Skip to main content

Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders

Abstract

Background

Structural rearrangements of the genome, which generally occur during meiosis and result in large-scale (> 1 kb) copy number variants (CNV; deletions or duplications ≥ 1 kb), underlie genomic disorders. Recurrent pathogenic CNVs harbor similar breakpoints in multiple unrelated individuals and are primarily formed via non-allelic homologous recombination (NAHR). Several pathogenic NAHR-mediated recurrent CNV loci demonstrate biases for parental origin of de novo CNVs. However, the mechanism underlying these biases is not well understood.

Methods

We performed a systematic, comprehensive literature search to curate parent of origin data for multiple pathogenic CNV loci. Using a regression framework, we assessed the relationship between parental CNV origin and the male to female recombination rate ratio.

Results

We demonstrate significant association between sex-specific differences in meiotic recombination and parental origin biases at these loci (p = 1.07 × 10–14).

Conclusions

Our results suggest that parental origin of CNVs is largely influenced by sex-specific recombination rates and highlight the need to consider these differences when investigating mechanisms that cause structural variation.

Peer Review reports

Background

Genomic disorders are caused by pathological structural variation in the human genome usually arising de novo during parental meiosis [1,2,3,4]. The most common pathogenic variety of these rearrangements are copy number variants (CNVs), i.e. a deletion or duplication of > 1 kb of genetic material [3, 5, 6]. The clinical phenotypes of genomic disorders are varied. They include congenital dysmorphisms, neurodevelopmental, neurodegenerative, and neuropsychiatric manifestations, and even more common complex phenotypes such as obesity and hypertension [7,8,9,10,11,12]. CNVs have been observed in 10% of sporadic cases of autism [13, 14], 15% of schizophrenia cases [15, 16], and 16% of cases of intellectual disability [17]. These and other associations highlight the importance of structural variation to human health and the need to understand the factors influencing how they arise.

There is an intense interest in understanding the mechanisms by which CNVs form [18, 19]. In several regions of the genome, de novo CNVs with approximately the same breakpoints recur in independent meioses (recurrent CNVs) [1, 20]. The presence of segmental duplications flanking these intervals is a hallmark feature of recurrent CNVs. It is hypothesized that misalignment and subsequent recombination between non-allelic low copy repeat (LCR) segments within the segmental duplication regions is the formative event giving rise to the CNV [21, 22], so-called non-allelic homologous recombination (NAHR). Risk factors that may favor NAHR have been investigated and include sequence composition and orientation of the LCRs themselves [21, 23] as well as the presence of inversions at the locus [24, 25].

Parental sex bias for the origin of recurrent de novo CNVs remains unexplained. De novo deletions at the 16p11.2 and 17q11.2 loci are more likely to arise on maternally inherited chromosomes [26,27,28,29]. Deletions at the 22q11.2 locus show a slight maternal bias as well [30]. In contrast, deletions at the 5q35.3 locus (Sotos syndrome [MIM: 117550]) display a paternal origin bias [31, 32]. Deletions at the 7q11.23 locus (Williams syndrome [MIM: 194050]) do not show a bias in parental origin [24]. While it has been suggested that sex-specific recombination rates might influence sex biases in NAHR [26], this hypothesis has not been formally tested.

The majority of recurrent CNVs are thought to form during meiosis when homologous chromosomes align and synapse during prophase I [33]. It is well established that meiosis differs significantly between males and females. In males, spermatagonia continuously divide and complete meiosis throughout postpubescent life with all four products of meiosis resulting in gametes. In contrast, in human females, oogonia are established in fetal life and enter into an extended period of prolonged stasis in prophase I of meiosis until they complete meiosis upon ovulation and fertilization [34]. Additionally, in female meiosis, only one of four products of meiosis result in a gamete. Sexual dimorphism in meiosis extends to the patterns and processes of recombination during meiosis [33]. Here we seek to ask whether local sex-specific rates in meiotic recombination can predict the parental bias for the origin of recurrent de novo CNVs.

