A Novel Intronic KMT2D Variant as a Cause of Kabuki Syndrome: A Case Report

Figures & data

Table 1 Clinical Characteristics Found in Our Patient and Literature

Clinical Characteristics in This Study	This Study	Niikawa et al^Citation27	Priolo et al^Citation28	Schrander-Stumpel et al^Citation29	Sanlaville et al^Citation30	Murakami H et al^Citation31	Paděrová, J et al^Citation32	Cheon CK et al^Citation33	Porntaveetus et al^Citation34	Shangguan et al^Citation35	Hernández-Woodbine et al^Citation36	Suarez Guerrero et al^Citation37	Osorio Alarcón et al^Citation38	Piro E et al^Citation39	Aref-Eshghi, Erfan et al^Citation16	Guo, Z et al^Citation40	de Billy, E^Citation41
Country	Colombia	Japan	Italy	Netherlands	France	Japan	Czech Republic	South Korea	Thailand	China	Colombia	Colombia	Colombia	Italy	Canada	China	Italy
Long palpebral fissures	Yes	62 of 62	108 of 120	20 of 20	23 of 24	28 of 35	12 of 14	10 of 10	7 of 7	3 of 7	1 of 1	1 of 2	1 of 1	1 of 1	1 of 1	1 of 1	1 of 1
Eversion of the lateral third of the lower eyelid	Yes	61 of 62	99 of 120	17 of 20	22 of 24	21 of 35	11 of 14	9 of 10	7 of 7	4 of 7	ND	1 of 2	1 of 1	1 of 1	1 of 1	1 of 1	1 of 1
Inverse epicantus	Yes	35 of 57	ND	ND	ND	ND	ND	9 of 10	ND	1 of 7	ND	ND	ND	ND	ND	ND	ND
Arched eyebrows	Yes	51 of 58	83 of 120	16 of 20	20 of 24	12 of 35	12 of 14	8 of 10	7 of 7	2 of 7	1 of 1	2 of 2	1 of 1	1 of 1	1 of 1	1 of 1	1 of 1
Wide nasal bridge	Yes	50 of 54	72 of 120	ND	ND	ND	14 of 14	ND	ND	3 of 7	1 of 1	2 of 2	1 of 1	1 of 1	ND	1 of 1	ND
Coloboma	Yes	ND	ND	2 of 20	ND	ND	1 of 14	0 of 10	ND	ND	ND	ND	ND	0 of 1	ND	ND	ND
Sensorineural hearing loss	Yes	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	0 of 1	ND	ND	1 of 1
Persistence of digital pads in hands	Yes	35 of 45	98 of 120	2 of 20	23 of 24	18 of 35	10 of 14	ND	7 of 7	1 of 7	1 of 1	2 of 2	1 of 1	ND	1 of 1	ND	ND
Postnatal growth deficiency	Yes	30 of 41	65 of 120	ND	13 of 24	16 of 35	10 of 14	ND	ND	4 of 7	ND	2 of 2	1 of 1	1 of 1	1 of 1	1 of 1	ND
Lordosis	Yes	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND	ND
Renal malformations	Yes	7 of 58	43 of 120	5 of 20	7 of 23	8 of 35	4 of 14	ND	1 of 7	3 of 7	1 of 1	2 of 2	ND	ND	ND	ND	ND
Intellectual disability	Yes	57 of 62	107 of 120	20 of 20	24 of 24	31 of 36	14 of 14	ND	7 of 7	5 of 6	ND	1 of 2	1 of 1	ND	ND	1 of 1	1 of 1
														Hypoplasia of the cerebellar vermis

Abbreviation: ND, not documented.

Table 2 Splice-Site Variants

Reports	Variant	Classification
This study	c.511‐2A>T	Likely Pathogenic
Murakami H et al^Citation31	c.4419‐2A>T	Pathogenic
	c.4239+5G>A	Likely Pathogenic
	c.5320‐2A>G	Pathogenic
	c.16338+1G>A	Pathogenic
	c.13531‐2A>T	Pathogenic
	c.400+1G>T	Pathogenic
	c.3906+1G>A	Pathogenic
	c.1258+5G>A	Likely Pathogenic
	c.4131+1G>C	Pathogenic
	c.2797+1G>A	Pathogenic
	c.15784+5G>C	Pathogenic
Piro E et al^Citation39	c.674‐1G > A	Pathogenic
Aref-Eshghi, Erfan et al^Citation16	c.15785‐10T>G	Likely Pathogenic
Guo, Z et al^Citation40	c.335‐1G > T	Likely Pathogenic
de Billy, E^Citation41	c.511‐1G>A	Likely Pathogenic

Figure 1 Facial characteristics. (A) Image of the patient where microphthalmia and eversion of the lateral third of the eyelid are observed. (B) Image of the patient with arched eyebrows, long palpebral fissures and wide nasal bridge, facial characteristics of kabuki syndrome. (C) Patient’s whole face image shows the dysmorphic characteristics previously described.

Figure 2 Pedigree information of the patient and Sanger sequencing electropherogram of both patient and her parents. The image shows a de novo mutation.

Figure 3 Alteration of splicing mechanism. (A) Schematic of the KMT2D genomic locus and variant c.511–2A>T. (B) Shows the splicing alteration, which represent a mis-splicing of KMT2D by mutation at the intron 4 resulting in the activation of alternative splice sites (green pin). (C) Shows the alteration of mRNA. The activation of cryptic splicing site in exon 5 results in an incomplete inclusion of this exon in the mRNA. Recognition of wild-type acceptor site of exon 6 results in a complete exclusion of exon 5 in the mRNA.

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