Summary
This dataset presents evidence for the haploinsufficiency of the ARID1B gene in patients with neurodevelopmental disorders. Four key cases include a 'translocation patient' with a chromosome 6 breakpoint truncating ARID1B, 'Patient 1' with a de novo balanced reciprocal translocation, 'Patient 2' with a 0.2-Mb intragenic deletion, and 'patients 3 and 4' with deletions confined to ARID1B. Each case manifests intellectual disability, severe speech impairment, and varying dysmorphic features. Inheritance was tested for the translocation patient and Patient 1, establishing de novo occurrence of the mutations. Clinical features of ARID1B-associated haploinsufficiency frequently involved corpus callosum abnormalities, intellectual disability, autism spectrum disorder, hypotonia, and feeding problems in infancy. Supporting these clinical correlations, functional studies including Quantitative polymerase chain reaction (Q-PCR) confirmed the gene-disease association with differential expression of ARID1B highlighting the functional impact of haploinsufficiency on neurodevelopmental phenotypes.
Evidence of Haploinsufficiency
Patient Identifier: translocation patient
Mutation Type: truncation
Mutation Details: chromosome 6 breakpoint truncated ARID1B
Clinical Phenotype: agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism
Inheritance Tested: Yes
Effect on Gene Function: haploinsufficiency of ARID1B
Direct Quote: "By next-generation mate-pair sequencing we mapped the chromosomal breakpoints of a patient with a de novo balanced translocation, t(1;6)(p31;q25), agenesis of corpus callosum (CC), intellectual disability, severe speech impairment, and autism. The chromosome 6 breakpoint truncated ARID1B which was also truncated in a recently published translocation patient with a similar phenotype."
Location in Paper: Abstract
Patient Identifier: Patient 1
Mutation Type: balanced reciprocal translocation
Mutation Details: de novo balanced reciprocal translocation t(1;6)(p31;q25)
Clinical Phenotype: intellectual disability, autism, speech impairment, ACC, and mild dysmorphic features
Inheritance Tested: Yes
Effect on Gene Function: Presumed loss of function of ARID1B due to translocation
Direct Quote: "Patient 1 is an 8-year-old male with a de novo balanced reciprocal translocation t(1;6)(p31;q25). He was diagnosed with intellectual disability, autism, speech impairment, ACC, and mild dysmorphic features according to various assessments. ARID1B at 6q25.3 was truncated."
Location in Paper: Discussion
Patient Identifier: Patient 2
Mutation Type: intragenic deletion
Mutation Details: a 0.2-Mb intragenic deletion in ARID1B detected
Clinical Phenotype: intellectual disability, severe speech impairment, various degrees of dysmorphic features
Inheritance Tested: No
Effect on Gene Function: Interstitial deletions affecting ARID1B
Direct Quote: "In patient 2, a 0.2-Mb intragenic deletion in ARID1B was detected. Overlapping clinical manifestations with other patients included intellectual disability, severe speech impairment, and various degrees of dysmorphic features."
Location in Paper: Discussion
Patient Identifier: patients 3 and 4
Mutation Type: deletion
Mutation Details: Deletions in patients 3 and 4 only involved ARID1B
Clinical Phenotype: intellectual disability, severe speech impairment, various degrees of dysmorphic features
Inheritance Tested: No
Effect on Gene Function: Interstitial deletions affecting ARID1B
Direct Quote: "Deletions in patients 3 and 4 only involved ARID1B. All eight patients had intellectual disability, severe speech impairment, and various degrees of dysmorphic features."
Location in Paper: Discussion
Clinical Features
Feature: Corpus callosum abnormalities
Frequency: common
Direct Quote: "Corpus callosum abnormalities are common brain malformations with a wide clinical spectrum..."
Location in Paper: Abstract
Feature: intellectual disability
Frequency: all eight patients
Direct Quote: "Overlapping clinical manifestations were present: all eight patients had intellectual disability, severe speech impairment, and various degrees of dysmorphic features."
Location in Paper: Discussion
Feature: severe speech impairment
Frequency: all eight patients
Direct Quote: "Overlapping clinical manifestations were present: all eight patients had intellectual disability, severe speech impairment, and various degrees of dysmorphic features."
Location in Paper: Discussion
Feature: autism
Frequency: associated
Direct Quote: "Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B."
Location in Paper: Abstract
Feature: autism spectrum disorder (ASD)
Frequency: diagnosed in three patients and two showed autistic traits
Direct Quote: "Three patients were diagnosed with ASD and another two showed autistic traits."
Location in Paper: Discussion
Feature: hypotonia
Frequency: 3 out of 7
Direct Quote: "Hypotonia was reported in three patients, and four patients had feeding problems or failure to thrive in infancy."
Location in Paper: Patients 2–8
Feature: feeding problems or failure to thrive in infancy
Frequency: 4 out of 7
Direct Quote: "Hypotonia was reported in three patients, and four patients had feeding problems or failure to thrive in infancy."
Location in Paper: Patients 2–8
Functional Studies
Study Type: Quantitative polymerase chain reaction (Q-PCR)
Methodology: Q-PCR data showed increased or decreased ARID1B expression in the patient relative to a non-related control set
Conclusions: haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism
Direct Quote: "Quantitative polymerase chain reaction (Q-PCR) data showed that a primer set proximal to the translocation showed increased expression of ARID1B, whereas primer sets spanning or distal to the translocation showed decreased expression in the patient relative to a non-related control set. Phenotype–genotype comparison of the translocation patient to seven unpublished patients with various sized deletions encompassing ARID1B confirms that haploinsufficiency of ARID1B is associated with CC abnormalities, intellectual disability, severe speech impairment, and autism."
Location in Paper: Abstract