Limits...
Chromosomal Microarray Analysis in Clinical Evaluation of Neurodevelopmental Disorders-Reporting a Novel Deletion of SETDB1 and Illustration of Counseling Challenge

View Article: PubMed Central - PubMed

ABSTRACT

Background: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is well supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in the clinic.

Methods: We analyzed the findings of CNV studies from a cohort referred for clinical genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID).

Results: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found 7 cases with more than 2 CNV and 2 with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with typical ASD and ID.

Conclusions: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNVs. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.

No MeSH data available.


The summary of genetic evaluation of 165 cases with ASD, ID, DD in genetic clinic
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC5382808&req=5

Figure 1: The summary of genetic evaluation of 165 cases with ASD, ID, DD in genetic clinic

Mentions: CMA was performed in 115 out 165 cases (69.7%) referred for genetics evaluation of ASD/DD/ID (Figure 1). The reasons varied for why CMA was not performed for 50 of the cases. The lack of insurance coverage and parental consent were two major issues encountered. CMA was performed in 83 males and 32 females with male to female ratio of 2.6 to 1. The mean age at the time of evaluation was 5.7 years, ranging from 18 months to 15.1 years with a 95% confidence interval of 5-6.3 years. There were 66 cases (66/115, 57.4 %) with a confirmed primary diagnosis of ASD and 49 cases (49/115, 42.6%) with the primary diagnosis of DD or ID at the time referred for clinical genetics evaluation. The clinical evidence to support these diagnoses varied. DSM-IV, DSM-5, ADOS, and ADI-R were used to support the diagnosis of ASD. IQ and DQ scores were used for diagnosis of ID and DD respectively. The referral providers include general pediatrician (33%), developmental pediatrician (41%), neurology (24.8%), others including child psychiatry and clinical psychology (1.2%).


Chromosomal Microarray Analysis in Clinical Evaluation of Neurodevelopmental Disorders-Reporting a Novel Deletion of SETDB1 and Illustration of Counseling Challenge
The summary of genetic evaluation of 165 cases with ASD, ID, DD in genetic clinic
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC5382808&req=5

Figure 1: The summary of genetic evaluation of 165 cases with ASD, ID, DD in genetic clinic
Mentions: CMA was performed in 115 out 165 cases (69.7%) referred for genetics evaluation of ASD/DD/ID (Figure 1). The reasons varied for why CMA was not performed for 50 of the cases. The lack of insurance coverage and parental consent were two major issues encountered. CMA was performed in 83 males and 32 females with male to female ratio of 2.6 to 1. The mean age at the time of evaluation was 5.7 years, ranging from 18 months to 15.1 years with a 95% confidence interval of 5-6.3 years. There were 66 cases (66/115, 57.4 %) with a confirmed primary diagnosis of ASD and 49 cases (49/115, 42.6%) with the primary diagnosis of DD or ID at the time referred for clinical genetics evaluation. The clinical evidence to support these diagnoses varied. DSM-IV, DSM-5, ADOS, and ADI-R were used to support the diagnosis of ASD. IQ and DQ scores were used for diagnosis of ID and DD respectively. The referral providers include general pediatrician (33%), developmental pediatrician (41%), neurology (24.8%), others including child psychiatry and clinical psychology (1.2%).

View Article: PubMed Central - PubMed

ABSTRACT

Background: The pathogenicity of copy number variations (CNV) in neurodevelopmental disorders is well supported by research literature. However, few studies have evaluated the utility and counseling challenges of CNV analysis in the clinic.

Methods: We analyzed the findings of CNV studies from a cohort referred for clinical genetics evaluation of autism spectrum disorders (ASD), developmental disability (DD), and intellectual disability (ID).

Results: Twenty-two CNV in 21 out of 115 probands are considered to be pathogenic (18.3%). Five CNV are likely pathogenic and 22 CNV are variants of unknown significance (VUS). We have found 7 cases with more than 2 CNV and 2 with a complex rearrangement of the 22q13.3 Phelan-McDermid syndrome region. We identified a new and de novo 1q21.3 deletion that encompasses SETDB1, a gene encoding methylates histone H3 on lysine-9 (H3K9) methyltransferase, in a case with typical ASD and ID.

Conclusions: We provide evidence to support the value of CNV analysis in etiological evaluation of neurodevelopmental disorders. However, interpretation of the clinical significance and counseling families are still challenging because of the variable penetrance and pleotropic expressivity of CNVs. In addition, the identification of a 1q21.3 deletion encompassing SETDB1 provides further support for the role of chromatin modifiers in the etiology of ASD.

No MeSH data available.