Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report
Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an in...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-05-01
|
| Series: | Journal of Personalized Medicine |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2075-4426/12/6/886 |
| _version_ | 1797485563308146688 |
|---|---|
| author | Jeffery L. Clothier Amy N. Grooms Patricia A. Porter-Gill Pritmohinder S. Gill G. Bradley Schaefer |
| author_facet | Jeffery L. Clothier Amy N. Grooms Patricia A. Porter-Gill Pritmohinder S. Gill G. Bradley Schaefer |
| author_sort | Jeffery L. Clothier |
| collection | DOAJ |
| description | Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, <i>DCAF1</i>. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the <i>DCAF1</i> gene. In silico analysis supports a deleterious effect on protein structure/function. <i>DCAF1</i> participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the <i>BRWD3</i> gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the <i>de novo DCAF1</i> variant may be a newly identified molecular cause of autism and intellectual disability. |
| first_indexed | 2024-03-09T23:20:36Z |
| format | Article |
| id | doaj.art-80440db301d746b1b4dd925afa825926 |
| institution | Directory Open Access Journal |
| issn | 2075-4426 |
| language | English |
| last_indexed | 2024-03-09T23:20:36Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Journal of Personalized Medicine |
| spelling | doaj.art-80440db301d746b1b4dd925afa8259262023-11-23T17:27:06ZengMDPI AGJournal of Personalized Medicine2075-44262022-05-0112688610.3390/jpm12060886Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case ReportJeffery L. Clothier0Amy N. Grooms1Patricia A. Porter-Gill2Pritmohinder S. Gill3G. Bradley Schaefer4Psychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USAPsychiatric Research Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USAArkansas Children’s Research Institute, Little Rock, AR 72202, USADepartment of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USAGenetics and Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR 72202, USAAutism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, <i>DCAF1</i>. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the <i>DCAF1</i> gene. In silico analysis supports a deleterious effect on protein structure/function. <i>DCAF1</i> participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the <i>BRWD3</i> gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the <i>de novo DCAF1</i> variant may be a newly identified molecular cause of autism and intellectual disability.https://www.mdpi.com/2075-4426/12/6/886autism spectrum disorders (ASDs)exome sequencingmethylationDCAF1 |
| spellingShingle | Jeffery L. Clothier Amy N. Grooms Patricia A. Porter-Gill Pritmohinder S. Gill G. Bradley Schaefer Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report Journal of Personalized Medicine autism spectrum disorders (ASDs) exome sequencing methylation DCAF1 |
| title | Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report |
| title_full | Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report |
| title_fullStr | Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report |
| title_full_unstemmed | Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report |
| title_short | Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report |
| title_sort | identification of dcaf1 by clinical exome sequencing and methylation analysis as a candidate gene for autism and intellectual disability a case report |
| topic | autism spectrum disorders (ASDs) exome sequencing methylation DCAF1 |
| url | https://www.mdpi.com/2075-4426/12/6/886 |
| work_keys_str_mv | AT jefferylclothier identificationofdcaf1byclinicalexomesequencingandmethylationanalysisasacandidategeneforautismandintellectualdisabilityacasereport AT amyngrooms identificationofdcaf1byclinicalexomesequencingandmethylationanalysisasacandidategeneforautismandintellectualdisabilityacasereport AT patriciaaportergill identificationofdcaf1byclinicalexomesequencingandmethylationanalysisasacandidategeneforautismandintellectualdisabilityacasereport AT pritmohindersgill identificationofdcaf1byclinicalexomesequencingandmethylationanalysisasacandidategeneforautismandintellectualdisabilityacasereport AT gbradleyschaefer identificationofdcaf1byclinicalexomesequencingandmethylationanalysisasacandidategeneforautismandintellectualdisabilityacasereport |