Further delineation of Kabuki syndrome in 48 well‐defined new individuals

Abstract

Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.

Molecular karyotyping in 17 patients and mutation screening in 41 patients with Kabuki syndrome

“…5 The cause of KS remains unknown, even though at least 400 patients have been known in a variety of ethnic groups since 1981. [3][4][5][6][7] Some works have ruled out several loci, e.g., 1q32-q41, 8p22-p23.1 and 22q11, from the candidate for KS. [8][9][10][11][12][13] A study of array-based comparative genomic hybridization (CGH) showed a disruption of C20orf133(MACROD2) gene by ~250 kb deletion on a patient with KS 14 , but the following mutation screening for the gene failed to find pathogenic base change within exons in other 19 patients with KS 14 and in 43 Japanese patients.…”

Kabuki syndrome revisited

“…Initially believed to have greatest incidence in the Japanese population, 12 KS has since been identified across numerous ethnic groups 2 with equal prevalence in both sexes. 23 It has however, taken a long period of time to determine the molecular basis of the condition owing to the complexity of the condition itself, and recent discoveries are likely to be attributable to the availability of cost effective and efficient sequencing technologies. The numerous inconclusive attempts at determining the causative gene have surely not been in vain, as it is the findings from inconclusive studies that often formed the foundations for successive ones, and may still be relevant in the search for the 'other' implicated genes unaccounted for by MLL2 gene defects.…”

“…The findings by Rodriguez et al 21 , were further supported with research by Su et al 22 , as they were also able to identify features of KS in a 13-year-old female with Turner syndrome mosaicism 45,X/46,X,r(X), and incomplete XIST gene expression on her ring X chromosome. Limitations to this theory, however, included the inability to extrapolate these findings to the cause of KS in male patients; with a potential argument reflected in the similar prevalence observed between males and females, 23 thus suggesting a common etiological cause to be most likely. In light of recent findings, however, pre-existing data pertaining to the significance of the X chromosome in this etiology may indeed still be of great relevance.…”

“…28 Such findings may now broadly give explanation to the variances identified in earlier studies that aimed to characterize the syndrome, and have thus reiterated initial suggestions for genetic heterogeneity. In 2005 Armstrong et al 23 investigated 48 'well defined' cases of KS. Associated with KS were a group of distinct craniofacial features observed in the majority, which were the basis for identifying the syndrome as a distinct clinical entity in its first instance.…”

Infrequent Manifestations of Kabuki Syndrome in a Patient with Novel <b><i>MLL2</i></b> Mutation

“…festations include early breast development in infant girls (25%), neonatal hypoglycemia (7-8%), persistent hypoglycemia (1%), and diaphragmatic defects (4-8%) [Niikawa et al, 1981;Geneviève et al, 2004;Adam and Hudgins, 2005;Armstrong et al, 2005]. Recently, mutations in the MLL2 gene were identified in KS patients.…”