Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV

Duyzend, Michael H.; Nuttle, Xander; Coe, Bradley P.; Baker, Carl; Nickerson, Deborah A.; Bernier, Raphael; Eichler, Evan E.

doi:10.1016/j.ajhg.2015.11.017

Cited by 54 publications

(64 citation statements)

References 54 publications

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“…The maternal bias we found in duplications did not seem in line with this theory. For further details, we consulted previous publications and found there were still similar findings with a maternal bias for duplications in some specific micro-duplication syndromes like 15q11-q13 duplication syndrome16 and duplications in 16p11.219. Furthermore, in our study, we also found difference in the degree of maternal bias between heterologous and homologous duplications, with more maternal CNVs in the heterologous duplications (Table 2).…”

Section: Discussionsupporting

confidence: 87%

A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies

Deng

Xia

et al. 2017

Sci Rep

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Copy number variation (CNV) is of great significance in human evolution and disorders. Through tracing the parent-of-origin of de novo pathogenic CNVs, we are expected to investigate the relative contributions of germline genomic stability on reproductive health. In our study, short tandem repeat (STR) and single nucleotide polymorphism (SNP) were used to determine the parent-of-origin of 87 de novo pathogenic CNVs found in unrelated patients with intellectual disability (ID), developmental delay (DD) and multiple congenital anomalies (MCA). The results shown that there was a significant difference on the distribution of the parent-of-origin for different CNVs types (Chi-square test, p = 4.914 × 10−3). An apparently paternal bias existed in deletion CNVs and a maternal bias in duplication CNVs, indicating that the relative contribution of paternal germline variations is greater than that of maternal to the origin of deletions, and vice versa to the origin of duplications. By analyzing the sequences flanking the breakpoints, we also confirmed that non-allelic homologous recombination (NAHR) served as the major mechanism for the formation of recurrent CNVs whereas non-SDs-based mechanisms played a part in generating rare non-recurrent CNVs and might relate to the paternal germline bias in deletion CNVs.

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Section: Discussionsupporting

confidence: 87%

A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies

Deng

Xia

et al. 2017

Sci Rep

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show abstract

“…1) [36, 216]. A strong maternal bias for these types of CNVs has been observed at specific loci [217], which might be explained by a higher local maternal recombination rate. Additionally, for a number of recurrent de novo CNVs, it has been shown that the parental allele carries an inversion that places the duplicated flanking regions in tandem.…”

Section: Box 2 De Novo Copy Number Variations and Other Structural Vamentioning

confidence: 99%

New insights into the generation and role of de novo mutations in health and disease

2016

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Aside from inheriting half of the genome of each of our parents, we are born with a small number of novel mutations that occurred during gametogenesis and postzygotically. Recent genome and exome sequencing studies of parent–offspring trios have provided the first insights into the number and distribution of these de novo mutations in health and disease, pointing to risk factors that increase their number in the offspring. De novo mutations have been shown to be a major cause of severe early-onset genetic disorders such as intellectual disability, autism spectrum disorder, and other developmental diseases. In fact, the occurrence of novel mutations in each generation explains why these reproductively lethal disorders continue to occur in our population. Recent studies have also shown that de novo mutations are predominantly of paternal origin and that their number increases with advanced paternal age. Here, we review the recent literature on de novo mutations, covering their detection, biological characterization, and medical impact.

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“…Family history is always an important consideration, including for phenotypic expression in 22q11.2DS . For other recurrent CNVs, studies show the influence of family background on neuropsychiatric expression, and comparable data for the 22q11.2 deletion indicate similar findings for intellect, particularly for verbal IQ …”

Section: Prenatal Predictors Of Neuropsychiatric Expressionmentioning

confidence: 99%

Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

2016

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Most major neuropsychiatric outcomes of concern to families are not detectable by prenatal ultrasound. The introduction of genome-wide chromosomal microarray analysis to prenatal clinical diagnostic testing has increased the detection of pathogenic 22q11.2 deletions, which cause the most common genomic disorder. The recent addition of this and other microdeletions to non-invasive prenatal screening methods using cell-free fetal DNA has further propelled interest in outcomes. Conditions associated with 22q11.2 deletions include intellect ranging from intellectual disability to average, schizophrenia and other treatable psychiatric conditions, epilepsy, and early-onset Parkinson’s disease. However, there is currently no way to predict how severe the lifetime expression will be. Available evidence suggests no major role in these neuropsychiatric outcomes for the congenital cardiac or most other structural anomalies that may be detectable on ultrasound. This article provides an outline of the lifetime neuropsychiatric phenotype of 22q11.2 deletion syndrome that will be useful to clinicians involved in prenatal diagnosis and related genetic counselling. The focus is on information that will be most relevant to two common situations: detection of a 22q11.2 deletion in a fetus or newborn, and new diagnosis of 22q11.2 deletion syndrome in a parent without a previous molecular diagnosis.

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Maternal Modifiers and Parent-of-Origin Bias of the Autism-Associated 16p11.2 CNV

Cited by 54 publications

References 54 publications

A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies

A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies

New insights into the generation and role of de novo mutations in health and disease

Neuropsychiatric aspects of 22q11.2 deletion syndrome: considerations in the prenatal setting

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