Summary
This dataset provides case-level evidence of haploinsufficiency in the ARID1B gene across nine patients exhibiting a spectrum of clinical phenotypes including severe developmental delay, intellectual disability, and muscular hypotonia. Each patient carried a heterozygous mutation predicted or proven to lead to loss of function, such as deletions, duplications creating null alleles, and nonsense or frameshift mutations. Mutations noted include a 2.5 Mb deletion, duplication of exons 5 and 6, and nonsense mutations like c.3919C>T and c.4038T>A. Frameshift mutations recorded include c.6463_6473del and c.1114dupC among others. Inheritance tests confirmed all these mutations occurred de novo. The clinical features strongly associated with ARID1B haploinsufficiency are consistent across cases, particularly intellectual disability and developmental delays. Functional studies including transcript analysis via RT-PCR supported the hypothesis that variants such as c.4110G>A induce exon skipping, leading to frameshifts and premature stop codons, confirming their role in disease phenotypes. Additionally, clinical observations underscore that the symptoms overlap between patients with point mutations and those with large genomic deletions, further validating ARID1B haploinsufficiency as the causal factor in the observed clinical manifestations.
Evidence of Haploinsufficiency
Patient Identifier: patient 1
Mutation Type: deletion
Mutation Details: 2.5 Mb deletion containing five genes in chromosomal region 6q25.3
Clinical Phenotype: severe developmental delay, muscular hypotonia, heart malformation (ASD)
Inheritance Tested: Yes
Effect on Gene Function: haploinsufficiency of ARID1B
Direct Quote: "In one male infant, we identified a 2.5 Mb deletion containing five genes in chromosomal region 6q25.3 ... Segregation analysis of both parents revealed a de novo origin of the deletion."
Location in Paper: The American Journal of Human Genetics 90, 565–572, March 9, 2012 565
Patient Identifier: patient 2
Mutation Type: duplication
Mutation Details: duplication of exons 5 and 6 leading to a null allele
Clinical Phenotype: intellectual disability (ID), moderate developmental delay, muscular hypotonia
Inheritance Tested: Yes
Effect on Gene Function: the duplication leads to a null allele
Direct Quote: "Patient 2 with a de novo duplication of exons 5 and 6...the duplication leads to a null allele."
Location in Paper: Figure 2
Patient Identifier: patient 3
Mutation Type: nonsense mutation
Mutation Details: c.3919C>T (p.Gln1307*)
Clinical Phenotype: severe developmental delay, muscular hypotonia, moderate to severe ID
Inheritance Tested: Yes
Effect on Gene Function: predicted null variant resulting in haploinsufficiency of ARID1B
Direct Quote: "we identified a c.3919C>T (p.Gln1307*) nonsense mutation in exon 16 of ARID1B in patient 3"
Location in Paper: The American Journal of Human Genetics 90, 565-572, March 9, 2012
Patient Identifier: patient 4
Mutation Type: frameshift mutation
Mutation Details: c.6463_6473del (p.Ser2155 Leufs*33)
Clinical Phenotype: moderate intellectual disability (IQ = 50), muscular hypotonia, autism spectrum disorder (ASD)
Inheritance Tested: Yes
Effect on Gene Function: predicted loss-of-function variant leading to haploinsufficiency of ARID1B
Direct Quote: "Patient 4 c.6463_ 6473del (p.Ser2155 Leufs*33) de novo"
Location in Paper: Table 1
Patient Identifier: patient 5
Mutation Type: nonsense mutation
Mutation Details: c.3304C>T (p.Arg1102*)
Clinical Phenotype: severe developmental delay, muscular hypotonia, hearing loss
Inheritance Tested: Yes
Effect on Gene Function: predicted null variant resulting in haploinsufficiency of ARID1B
Direct Quote: "Patient 5 - c.3304C>T (p.Arg1102*) - severe developmental delay"
Location in Paper: Table 1
Patient Identifier: patient 6
Mutation Type: frameshift mutation
Mutation Details: c.3323_3324delAA (p.Lys1108Argfs*9)
Clinical Phenotype: mild to moderate ID, not specified in provided text
Inheritance Tested: Yes
Effect on Gene Function: predicted loss-of-function variant leading to haploinsufficiency of ARID1B
Direct Quote: "Patient 6 c.3323_ 3324delAA (p.Lys1108 Argfs*9) de novo"
Location in Paper: Table 1
