
chemical_list: C492515:ANKRD11 protein, human; D009711:Nucleotides; D012097:Repressor Proteins
keywords: absent speech; autism; bilateral single transverse palmar creases; broad nasal tip; clinodactyly of the 5th finger; developmental regression; generalized tonic–clonic seizures on awakening; intellectual disability, moderate; low CSF 5-methyltetrahydrofolate; pes planus; short philtrum; short toe