KBG syndrome, caused by loss-of-function of the Ankyrin repeat domain-containing protein 11 gene (ANKRD11), is a neurodevelopmental disorder (NDD) named after the surname initials (K, B and G) of the first three families with KBG syndrome, and first described by Herrmann et al. (1975). Today, approximately 180 patients have been reported worldwide (Sirmaci et al., 2011; Ockeloen et al., 2015; Walz et al., 2015; Goldenberg et al., 2016; Low et al., 2016). ANKRD11 appeared one of the most frequently mutated genes in a study of 4293 children with severe developmental disorders. Accordingly, KBG syndrome appears to be much more common than previously recognized (The Deciphering Developmental Disorders Study, 2015).

Although clinical features may vary, the core symptoms of KBG syndrome are developmental delay (DD)/intellectual disability (ID), dental anomalies, triangular facies, brachycephaly, hypertelorism, protruding ears and an upturned nose with full nasal tip. In addition, KBG syndrome is frequently associated with hearing problems, short stature as well as cardiac defects, palate abnormalities, sleep disturbances and feeding difficulties during infancy (Skjei et al., 2007; Ockeloen et al., 2015; Goldenberg et al., 2016; Low et al., 2016). Abnormal electroencephalogram (EEG) findings both with and without epileptic seizures are often found (Brancati et al., 2004; Skjei et al., 2007; Kim et al., 2015; Goldenberg et al., 2016; Low et al., 2016). Neuroimaging studies show small cerebelli (Tunovic et al., 2014; Kim et al., 2015; Goldenberg et al., 2016), enlargement of the ventricles, and/or white matter anomalies in half of the patients included in these imaging studies (Skjei et al., 2007; Miyatake et al., 2013; Low et al., 2016).

As to psychopathology, the limited amount of research on KBG syndrome mainly comprises case studies, presenting anecdotal evidence of both children and adults with ADHD symptoms as well as autism related problems (Brancati et al., 2004; Skjei et al., 2007; Hah et al., 2009; Ockeloen et al., 2015; Goldenberg et al., 2016; Low et al., 2016). Incidentally reported are anxiety, as well as aggressive and compulsive behavior (Maegawa et al., 2004; Lo-Castro et al., 2013; Ockeloen et al., 2015; Goldenberg et al., 2016; Low et al., 2016). Even less is known about the phenotypical presentation in terms of cognitive functioning. The establishment and understanding of neurocognitive deficits that may underlie or contribute to psychopathology, can provide directions for personalized patient care regarding education, daily living and treatment. In the above-mentioned studies delayed speech and motor development (Kim et al., 2015; Goldenberg et al., 2016; Low et al., 2016) as well as mild to moderate intellectual disabilities have often been mentioned (Sirmaci et al., 2011; Ockeloen et al., 2015; Goldenberg et al., 2016), however cases with borderline to normal intelligence levels have also been described (Oegema et al., 2010; Walz et al., 2015; Goldenberg et al., 2016). Although intellectual disabilities have nearly always been reported in case studies, these classifications were only sporadically substantiated by systematic measurements of intelligence and neurocognitive functions. Up till now, only two case studies that both include two patients, have used cognitive tests in patients with KBG syndrome (Hah et al., 2009; Lo-Castro et al., 2013), suggesting problems in executive functions and visuo-spatial abilities. However, no correction for intelligence levels or comparison with IQ-matched individuals was mentioned. Comparison of patients with ID to controls with an equal level of general intelligence is essential for adequate interpretation of neuropsychological data as patients with ID will likely deviate on all domains of cognitive functioning compared to healthy controls. Specific cognitive deficits related to KBG syndrome would otherwise remain unnoticed. Potential cognitive deficits can only be identified as a specific characteristic of KBG syndrome when these deficits are reflected by differences in cognitive performance between individuals with KBG syndrome and individuals with a similar general level of intellectual functioning.

Thus, identification of the general level of intellectual functioning (total intelligence coefficient, a composite score reflecting achievements on all 10 subtasks of the intelligence battery), is a prerequisite to the identification of a specific neurocognitive profile in patients with KBG syndrome. Subsequently, neuropsychological screening based on exploration of intelligence profiles may then identify more specific deficits in information processing. Exploration of the intelligence profiles includes the comparison of achievements on different subtests within the intelligence battery, which all reflect different aspects of cognitive functioning. Establishment of strengths and weaknesses in cognitive functioning may provide direction for education, employment and therapy in patients with KBG syndrome. As mentioned above, in order to explore these potential deficits in information processing related to KBG syndrome, a comparison with control patients with similar levels of intelligence is necessary. The aim of the current study is precisely this and strives to explore the intellectual profiles of KBG syndrome in a larger, substantial cohort of patients (n = 18), compared with a suitable control group, which includes a mixed group of patients with different genetic syndromes other than KBG syndrome who also have an ID/DD and display behavioral difficulties.