Patient Identifier: patient 7
Mutation Type: frameshift
Mutation Details: c.4110G>A (p.Arg1338Argfs*76)
Clinical Phenotype: moderate to severe ID, single words
Inheritance Tested: Yes
Effect on Gene Function: Predicted loss of function
Direct Quote: "Patient 7 c.4110G>A (p.Arg1338 Argfs*76) de novo"
Location in Paper: Table 1
Patient Identifier: patient 8
Mutation Type: nonsense mutation
Mutation Details: c.4038T>A (p.Tyr1346*)
Clinical Phenotype: moderate ID, short sentences and sufficient working vocabulary
Inheritance Tested: Yes
Effect on Gene Function: Predicted loss of function
Direct Quote: "Patient 8 c.4038T>A (p.Tyr1346*) de novo"
Location in Paper: Table 1
Patient Identifier: patient 9
Mutation Type: frameshift
Mutation Details: c.1114dupC (p.Arg372Profs*163)
Clinical Phenotype: moderate ID, delayed
Inheritance Tested: Yes
Effect on Gene Function: Predicted loss of function
Direct Quote: "Patient 9 c.1114dupC (p.Arg372Profs*163) de novo"
Location in Paper: Table 1
Clinical Features
Feature: Intellectual disability (ID)
Frequency: common
Direct Quote: "Our findings thus indicate that ARID1B-haploinsufficiency-causing mutations, but not missense variants, are a common cause of ID."
Location in Paper: The American Journal of Human Genetics 90, 565–572
Feature: Developmental delay
Frequency: all patients
Direct Quote: "All individuals presented with moderate to severe psychomotor retardation"
Location in Paper: Page 567
Feature: Muscular hypotonia
Frequency: most patients
Direct Quote: "most showed evidence of muscular hypotonia"
Location in Paper: Page 567
Feature: Speech impairment
Frequency: many patients
Direct Quote: "In many of the patients, expressive speech was reported to be more severely affected than receptive function"
Location in Paper: Page 567
Feature: Head shape and ear anomalies
Frequency: consistent findings in most patients
Direct Quote: "consistent findings in most of the patients were an abnormal head shape and low-set, posteriorly rotated, and abnormally shaped ears"
Location in Paper: Page 567
Feature: Short stature
Frequency: majority of patients
Direct Quote: "The majority of patients had short stature of postnatal onset or body height within the lower normal range"
Location in Paper: Page 567
Feature: Autism spectrum disorder or traits
Frequency: reported in five patients
Direct Quote: "either autism spectrum disorder or autistic traits were reported in five patients with larger genomic or intragenic deletions"
Location in Paper: Page 567
Feature: Low-set and/or posteriorly rotated ears
Frequency: 4/4 patients
Direct Quote: "Low-set and/or posteriorly rotated ears 4/4"
Location in Paper: Table 1
Feature: Abnormal shape of head
Frequency: 3/4 patients with plagiocephaly
Direct Quote: "Abnormal shape of head 3/4 with plagiocephaly"
Location in Paper: Table 1
Feature: High palate
Frequency: 2/4 patients with palatal anomalies
Direct Quote: "Cleft palate 0/4 with cleft palate and 2/4 with palatal anomalies"
Location in Paper: Table 1
Feature: Bulbous nasal tip
Frequency: 3/3 patients
Direct Quote: "Bulbous nasal tip 3/3"
Location in Paper: Table 1
Functional Studies
Study Type: Transcript analysis
Methodology: RT-PCR on RNA from peripheral blood leukocytes to examine exon skipping
Conclusions: The synonymous variant in the last base pair of exon 17 induced exon skipping of exon 17 and is predicted to cause a frameshift resulting in a premature translational termination
Direct Quote: "Synonymous variant in the last codon of exon 17 induces exon skipping of exon 17 in patient 7...is predicted to result in a frameshift and premature stop codon after 76 amino acids (p.Arg1338Argfs*76)."
Location in Paper: Figure 2B and 2C
Study Type: Clinical observation
Methodology: Comparison of phenotype in patients with point mutations and large genomic deletions
Conclusions: Phenotype overlaps in patients with point mutations and large genomic deletions, confirming haploinsufficiency of ARID1B is responsible for most symptoms
Direct Quote: "With regard to these aspects, the phenotype of patients with point mutations overlaps with that observed in patients with large genomic deletions on chromosome 6q or intragenic deletions within ARID1B"
Location in Paper: Page 567