Summary
This dataset pertains to a study on the gene KMT2C and its role in neurodevelopmental disorders. Out of the clinical genetics centers at the Radboudumc and Maastricht UMC, five individuals exhibiting symptoms of intellectual disability (ID), language and motor delay, autism or Pervasive Developmental Disorder (PDD) were identified with de novo KMT2C mutations predicted to induce loss of function. These mutations included a frameshift mutation c.5216del (p.Pro1739Leufs*2) in individual 1, a mosaic nonsense mutation c.7550C>G (p.Ser2517*) in approximately 30% of blood cells of individual 2, another nonsense mutation c.1690A>T (p.Lys564*) in individual 3, a frameshift mutation c.10812_10815del (p.Lys3605fs) in individual 4, and a de novo deletion involving an intragenic 203kb segment (Chr7: 151858920–152062163)x1 in individual 5. Inheritance testing confirmed the de novo status of these mutations. Additionally, clinical features recurrent across cases included short stature, microcephaly, childhood hypotonia, kyphosis, scoliosis, recurrent respiratory infections, and Kleefstra-like facial dysmorphisms. Functional studies supported the relationship between KMT2C mutations and the disease phenotype, particularly an intragenic de novo deletion identified by microarray-based comparative genomic hybridization and confirmed by locus-specific qPCR in one patient. These findings collectively support a role of haploinsufficiency in KMT2C contributing to the clinical phenotype of the disease.
Evidence of Haploinsufficiency
Patient Identifier: individual 1
Mutation Type: frameshift mutation
Mutation Details: c.5216del (p.Pro1739Leufs*2)
Clinical Phenotype: ID, language and motor delay, and autism
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause loss of function
Direct Quote: "Through the large scale application of diagnostic whole exome sequencing for unexplained neurodevelopmental disorders in the clinical genetics centers at the Radboudumc and Maastricht UMC [29], we identified five de novo KMT2C mutations. All these mutations are predicted to cause loss of function, including c.5216del (p.Pro1739Leufs*2) in individual 1"
Location in Paper: Results
Patient Identifier: individual 2
Mutation Type: nonsense mutation
Mutation Details: c.7550C>G (p.Ser2517*) in mosaic (≈30% of blood cells)
Clinical Phenotype: ID, language and motor delay, and PDD
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause loss of function
Direct Quote: "Through the large scale application of diagnostic whole exome sequencing for unexplained neurodevelopmental disorders in the clinical genetics centers at the Radboudumc and Maastricht UMC [29], we identified five de novo KMT2C mutations. ... and c.7550C>G (p.Ser2517*) in mosaic (≈30% of blood cells) in individual 2"
Location in Paper: Results
Patient Identifier: individual 3
Mutation Type: nonsense mutation
Mutation Details: c.1690A>T (p.Lys564*)
Clinical Phenotype: ID, language and motor delay, and autism
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause loss of function
Direct Quote: "Using microarray-based comparative genomic hybridization for patient 5, an intragenic 203kb de novo deletion (Chr7: 151858920–152062163)x1 was identified (Fig 1A) and confirmed by locus-specific qPCR."
Location in Paper: Results
Patient Identifier: individual 4
Mutation Type: frameshift mutation
Mutation Details: c.10812_10815del (p.Lys3605fs)
Clinical Phenotype: ID, language and motor delay, and autism
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause loss of function
Direct Quote: "Using microarray-based comparative genomic hybridization for patient 5, an intragenic 203kb de novo deletion (Chr7: 151858920–152062163)x1 was identified (Fig 1A) and confirmed by locus-specific qPCR."
Location in Paper: Results
Patient Identifier: individual 5
Mutation Type: deletion
Mutation Details: 203kb de novo deletion (Chr7: 151858920–152062163)x1
Clinical Phenotype: ID, language and motor delay, and autism
Inheritance Tested: Yes
Effect on Gene Function: predicted to cause loss of function
Direct Quote: "Identification of these five novel mutations, in addition to the previously published case [9], has allowed us to establish the clinical phenotype associated with KMT2C mutations."
Location in Paper: Results
Clinical Features
Feature: Intellectual disability
Frequency: 6/6
Direct Quote: "All individuals had ID, ranging from mild to severe"
Location in Paper: Results
Feature: Language and motor delay
Frequency: 6/6
Direct Quote: "All individuals had ... language and motor delay"
Location in Paper: Results
Feature: Autism or Pervasive Developmental Disorder (PDD)
Frequency: 6/6
Direct Quote: "All individuals had ... autism or Pervasive Developmental Disorder (PDD)"
Location in Paper: Results
Feature: Short stature
Frequency: 2/6
Direct Quote: "Other recurrent clinical features were short stature (2/6)"
Location in Paper: Results
Feature: Microcephaly
Frequency: 3/6
Direct Quote: "Other recurrent clinical features were... microcephaly (3/6)"
Location in Paper: Results
Feature: Childhood hypotonia
Frequency: 3/6
Direct Quote: "Other recurrent clinical features were... childhood hypotonia (3/6)"
Location in Paper: Results
Feature: Kyphosis/Scoliosis
Frequency: 3/6
Direct Quote: "Other recurrent clinical features were... kyphosis/scoliosis (3/6)"
Location in Paper: Results
Feature: Recurrent respiratory infections
Frequency: 2/6
Direct Quote: "Other recurrent clinical features were... recurrent respiratory infections (2/6)"
Location in Paper: Results
Feature: Kleefstra-like facial dysmorphisms
Frequency: Not specified
Direct Quote: "Kleefstra-like facial dysmorphisms, including flattened midface, prominent eyebrows, everted lower lip, and thick ear helices, were observed in several individuals"
Location in Paper: Results
Functional Studies
Study Type: microarray-based comparative genomic hybridization and locus-specific qPCR
Methodology: Identification of intragenic de novo deletion via microarray and confirmation by qPCR
Conclusions: The identified intragenic de novo deletion is implicated in the clinical phenotype associated with KMT2C mutations
Direct Quote: "Using microarray-based comparative genomic hybridization for patient 5, an intragenic 203kb de novo deletion (Chr7: 151858920–152062163)x1 was identified (Fig 1A) and confirmed by locus-specific qPCR."
Location in Paper: Results