Methods

Parent of origin determination

Literature search and parental origin data curation

For this analysis, we considered the 55 known genomic disorder CNV loci described in Coe et al. [7]. A locus was eligible for inclusion in the current analysis if it is flanked by LCRs, i.e. mediated by NAHR, and not imprinted (n = 38 eligible loci). For each of these 38 loci, we performed a systematic PubMed search to identify published data on parental origin. Studies were admitted to this paper’s analysis when the following criteria were met: (1) the study detailed parent of origin data for one of the 38 eligible NAHR-mediated loci as designated by Coe et al. [7], (2) the authors of the study interrogated the entire canonical CNV interval to confirm the presence of a deletion or duplication in the patients, (3) the authors determined the investigated CNVs were de novo, and (4) the study clearly treated monozygotic twins as one meiotic event and not two (Additional file 1: Supplemental Methods, Additional file 2: Table S1, and Additional file 3: Table S2). The literature search led to a manual review of 1268 papers, out of which we identified 77 manuscripts across 24 loci with suitable data for analysis: 1q21.1 [35,36,37,38,39], 1q21.1 TAR [40], 2q13 [37], 3q29 [37,38,39,40,41,42], 5q35 [31, 32], 7q11.23 [24, 40, 43,44,45,46,47,48,49,50,51,52,53,54], 8p23.1 [55, 56], 11q13.2q13.4 [57], 15q13.3 [38, 40, 58], 15q24 (AC, AD, BD, and BE intervals) [59,60,61,62,63,64], 15q25.2 [65,66,67],16p11.2 [26, 37, 40, 68,69,70], distal 16p11.2 [37, 38, 70], 16p11.2p12.1 [71], 16p31.11 [37], 17p11.2 [72,73,74,75,76], 17q11.2 [28, 29, 77], 17q12 [37, 38, 78], 17q21.31 [19, 25, 67, 79,80,81,82,83,84], 17q23.1q23.2 [69, 85] and 22q11.2 [30, 43, 53, 86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102] (Table 1). For the remaining 14 loci, no published parent of origin data could be identified. At the 3q29 locus, we generated new data to determine the parent of origin for de novo events (http://genome.emory.edu/3q29/).

Table 1 Summary of CNV loci included in literature search and curated studies

Determination of parental origin for 3q29 deletion

Study subject recruitment

This study was approved by Emory University’s Institutional Review Board (IRB00064133). Individuals with a clinically confirmed diagnosis of 3q29 deletion were ascertained through the internet-based 3q29 registry (https://3q29deletion.patientcrossroads.org/) as previously described [103]. Blood samples were obtained from 14 families. SNP genotyping was performed on 12 of the 14 families (10 full trios, 2 mother–child pairs) using the Illumina GSA-24 v 3.0 array. For 2 full trios (6 samples), parent of origin was determined from whole-genome sequence data on Illumina's NovaSeq 6000 platform. Quality control was performed with PLINK 1.9 [104] and our custom pipeline (Additional file 1: Supplemental Methods).

Parental origin analysis

Parental origin of the 3q29 deletion was determined for all 14 families using PLINK 1.9 [104]. SNPs located within the 3q29 deletion region (chr3:196029182–197617792; hg38) were isolated for analysis and the pattern of Mendelian errors (MEs) were analyzed. The parent with the most MEs was considered the parent of origin for the 3q29 deletion (Additional file 1: Supplemental Methods). The mean age of fathers in our 3q29 cohort was collected from self-reported data in conjunction with the Emory University 3q29 project (http://genome.emory.edu/3q29/) and compared to the U.S. average (NCHS; https://www.cdc.gov/nchs/index.htm) via a two-tailed two-sample t-test using R [105].

Calculation of recombination rates and ratios

Chromosome male and female recombination rates (cM/Mb) were obtained from the deCODE sex-specific maps, which are based on over 4.5 million crossover recombination events from 126,427 meioses, with an average resolution of 682 base pairs [106]. The recombination rate (cM/Mb) data from deCODE is publicly available as recombination rates calculated for a physical genomic interval bounded by two SNP markers (Additional file 1: Supplemental Methods). Therefore, for our calculation of the average male and female recombination rates, each bounded recombination rate was weighted by the total number of base pairs contained within the respective SNP marker interval. Weighted rates were then averaged across the CNV interval for males and females, separately. The ratio of the weighted average male and female recombination rates was then calculated for each CNV interval by dividing the weighted average male recombination rate by the weighted average female recombination rate (Additional file 1: Figure S1). To account for slight differences in the recombination rate ratios calculated for the different LCR22 intervals at the 22q11.2 locus we used an adjusted recombination rate ratio composed of the weighted recombination rate ratios calculated for each LCR22 interval. Weights were based on the estimated population prevalence of the different 22q11.2 deletion intervals (Additional file 1: Table S3) [107].