In Table 2 mean total intelligence coefficients (TIQ) as well as mean WSS per subtest of both KBG and PGC groups are presented. Performances in terms of TIQ and WSS show dispersion between the individual patients in all four groups. Classifications of the total intelligence range from a moderate ID (TIQ: 45) to normal intelligence (TIQ: 99), see Table 3 for frequency distribution per group. No significant differences were found on TIQ between KBG-c and PGC-c (t₍₂₂₎ = 0.23, p = 0.82, d = 0.41). Likewise, KBG-a and PGC-a did not differ in TIQ (t₍₉₎ = −0.20, p = 0.85, d = 0.01). For the subtests, WSS range from “far below average” (WSS: 1) to “above average” (WSS: 13) with a relatively high amount of (very) low scores in children of both groups.

GLM multivariate analyses of the WSS showed an overall significant difference between the four groups (F_(12,74) = 3.07, p = 0.001, η² = 0.30). However, additional comparison of results on the individual subtests did not display significant specific group differences. So, group performances did not differ for the subtests Block Design (F_(3,31) = 0.90, p = 0.454, η² = 0.08), Vocabulary (F_(3,31) = 0.17, p = 0.919, η² = 0.02) and Arithmetic (F_(3,31) = 0.25, p = 0.864, η² = 0.02). A marginal significant difference was found on Coding (F_(3,31) = 2.81, p = 0.056, η² = 0.21). Planned contrasts revealed that this difference is possibly due to significantly higher performance of KBG-c when compared to KBG-a (p = 0.023).

Intellectual functioning in KBG syndrome was investigated in a case-control study, that included patient genetic controls. Total IQ of patients with KBG syndrome varied from moderate ID to normal intelligence. When compared with PGC, there were no significant differences on the four Wechsler subtest results. According to the results on Coding, there was a marginal significant difference in speed of information processing, which was mainly constituted by differences in functioning between KBG-c (faster) and KBG-a (slower).

The established level of intellectual functioning is in line with previously performed descriptive studies on KBG syndrome (Sirmaci et al., 2011; Ockeloen et al., 2015; Goldenberg et al., 2016). Intelligence in the current study ranges from moderate ID to normal intelligence, with most patients having a mild ID. Heterogeneity within both KBG-c and KBG-a groups was evident regarding both global intelligence and intelligence subtest profiles. In contrast to what may have been expected, Wechsler subtest results of both KBG groups were not significantly different from those of both control groups, meaning that patients with KBG syndrome did not display specific strengths or weaknesses in measures of speed of information processing, working memory, verbal comprehension or perceptual reasoning compared to the control patients with other genetic syndromes.

Although patients with KBG syndrome clearly deviated from the healthy population in both the general level of intelligence and intelligence profiles (as reflected in the low TIQ and WSS scores), there are no indications for more specific weaknesses in cognitive functioning in KBG syndrome. Previously, the behavioral phenotype of KBG syndrome has often been characterized as “ADHD-like behavior”. Given the fact that patients with ADHD have demonstrated impairments in speed of information processing and working memory in Wechsler profiles (Mayes and Calhoun, 2006; Theiling and Petermann, 2016), specific deficits in these domains could also be expected in patients with KBG syndrome. However, this study indicates that the behavioral phenotype of KBG syndrome is not directly related to specific impairments in speed of information processing or working memory performance. Alternatively, neurocognitive functions such as attention and executive functioning (EF) may underlie or contribute to this phenotype, regarding the fact that prominent neuropsychological theories on ADHD state that this psychopathology is related to specific deficits in EF. Meta analysis of case-control studies of patients with ADHD, for example, display significant weaknesses in several key EF domains like response inhibition, vigilance and planning (Willcutt et al., 2005). As Wechsler batteries primarily tap into crystallized intelligence and do not specifically measure attention and EF (van Aken et al., 2014, 2017), future studies on KBG syndrome could focus on more specific aspects of neurocognitive functioning.

In conclusion, the current study demonstrates a wide range in the level of intellectual functioning in patients with KBG syndrome, varying from a moderate ID to average levels of intelligence, with a majority of patients demonstrating a mild ID. Furthermore, when compared with PGC, patients display quite similar Wechsler subtest results, which indicates that specific behavioral problems associated with KBG syndrome are not related to a specific intelligence profile. In order to further clarify the KBG behavioral phenotype, future studies should include more specific measures of neurocognitive functioning including measures of attention and EF.

LCMD, JIME, TK and EW designed and planned the study. LCVD and AGB-R acquired the data and performed neuropsychological assessments. WO analyzed the neuropsychological data and contributed to the interpretation of the results. CWO and TK diagnosed and recruited the patients and contributed to the interpretation of the genetic analyses. LCMD, EW and JIME drafted the manuscript. TK, WO, AGB-R and CWO critically reviewed the manuscript. All authors read and authorized the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.