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) in ANKRD11, which was validated by Sanger sequencing. This single-nucleotide duplication is predicted to lead to a premature stop codon and loss of function in ANKRD11, 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.
Highlights
Whole-exome sequencing (WES) is a method that mainly targets regions of the genome that code for proteins and is useful for detecting disease-contributing variants in genes associated with rare genetic syndromes (Bamshad et al 2011; Lyon and Wang 2012; Lyon and Segal 2013; Biesecker and Green 2014; Chong et al 2015; Guo et al 2015; He et al 2015; Lyon and O’Rawe 2015)
The Social Communication Questionnaire (SCQ) (Corsello et al 2007) filled in by the parents was scored at 23, indicating the need for additional comprehensive evaluation by a specialist such as a child psychiatrist, psychologist, or developmental pediatrician trained in diagnosing autism spectrum disorder (ASD)
This stands in contrast to a mildly low level of 5-MTHF detected in cerebrospinal fluid (CSF) for the proband, in the context of a lack of control data for 5-MTHF measured longitudinally in thousands of healthy children (Frye et al 2013; Shoffner et al 2016)
Summary
Whole-exome sequencing (WES) is a method that mainly targets regions of the genome that code for proteins and is useful for detecting disease-contributing variants in genes associated with rare genetic syndromes (Bamshad et al 2011; Lyon and Wang 2012; Lyon and Segal 2013; Biesecker and Green 2014; Chong et al 2015; Guo et al 2015; He et al 2015; Lyon and O’Rawe 2015). We report the identification of a de novo mutation in ANKRD11, which led to the recognition of KBG syndrome (Ockeloen et al 2015; Walz et al 2015) in the sequenced proband. KBG syndrome (OMIM #148050) is a rare, but increasingly recognized, autosomal dominant genetic condition. Our primary goal in reporting this detailed case description is to provide rich phenotypic information that is still typically missing from many studies (Hall 2003), enabling a better description and accounting of the tremendous variable expressivity (Lyon and O’Rawe 2015) and stochastic developmental variation (SDV) (Vogt 2015) in all diseases
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