The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions

Moreno-De-Luca, Andrés; Evans, David W.; Boomer, K. B.; Hanson, Ellen; Bernier, Raphael; Goin‐Kochel, Robin P.; Myers, Scott M.; Challman, Thomas D.; Moreno‐De‐Luca, Daniel; Slane, Mylissa M.; Hare, Abby; Chung, Wendy K.; Spiro, John E.; Faucett, W. Andrew; Martin, Christa Lese; Ledbetter, David H.

doi:10.1001/jamapsychiatry.2014.2147

Cited by 119 publications

(147 citation statements)

References 35 publications

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“…This burden is even higher among probands with strong family history of neurodevelopmental or psychiatric disease, explaining their more severe clinical manifestation compared to probands with mild or negative family history of disease. These results provide an interpretation for the previously reported role of parental profiles towards the final clinical outcome in probands carrying inherited rare CNVs 89,90 , and highlight the importance of interrogating the family history of psychiatric and neurodevelopmental disease for more accurate diagnostic assessment of the affected children.…”

Section: Cc-by-nd 40 International License Peer-reviewed) Is the Autsupporting

confidence: 69%

“…In fact, the cognitive and social outcomes in probands with de novo 16p11.2 BP4-BP5 deletion or 22q11.2 deletion have been reported to positively correlate with the cognitive and social skills of their parents 89,90 . However, the genetic basis of such background effects has not been sufficiently studied.…”

Section: Secondary Variants Account For Disease Expressivity In 16p12mentioning

confidence: 99%

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

Pizzo

Jensen

Polyak

et al. 2018

Preprint

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Rare copy-number variants (CNVs) and gene-disruptive mutations associated with neurodevelopmental disease are characterized by phenotypic heterogeneity. When affected children inherit these mutations, they usually present more severe features than carrier parents, leading to challenges in diagnosis and management. To understand how the genetic background modulates phenotypes of these variants, we analyzed clinical and exome-sequencing data from 757 probands and 233 parents and siblings who carry disease-associated mutations. We found that the number of rare pathogenic secondary mutations in developmental genes (second-hits) modulates the expressivity of disease in probands with 16p12.1 deletion (n=26, p=0.014) and in autism probands with gene-disruptive mutations (n=184, p=0.031) when compared to their carrier family members. Probands with 16p12.1 deletion and a strong family history of neuropsychiatric disease were more likely to manifest multiple and more severe clinical features (p=0.035) and carry a higher burden of second-hits compared to those with mild or no family history (p=0.001). The amount of secondary variants determined the severity of cognitive impairment in 432 probands carrying pathogenic rare CNVs or de novo mutations in disease genes and negatively correlated with head size in 84 probands with 16p11.2 deletion, suggesting an effect of the genetic background across multiple phenotypic domains. These second-hits involved known disease genes, such as SETD5, AUTS2, and NRXN1, and novel candidate modifiers, such as CDH23, RYR3, and DNAH3, affecting core developmental processes. Our findings suggest that in the era of personalized medicine, accurate diagnosis will require complete evaluation of the genetic background even after a candidate gene mutation is identified.

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Section: Cc-by-nd 40 International License Peer-reviewed) Is the Autsupporting

confidence: 69%

Section: Secondary Variants Account For Disease Expressivity In 16p12mentioning

confidence: 99%

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

Pizzo

Jensen

Polyak

et al. 2018

Preprint

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“…There is a similar 10-fold enrichment of deletions and duplications in ASD cohorts (11,12), and both CNVs have large effects on IQ (Z scores of 1.5 and 0.8, respectively) and Social Responsiveness Scale (SRS) (Z scores of 1 and 2, respectively) (10,(13)(14)(15). However, there are phenotypic differences between both CNVs: the 10-fold enrichment in schizophrenia cohorts (16,17) is only observed for duplications, and only deletions affect measures of language by 1.5 Z scores (18).…”

