KBG syndrome involving a single-nucleotide duplication in ANKRD11

• Published in: Cold Spring Harbor molecular case studies Vol. 2; no. 6; p. a001131
• Main Authors: Kleyner, Robert, Malcolmson, Janet, Tegay, David, Ward, Kenneth, Maughan, Annette, Maughan, Glenn, Nelson, Lesa, Wang, Kai, Robison, Reid, Lyon, Gholson J
• Format: Journal Article
• Language: English
• Published: United States Cold Spring Harbor Laboratory Press 01.11.2016
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Bone Diseases, Developmental - genetics; Chromosome Deletion; Chromosomes, Human, Pair 16 - genetics; Facies; Heterozygote; Humans; Intellectual Disability - genetics; Male; Nucleotides - genetics; Pedigree; Phenotype; Repressor Proteins - genetics; Repressor Proteins - metabolism; Research Report; Tooth Abnormalities - genetics; Whole Exome Sequencing - methods; short toe; absent speech; generalized tonic–clonic seizures on awakening; low CSF 5-methyltetrahydrofolate; short philtrum; pes planus; clinodactyly of the 5th finger; developmental regression; broad nasal tip; intellectual disability, moderate; autism; bilateral single transverse palmar creases
• ISSN: 2373-2873; 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a001131

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) in which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in 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.