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A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism.

Kumar RA, Sudi J, Babatz TD, Brune CW, Oswald D, Yen M, Nowak NJ, Cook EH, Christian SL, Dobyns WB - J. Med. Genet. (2009)

Bottom Line: A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3.To search for submicroscopic chromosomal rearrangements in the child, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (BAC) array and the Illumina 610-Quad BeadChip microarray.A de novo 3.3 Mb deletion containing approximately 43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH).

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago,Chicago, Illinois 60637, USA.

ABSTRACT

Background: A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. The hypothesis is tested that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders.

Methods: To search for submicroscopic chromosomal rearrangements in the child, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (BAC) array and the Illumina 610-Quad BeadChip microarray. Ingenuity pathway analysis (IPA) was used to construct functional biological networks to identify candidate autism genes. To identify putative functional variants in candidate genes, mutation screening was performed using polymerase chain reaction (PCR) based Sanger sequencing in 512 unrelated autism patients and 462 control subjects.

Results: A de novo 3.3 Mb deletion containing approximately 43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified Regulating Synaptic Membrane Exocytosis 3 (RIMS3) as the most promising autism candidate gene. Mutation screening of this gene in autism patients identified five inherited coding variants, including one (p.E177A) that segregated with the autism phenotype in a sibship, was predicted to be deleterious, and was absent in 1161 controls.

Conclusions: This case report and mutation screening data suggest that RIMS3 is an autism causative or contributory gene. Functional studies of RIMS3 variants such as p.E177A should provide additional insight into the role of synaptic proteins in the pathophysiology of autism.

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Mutation analysis of RIMS3 identifies two missense variants that segregate with autism and autism related phenotypes. (A) The pedigree for family AU0247 shows that the p.E177A missense variant is present in a patient with autism (AU0247-03), in a sibling with Not Quite Autism (NQA) (AU0247-04), and in the mother who presents with psychiatric symptoms. Chromatograms indicate the presence of the A/C substitution. The SIFT program predicted the p.E177A substitution to be deleterious. (B) The pedigree for family AU0125 shows that the p.M260V missense variant is present in two siblings with autism (AU0125-03 and AU0125-04) as well as in the father who presents with psychiatric symptoms, including obsessive–compulsive disorder (OCD). Chromatograms indicate the presence of the A/G substitution. The variant is not predicted to affect protein function.
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fig3: Mutation analysis of RIMS3 identifies two missense variants that segregate with autism and autism related phenotypes. (A) The pedigree for family AU0247 shows that the p.E177A missense variant is present in a patient with autism (AU0247-03), in a sibling with Not Quite Autism (NQA) (AU0247-04), and in the mother who presents with psychiatric symptoms. Chromatograms indicate the presence of the A/C substitution. The SIFT program predicted the p.E177A substitution to be deleterious. (B) The pedigree for family AU0125 shows that the p.M260V missense variant is present in two siblings with autism (AU0125-03 and AU0125-04) as well as in the father who presents with psychiatric symptoms, including obsessive–compulsive disorder (OCD). Chromatograms indicate the presence of the A/G substitution. The variant is not predicted to affect protein function.

Mentions: Sequencing of parental DNA indicated that all five coding variants were inherited. We performed segregation analysis in families by sequencing each variant in affected and/or unaffected siblings. In two multiplex families (AU0247 and AU0125, figure 3), the variant segregated with the autism phenotype in siblings. In family AU0247, the maternally inherited p.E177A variant first identified in patient HI0515 was also present in a sibling with NQA, but absent in 1161 control subjects. We reviewed available phenotype data on the carrier mother, who had depression and symptoms of bipolar disorder and anxiety. She also had a repaired cleft palate and had received speech language therapy (the father had received speech language therapy as well). The heterozygous sib had a ventricular septal defect that closed spontaneously by 1 year and diastasis recti. CNV analysis on this family provided on the AGRE website ruled out known CNVs associated with autism, including microdeletion of 22q11.


A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism.

