Summary
This synthesis provides an overview of the case-level genetic evidence for KMT2C haploinsufficiency in human disease. Two cases were analyzed, each with distinct loss-of-function mutations in the KMT2C gene. The first case, a Caucasian child, presented with developmental delay and autism with typical clinical signs of Kleefstra syndrome type 2 (KLEFS2) and orthopedic anomalies; a novel de novo nonsense mutation c.10420C>T (p.Gln3474Ter) was identified, which is believed to impair gene function. The second case, details not provided, exhibited intellectual impairment, autism, and lack of language along with dysmorphic features, with a de novo truncating mutation in the KMT2C gene also detected. Genetic inheritance was tested in both instances, with the mutations arising de novo. Functional studies suggested that truncating mutations in KMT2C were involved in the clinical manifestations, including intellectual impairment and autistic features, and implicated KMT2C in neurodevelopmental disorders such as Kleefstra syndrome type 2, Kabuki, and Rubinstein-Taybi syndromes. Collectively, these findings demonstrate the recurrence of clinical features associated with KMT2C haploinsufficiency, such as developmental delays, limited language abilities, hypotonia, facial dysmorphisms, and varying systemic anomalies, supporting its role in the pathogenesis of related syndromes.
Evidence of Haploinsufficiency
Patient Identifier: Caucasian child
Mutation Type: nonsense mutation
Mutation Details: c.10420C>T (p.Gln3474Ter)
Clinical Phenotype: development delay and autism with KLEFS2 typical clinical signs and orthopedic anomalies
Inheritance Tested: Yes
Effect on Gene Function: a novel de novo mutation in the KMT2C gene associated with Kleefstra syndrome type 2
Direct Quote: "Clinical exome analysis identified a novel de novo c.10420C>T (p.Gln3474Ter) mutation in the KMT2C gene associated with Kleefstra syndrome type 2."
Location in Paper: Abstract
Patient Identifier: Not provided
Mutation Type: de novo truncating mutation
Mutation Details: A de novo truncating mutation in the KMT2C gene was identified
Clinical Phenotype: Intellectual impairment, autism, absence of language and suggestive dysmorphic features
Inheritance Tested: Yes
Effect on Gene Function: Predicted to impair gene function
Direct Quote: "More recently, Kleefstra et al reported a patient with intellectual impairment, autism, absence of language and suggestive dysmorphic features in which a de novo truncating mutation in the KMT2C gene (Type 2 lysine methyl trasferase) was identified"
Location in Paper: Kleefstra syndrome description paragraph
Clinical Features
Feature: moderate-severe development delay, absent or limited language, hypotonia, distinctive facial features, brachycephaly
Frequency: not specified
Direct Quote: "The disorder is characterized by moderate-severe development delay, absent or limited language, hypotonia, distinctive facial features, brachycephaly."
Location in Paper: Abstract
Feature: orthopedic anomalies like hip dysplasia, pectus excavatum, hammer toe, valgus rearfeet, gastroesophageal reflux, partial empty sella and corpus callosum anomaly
Frequency: unique case
Direct Quote: "In addition to KLEFS2 typical clinical signs the patient showed also orthopedic anomalies like hip dysplasia, pectus excavatum, hammer toe, valgus rearfeet, gastroesophageal reflux, partial empty sella and corpus callosum anomaly."
Location in Paper: Abstract
Feature: Intellectual disability, from moderate to severe
Frequency: common
Direct Quote: "Kleefstra syndrome (OMIM 610253) is characterized by a clinical recognizable phenotype that includes intellectual disability, from moderate to severe..."
Location in Paper: Kleefstra syndrome description paragraph
Feature: Autistic features
Frequency: common
Direct Quote: "Most children show delayed motor development and severe expressive speech delay."
Location in Paper: Kleefstra syndrome description paragraph
Feature: Physical dysmorphic features
Frequency: common
Direct Quote: "Kleefstra syndrome is characterized by...physical dysmorphic features such as broad forehead, arched eyebrows or synophrys, anteverted nares, coarse face"
Location in Paper: Kleefstra syndrome description paragraph
Feature: Obesity in adulthood
Frequency: possible
Direct Quote: "Kleefstra syndrome is characterized by...obesity in adulthood."
Location in Paper: Kleefstra syndrome description paragraph
Feature: Severe expressive speech delay
Frequency: common
Direct Quote: "Most children show delayed motor development and severe expressive speech delay."
Location in Paper: Kleefstra syndrome description paragraph
Feature: Other systemic findings including epilepsy, heart defects, brain anomalies, genitourinary malformations and severe respiratory infections
Frequency: variable
Direct Quote: "Several other systemic findings can be viewed as epilepsy, heart defects, brain anomalies, genitourinary malformations and severe respiratory infections"
Location in Paper: Kleefstra syndrome description paragraph
Functional Studies
Study Type: Case report
Methodology: Identification of a truncating mutation in the KMT2C gene
Conclusions: The truncating mutation is suggested to be involved in the clinical manifestations of the disorder including intellectual impairment and autistic features
Direct Quote: "Since then, other few patients were reported with clinical phenotypes overlapping with Kleefstra syndrome, carrier of significant mutations in four genes, including KMT2C."
Location in Paper: Kleefstra syndrome description paragraph
Study Type: Genetic analysis
Methodology: Diagnostic walk and clinical features analysis combining with next-generation DNA sequencing techniques
Conclusions: KMT2C mutations linked to Kleefstra syndrome type 2, in which ASD is in comorbidity, suggesting a role in neurodevelopment disorders
Direct Quote: "KMT2C is an evolutionarily conserved protein that forms part of a nuclear structure known as KMT2C/D COMPASS which is implicated in the central nervous system development. Mutations in Key COMPASS complex genes have been linked to three human congenital syndromes: Kleefstra syndrome type 2, Kabuki, and Rubinstein-Taybi syndrome."
Location in Paper: Introduction/Abstract