Phenotypic Heterogeneity of Genomic Disorders and Rare Copy-Number Variants

Abstract

BACKGROUND Some copy-number variants are associated with genomic disorders with extreme phenotypic heterogeneity. The cause of this variation is unknown, which presents challenges in genetic diagnosis, counseling, and management. METHODS We analyzed the genomes of 2312 children known to carry a copy-number variant associated with intellectual disability and congenital abnormalities, using array comparative genomic hybridization. RESULTS Among the affected children, 10.1% carried a second large copy-number variant in addition to the primary genetic lesion. We identified seven genomic disorders, each defined by a specific copy-number variant, in which the affected children were more likely to carry multiple copy-number variants than were controls. We found that syndromic disorders could be distinguished from those with extreme phenotypic heterogeneity on the basis of the total number of copy-number variants and whether the variants are inherited or de novo. Children who carried two large copy-number variants of unknown clinical significance were eight times as likely to have developmental delay as were controls (odds ratio, 8.16; 95% confidence interval, 5.33 to 13.07; P = 2.11×10−38). Among affected children, inherited copy-number variants tended to co-occur with a second-site large copy-number variant (Spearman correlation coefficient, 0.66; P<0.001). Boys were more likely than girls to have disorders of phenotypic heterogeneity (P<0.001), and mothers were more likely than fathers to transmit second-site copy-number variants to their offspring (P = 0.02). CONCLUSIONS Multiple, large copy-number variants, including those of unknown pathogenic significance, compound to result in a severe clinical presentation, and secondary copy-number variants are preferentially transmitted from maternal carriers. (Funded by the Simons Foundation Autism Research Initiative and the National Institutes of Health.)

Interstitial deletion of 3p22.3p22.2 encompassing ARPP21 and CLASP2 is a potential pathogenic factor for a syndromic form of intellectual disability: A co‐morbidity model with additional copy number variations in a large family

“…Our conclusions are in agreement with the observations made by Girirajan et al [2012], showing that multiple CNVs, often inherited and with unknown clinical significance, can account for phenotypic variability of well defined syndromic forms of ID associated with primary large chromosome rearrangements.…”

“…In addition, multiple structurally unrelated copy number variants, including those of unknown pathogenic significance, can be found in single patients and they can account for phenotypic variability of major rearrangements, according to a second-side, or multiple-side, model of disease. The combination of different variants was recently reported as the underlying mechanism for the phenotypic heterogeneity of some clinically well defined conditions associated with a primary large CNV, and even multiple CNVs of small size were considered to cause a cumulative burden of genomic mutations leading to ID [Girirajan et al, 2012].…”

Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example

“…Second alterations were also found in 25% (17/69) of del15q11.2 patients by Burnside et al In one of the patients the second CNV was confirmed de novo [Burnside et al, 2011]. In the study of Girirajan et al [2012] the del15q11.2 was the most likely genomic disorder where additional large variants occurred in affected children in comparison to controls (P ¼ 0.00093).…”

“…Such a model of "second hits" was proposed by Girirajan et al, who described that a quarter of individuals with del16p12.1 carried a second genomic alteration [Girirajan et al, 2010;Veltman and Brunner, 2010]. Of interest, del15q11.2 has a low penetrance yet a high number of second hits [Girirajan et al, 2012;Rosenfeld et al, 2012].…”

“…Also there is no parent of origin effect [Girirajan et al, 2012]. Of interest, Girirajan et al, found a significant shift towards maternal transmission of "second hit" variants instead.…”