Kumar RA, Sudi J, Babatz TD, Brune CW, Oswald D, Yen M, Nowak NJ, Cook EH, Christian SL, Dobyns WB - J. Med. Genet. (2009)

Mutation analysis of RIMS3 identifies two missense variants that segregate with autism and autism related phenotypes. (A) The pedigree for family AU0247 shows that the p.E177A missense variant is present in a patient with autism (AU0247-03), in a sibling with Not Quite Autism (NQA) (AU0247-04), and in the mother who presents with psychiatric symptoms. Chromatograms indicate the presence of the A/C substitution. The SIFT program predicted the p.E177A substitution to be deleterious. (B) The pedigree for family AU0125 shows that the p.M260V missense variant is present in two siblings with autism (AU0125-03 and AU0125-04) as well as in the father who presents with psychiatric symptoms, including obsessive–compulsive disorder (OCD). Chromatograms indicate the presence of the A/G substitution. The variant is not predicted to affect protein function.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2921284&req=5

fig3: Mutation analysis of RIMS3 identifies two missense variants that segregate with autism and autism related phenotypes. (A) The pedigree for family AU0247 shows that the p.E177A missense variant is present in a patient with autism (AU0247-03), in a sibling with Not Quite Autism (NQA) (AU0247-04), and in the mother who presents with psychiatric symptoms. Chromatograms indicate the presence of the A/C substitution. The SIFT program predicted the p.E177A substitution to be deleterious. (B) The pedigree for family AU0125 shows that the p.M260V missense variant is present in two siblings with autism (AU0125-03 and AU0125-04) as well as in the father who presents with psychiatric symptoms, including obsessive–compulsive disorder (OCD). Chromatograms indicate the presence of the A/G substitution. The variant is not predicted to affect protein function.
Mentions: Sequencing of parental DNA indicated that all five coding variants were inherited. We performed segregation analysis in families by sequencing each variant in affected and/or unaffected siblings. In two multiplex families (AU0247 and AU0125, figure 3), the variant segregated with the autism phenotype in siblings. In family AU0247, the maternally inherited p.E177A variant first identified in patient HI0515 was also present in a sibling with NQA, but absent in 1161 control subjects. We reviewed available phenotype data on the carrier mother, who had depression and symptoms of bipolar disorder and anxiety. She also had a repaired cleft palate and had received speech language therapy (the father had received speech language therapy as well). The heterozygous sib had a ventricular septal defect that closed spontaneously by 1 year and diastasis recti. CNV analysis on this family provided on the AGRE website ruled out known CNVs associated with autism, including microdeletion of 22q11.

Bottom Line: A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3.To search for submicroscopic chromosomal rearrangements in the child, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (BAC) array and the Illumina 610-Quad BeadChip microarray.A de novo 3.3 Mb deletion containing approximately 43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH).

View Article: PubMed Central - PubMed

Affiliation: Department of Human Genetics, University of Chicago,Chicago, Illinois 60637, USA.

ABSTRACT

Background: A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. The hypothesis is tested that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders.

Methods: To search for submicroscopic chromosomal rearrangements in the child, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (BAC) array and the Illumina 610-Quad BeadChip microarray. Ingenuity pathway analysis (IPA) was used to construct functional biological networks to identify candidate autism genes. To identify putative functional variants in candidate genes, mutation screening was performed using polymerase chain reaction (PCR) based Sanger sequencing in 512 unrelated autism patients and 462 control subjects.

Results: A de novo 3.3 Mb deletion containing approximately 43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified Regulating Synaptic Membrane Exocytosis 3 (RIMS3) as the most promising autism candidate gene. Mutation screening of this gene in autism patients identified five inherited coding variants, including one (p.E177A) that segregated with the autism phenotype in a sibship, was predicted to be deleterious, and was absent in 1161 controls.

Conclusions: This case report and mutation screening data suggest that RIMS3 is an autism causative or contributory gene. Functional studies of RIMS3 variants such as p.E177A should provide additional insight into the role of synaptic proteins in the pathophysiology of autism.

Show MeSH
Related in: MedlinePlus