Chromosomal microarray analysis in developmental delay and intellectual disability with comorbid conditions

Abstract

BackgroundDevelopmental delay (DD) and intellectual disability (ID) are frequently associated with a broad spectrum of additional phenotypes. Chromosomal microarray analysis (CMA) has been recommended as a first-tier test for DD/ID in general, whereas the diagnostic yield differs significantly among DD/ID patients with different comorbid conditions.MethodsTo investigate the genotype-phenotype correlation, we examined the characteristics of identified pathogenic copy number variations (pCNVs) and compared the diagnostic yields among patient subgroups with different co-occurring conditions.ResultsThis study is a retrospective review of CMA results generated from a mixed cohort of 710 Chinese patients with DD/ID. A total of 247 pCNVs were identified in 201 patients (28%). A large portion of these pCNVs were copy number losses, and the size of copy number losses was generally smaller than gains. The diagnostic yields were significantly higher in subgroups with co-occurring congenital heart defects (55%), facial dysmorphism (39%), microcephaly (34%) or hypotonia (35%), whereas co-occurring conditions of skeletal malformation (26%), brain malformation (24%) or epilepsy (24%) did not alter the yield. In addition, the diagnostic yield nominally correlated with ID severity.ConclusionVaried yields exist in DD/ID patients with different phenotypic presentation. The presence of comorbid conditions can be among factors to consider when planning CMA.Electronic supplementary materialThe online version of this article (10.1186/s12920-018-0368-4) contains supplementary material, which is available to authorized users.

Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder

“…Besides the potential bias in patient origin and CNV analysis, the difference of diagnostic yields could be attributed to the presence of comorbidity in the cohort. When CMA was performed in ASD patients with comorbid intellectual disability, microcephaly or other congenital anomalies in our center, the yield increased to 15% (Fan et al, 2018). Affected individuals in this study were relatively “pure”–over 95% of the ASD cohort were free of major systemic anomalies.…”

The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing

“…Chromosome microarray (CMA) has been recommended as the first-tier diagnostic test for ID, and so, CNVs might have the highest positive rate with regard to ID [14,15]. Most of the previous studies conducted on the investigation of genetic etiologies of ID were based on CMA [16][17][18]. According to a previous study, chromosome abnormality and genome-wide microdeletion or microduplication accounted for 10-20% of ID [3,19].…”

“…The genetic research studies on ID of Chinese populations were less. And majority of these studies focused on CNVs through CMA [18]. Investigating the distribution of CNVs, proportion of single gene defects, and evaluation of the effects of different diagnostic platforms in Chinese ID populations provided the proof for selecting appropriate clinical genetic diagnostic method in Chinese ID populations.…”

The diagnostic yield of intellectual disability: Combined whole genome low-coverage sequencing and medical exome sequencing

“…Chromosome microarray (CMA) has been recommended as the first-tier diagnostic test for ID and so, CNVs may have the highest positive rate with regard to ID 14,15 . Most of the previous studies conducted on genetic etiology of ID were based on CMA [16][17][18] . According to a previous study, chromosome abnormality and genome-wide microdeletion or microduplication accounted for 10%-20% of ID 3,19 .…”

“…The ID genetic research studies on Chinese population were less. And majority of these studies focused on CNVs through CMA 18 . Investigating the distribution of CNVs, proportion of single gene defects, and evaluation of effects of different diagnostic platforms in Chinese ID populations provided the proof for selecting appropriate method of clinical genetic diagnosis in Chinese ID populations.…”