Kabuki Syndrome—Clinical Review with Molecular Aspects

Abstract

Kabuki syndrome (KS) is a rare developmental disorder principally comprised of developmental delay, hypotonia and a clearly defined dysmorphism: elongation of the structures surrounding the eyes, a shortened and depressed nose, thinning of the upper lip and thickening of the lower lip, large and prominent ears, hypertrichosis and scoliosis. Other characteristics include poor physical growth, cardiac, gastrointestinal and renal anomalies as well as variable behavioral issues, including autistic features. De novo or inherited pathogenic/likely pathogenic variants in the KMT2D gene are the most common cause of KS and account for up to 75% of patients. Variants in KDM6A cause up to 5% of cases (X-linked dominant inheritance), while the etiology of about 20% of cases remains unknown. Current KS diagnostic criteria include hypotonia during infancy, developmental delay and/or intellectual disability, typical dysmorphism and confirmed pathogenic/likely pathogenic variant in KMT2D or KDM6A. Care for KS patients includes the control of physical and psychomotor development during childhood, rehabilitation and multi-specialist care. This paper reviews the current clinical knowledge, provides molecular and scientific links and sheds light on the treatment of Kabuki syndrome individuals.

Decoding the role of coiled-coil motifs in human prion-like proteins

“…KMT2D contains a cluster of conserved domains at the C-terminal end, comprising a PHD (plant homeodomain)-zinc-finger like domain, two phenylalanine, and tyrosine (FY)-rich motifs (F/Y-rich N-terminus (FYRN) and F/Y-rich C-terminus (FYRC)) and a catalytic SET domain (SET: Su(var)3–9, Enhancer-of-zeste (E(z)), and Trithorax) that are needed for its enzymatic function [ 72 ]. KMT2D is a major regulator of cell-type-specific gene expression in cell differentiation during tissue development and embryogenesis [ 73 , 74 ]. In addition, KMT2D has also been related to tumour suppression and immune signalling [ 74–76 ].…”

“…KMT2D is a major regulator of cell-type-specific gene expression in cell differentiation during tissue development and embryogenesis [ 73 , 74 ]. In addition, KMT2D has also been related to tumour suppression and immune signalling [ 74–76 ].…”

“…Most KMT2D mutations are assumed to cause truncated proteins that do not perform the function properly due to loss of the catalytic SET domain [ 72 ]. Mutated KMT2D has been linked to developmental disorders including Kabuki syndrome [ 77 ], congenital heart disease [ 78 ], and multiple cancer types such as medulloblastoma, lymphoma, hepatocellular carcinoma, gastric cancer, breast cancer and prostate cancer [ 73 , 74 ]. This pleiotropic effect results from the fact that its pathogenic variants cause the interruption of histone methylation and abnormal enhancer regulation, leading to changes in transcription, thus affecting normal growth and development [ 74 ].…”

“…Mutated KMT2D has been linked to developmental disorders including Kabuki syndrome [ 77 ], congenital heart disease [ 78 ], and multiple cancer types such as medulloblastoma, lymphoma, hepatocellular carcinoma, gastric cancer, breast cancer and prostate cancer [ 73 , 74 ]. This pleiotropic effect results from the fact that its pathogenic variants cause the interruption of histone methylation and abnormal enhancer regulation, leading to changes in transcription, thus affecting normal growth and development [ 74 ]. The exon 39 (3581–4510 aa) constitutes a mutational hotspot [ 79 ] and, interestingly enough, it contains the most extended prion-like domain, with missense disease-associated mutations clustering at the predicted CC and Q-rich motifs comprising residues 3897–3975 [ 70 ].…”

Angelman Syndrome and Angelman-like Syndromes Share the Same Calcium-Related Gene Signatures

“…Kabuki Syndrome (KS) is an additional neurodevelopmental disorder that has a different clinical presentation from AS and is considered a non-AS-like syndrome. KS is characterized by distinct facial dimorphism, growth retardation, psychomotor developmental delay, and a wide spectrum of other manifestations affecting various body systems [58]. KS is a result of a loss of function of either KMT2D or KDM6A proteins.…”