Copy number variants (CNVs) analysis in a deeply phenotyped cohort of individuals with intellectual disability (ID)

Abstract

BackgroundDNA copy number variants (CNVs) are found in 15% of subjects with ID but their association with phenotypic abnormalities has been predominantly studied in smaller cohorts of subjects with detailed yet non-systematically categorized phenotypes, or larger cohorts (thousands of cases) with smaller number of generalized phenotypes.MethodsWe evaluated the association of de novo, familial and common CNVs detected in 78 ID subjects with phenotypic abnormalities classified using the Winter-Baraitser Dysmorphology Database (WBDD) (formerly the London Dysmorphology Database). Terminology for 34 primary (coarse) and 169 secondary (fine) phenotype features were used to categorize the abnormal phenotypes and determine the prevalence of each phenotype in patients grouped by the type of CNV they had.ResultsIn our cohort more than 50% of cases had abnormalities in primary categories related to head (cranium, forehead, ears, eye globes, eye associated structures, nose) as well as hands and feet. The median number of primary and secondary abnormalities was 12 and 18 per subject, respectively, indicating that the cohort consisted of subjects with a high number of phenotypic abnormalities (median De Vries score for the cohort was 5). The prevalence of each phenotypic abnormality was comparable in patients with de novo or familial CNVs in comparison to those with only common CNVs, although a trend for increased frequency of cranial and forehead abnormalities was noted in subjects with rare de novo and familial CNVs. Two clusters of subjects were identified based on the prevalence of each fine phenotypic feature, with an average of 28.3 and 13.5 abnormal phenotypes/subject in the two clusters respectively (P < 0.05).ConclusionsOur study is a rare example of using standardized, deep morphologic phenotype clustering with phenotype/CNV correlation in a cohort of subjects with ID. The composition of the cohort inevitably influences the phenotype/genotype association, and our studies show that the influence of the de novo CNVs on the phenotype is less obvious in cohorts consisting of subjects with a high number of phenotypic abnormalities. The outcome of phenotype/genotype analysis also depends on the choice of phenotypes assessed and standardized phenotyping is required to minimize variability.

Xp11.2 microduplications including IQSEC2, TSPYL2 and KDM5C genes in patients with neurodevelopmental disorders

“…For example, Cooper et al 5 show that 25.7% of ID/DD children harbor an event of 4400 kb compared with 11.5% of controls, suggesting that an estimated 14.2% of ID/DD is due to CNV 4400 kb. Similarly, large CNVs (4400 kb) are estimated to be causative between 15 and 20% of cases with ID, 2,[5][6][7] and as high as 25% of cases with ID and multiple congenital abnormalities. 8 With increasingly large patient cohorts being harnessed, morbidity mapping of CNVs has identified a noticeable burden of smaller CNVs.…”

Interactive Exploration, Analysis, and Visualization of Complex Phenome-Genome Datasets with ASPIREdb

“…Qiao et al. () identified de novo, familial, and common CNVs in 78 subjects with ID using array‐CGH [Qiao et al., ], and present a number of burden and phenotype association analyses of the data. As we show here, most of the analyses presented by Qiao et al.…”

“…All other types of burden analyses, such as comparing variant effect type between subject groups, use the Chi‐square test to test for significant association between categorical variables [Yates, ]. These statistical tests are regularly used for burden analysis of mutation data [Iossifov et al., ; Qiao et al., ]. Hierarchical clustering, a commonly used data clustering method [Kaufman and Rousseeuw, ], is performed using the average linkage algorithm in the matrix2viz package.…”

Rare variants in the genetic background modulate the expressivity of neurodevelopmental disorders

“…http://dx.doi.org/10.1101/257758 doi: bioRxiv preprint first posted online Feb. 1, 2018; We used a modified de Vries scoring system for quantifying the number and severity of phenotypic abnormalities in affected children, which allows for a uniform assessment of developmental phenotypes from clinical records (Table S1) 6,37-40 . Originally used for characterizing phenotypes associated with subtelomeric and balanced chromosomal rearrangements, this method, used reliably in several studies, allows for a uniform assessment of developmental phenotypes from clinical records [38][39][40] . Using keyword searches for more than 50…”