mentioning

confidence: 87%

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

Martin

Rodríguez-Herreros

Nielsen

et al. 2018

Biological Psychiatry

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BACKGROUND: 16p11.2 breakpoint 4 to 5 copy number variants (CNVs) increase the risk for developing autism spectrum disorder, schizophrenia, and language and cognitive impairment. In this multisite study, we aimed to quantify the effect of 16p11.2 CNVs on brain structure. METHODS: Using voxel-and surface-based brain morphometric methods, we analyzed structural magnetic resonance imaging collected at seven sites from 78 individuals with a deletion, 71 individuals with a duplication, and 212 individuals without a CNV. RESULTS: Beyond the 16p11.2-related mirror effect on global brain morphometry, we observe regional mirror differences in the insula (deletion . control . duplication). Other regions are preferentially affected by either the deletion or the duplication: the calcarine cortex and transverse temporal gyrus (deletion . control; Cohen's d . 1), the superior and middle temporal gyri (deletion , control; Cohen's d , 21), and the caudate and hippocampus (control . duplication; 20.5 . Cohen's d . 21). Measures of cognition, language, and social responsiveness and the presence of psychiatric diagnoses do not influence these results. CONCLUSIONS: The global and regional effects on brain morphometry due to 16p11.2 CNVs generalize across site, computational method, age, and sex. Effect sizes on neuroimaging and cognitive traits are comparable. Findings partially overlap with results of meta-analyses performed across psychiatric disorders. However, the lack of correlation between morphometric and clinical measures suggests that CNV-associated brain changes contribute to clinical manifestations but require additional factors for the development of the disorder. These findings highlight the power of genetic risk factors as a complement to studying groups defined by behavioral criteria. Autism spectrum disorder (ASD) and related neurodevelopmental disorders are defined behaviorally and characterized by a significant clinical and etiologic heterogeneity. As a consequence, investigating ASD under the assumption of an underlying homogeneous condition has resulted in controversial findings in the field of neuroimaging (1). Increased brain growth early in development (2-4) and alterations of many regional brain volumes (5) have been implicated in ASD, but results have proven difficult to replicate (1,(6)(7)(8).To mitigate some of these issues, cohorts of individuals with shared genetic risk factors have been assembled to minimize the noise introduced by etiologic and biological heterogeneity (9). Such a "genetic-first" study design provides the opportunity to investigate a given neurodevelopmental risk (and associated mechanism) shared by individuals who carry the same genetic etiology irrespective of the psychiatric diagnosis.Copy number variants (CNVs) at the 16p11.2 (breakpoints 4-5, 29.6-30.2 Mb-hg19) (10) are among the most frequent risk factors for neurodevelopmental and psychiatric conditions.

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“…Deficits in contextual conditioning and passive avoidance were reported for the Mills line (Tian et al 2015). These findings, along with the prevalence and severity of intellectual disabilities in 16p11.2 deletion syndrome (Moreno- De-Luca et al 2015), prompted the current study that evaluated the Dolmetsch 16p11.2+/2 line in a broader range of cognitive assays.…”

mentioning

confidence: 94%

“…16p11.2 deletion syndrome presents with a range of mild-to-severe cognitive impairments, with IQ scores averaging 2 SDs lower than controls, and a confirmed diagnosis of autism in 15% of affected individuals (Hanson et al 2010Zufferey et al 2012;Qureshi et al 2014). 16p11.2 deletion carriers are affected in multiple cognitive domains, including verbal and nonverbal IQ, cognitive flexibility, and spatial working memory (Hanson et al 2010Stefansson et al 2014;Moreno-De-Luca et al 2015). 16p11.2 deletion syndrome is also associated with speech disorders, developmental delays, psychiatric disorders, and physical abnormalities (Rosenberg et al 2006;Bijlsma et al 2009;Guilmatre et al 2009;Fernandez et al 2010;Hanson et al 2010;Puvabanditsin et al 2010;Steinberg et al 2014;Duyzend and Eichler 2015;Hanson et al 2015).…”

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confidence: 99%

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

et al. 2015

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Chromosomal 16p11.2 deletion syndrome frequently presents with intellectual disabilities, speech delays, and autism. Here we investigated the Dolmetsch line of 16p11.2 heterozygous (+/2) mice on a range of cognitive tasks with different neuroanatomical substrates. Robust novel object recognition deficits were replicated in two cohorts of 16p11.2+/2 mice, confirming previous findings. A similarly robust deficit in object location memory was discovered in +/2, indicating impaired spatial novelty recognition. Generalizability of novelty recognition deficits in +/2 mice extended to preference for social novelty. Robust learning deficits and cognitive inflexibility were detected using Bussey-Saksida touchscreen operant chambers. During acquisition of pairwise visual discrimination, +/2 mice required significantly more training trials to reach criterion than wild-type littermates (+/+), and made more errors and correction errors than +/+. In the reversal phase, all +/+ reached criterion, whereas most +/2 failed to reach criterion by the 30-d cutoff. Contextual and cued fear conditioning were normal in +/2. These cognitive phenotypes may be relevant to some aspects of cognitive impairments in humans with 16p11.2 deletion, and support the use of 16p11.2+/2 mice as a model system for discovering treatments for cognitive impairments in 16p11.2 deletion syndrome.Recurrent heterozygous deletions of a 600-kb segment on human chromosome 16 is found in 0.4% of individuals with intellectual disability (Bijlsma et al. 2009;Hanson et al. 2015) and 0.6% of individuals with autism (Marshall et al. 2008;Weiss et al. 2008;Walsh and Bracken 2011). 16p11.2 deletion syndrome presents with a range of mild-to-severe cognitive impairments, with IQ scores averaging 2 SDs lower than controls, and a confirmed diagnosis of autism in 15% of affected individuals (Hanson et al.

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The Role of Parental Cognitive, Behavioral, and Motor Profiles in Clinical Variability in Individuals With Chromosome 16p11.2 Deletions

Cited by 119 publications

References 35 publications

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

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

Quantifying the Effects of 16p11.2 Copy Number Variants on Brain Structure: A Multisite Genetic-First Study

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

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