Logistic regression analysis

Parental origin data was curated for CNVs at the 24 CNV loci from 77 independent studies; only independent samples were included in the analysis (duplicate or overlapping samples were removed). For each CNV locus, the male to female recombination rate ratio was calculated as described above. A logistic regression model was fitted to the data with the loge-transformed male to female recombination rate ratio as the predictor and parental origin (paternal vs. maternal) as the response variable. We performed a secondary analysis stratified by deletions and duplications. See Table 2 and Additional file 4: Table S4 for the data calculated and used in the logistic regression analyses.

Table 2 Summary of genomic disorder loci CNVs recombination calculations

Linear regression analysis

For linear regression, locus-specific estimates for parental origin were derived by combining the data from all published studies for a given locus. To alleviate the uncertainty introduced by small sample sizes, only those loci with more than 10 observations were included. The loge-transformed combined male to female parental origin count ratio for each locus was regressed on the calculated average loge-transformed average male to female recombination rate ratio for that locus’ CNV interval. Each locus was weighted based on its sample size.

Results

Recurrent genomic disorder loci literature search

We conducted a systematic literature search for the 38 non-imprinted and NAHR-mediated CNV loci in Coe et al. [7] (Table 1, Additional file 2: Table S1). We identified parent-of-origin studies that met inclusion criteria as stated in “Methods” section. 77 studies met inclusion criteria; from these 77 studies, data were curated for 24 loci, including copy number variants at 1q21.1 [35,36,37,38,39], 1q21.1 TAR [40], 2q13 [37], 3q29 [37,38,39,40,41,42], 5q35 [31, 32], 7q11.23 [24, 40, 43,44,45,46,47,48,49,50,51,52,53,54], 8p23.1 [55, 56], 11q13.2q13.4 [57], 15q13.3 [38, 40, 58], 15q24 (AC, AD, BD, and BE intervals) [59,60,61,62,63,64], 15q25.2 [65,66,67],16p11.2 [26, 37, 40, 68,69,70], distal 16p11.2 [37, 38, 70], 16p11.2p12.1 [71], 16p31.11 [37], 17p11.2 [72,73,74,75,76], 17q11.2 [28, 29, 77], 17q12 [37, 38, 78], 17q21.31 [19, 25, 67, 79,80,81,82,83,84], 17q23.1q23.2 [69, 85] and 22q11.2 [30, 43, 53, 86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102] (Table 2). Each locus has between one and twenty independent studies representing in total 1977 de novo deletion (N = 1913) and duplication (N = 64) events (Table 2).

Parent of origin of 3q29 deletion

We determined parent of origin in 12 full trios where a proband had a de novo 3q29 deletion; in 2 additional trios where only proband and maternal DNA samples were available, parent of origin was inferred. For the 12 trios evaluated by SNP arrays, in all cases, the number of Mendelian errors between the presumed inherited (intact) parental allele was zero, and the mean Mendelian errors for the presumed de novo parent of origin allele were 41, with a range of 27–66. For the two trios evaluated with sequence data, Mendelian errors were 20–33-fold elevated when comparing the inherited versus de novo parent. In these 14 trios, 13 deletions (92.9%) arose on the paternal genome indicating a significant departure from the null expectation of 50% (p = 0.002, binomial exact). When accounting for only full trios, 11 of 12 (91.7%) deletions arose on paternal haplotypes (p = 0.006, binomial exact), altogether indicating there is a paternal bias for origin of the 3q29 deletion (Additional file 1: Table S5). We examined the age distribution of male parents in our cohort; the mean age is 34 years (median = 34 years) and is not significantly different from the 2018 U.S national average, (31.8 years) (p = 0.08, Two-tailed two-sample t-test), These data indicate the bias in the 3q29 sample is unlikely to be due to oversampling of older fathers (Additional file 1: Table S5).

Meiotic recombination and parental origin

We tested the hypothesis that sex-dependent differences in meiotic recombination could explain the parental biases observed for recurrent genomic disorder loci mediated by NAHR. We determined the male and female origin counts of the CNVs curated from the literature search. Of the 1977 CNVs, 870 were paternal in origin and 1107 were of maternal origin. We calculated the average male and female recombination rates (cM/Mb) across the CNV intervals at all 24 loci using recombination rates published by the deCODE genetics group [106] (Additional file 1: Figure S2–S12). We fit a simple logistic model to the data, with the male-to-female recombination rate ratio as the predictor and parental origin as the response variable (Table 2; Additional file 4: Table S4). Our data reveal that the sex-dependent recombination rate ratio significantly predicts parental de novo origin of a given CNV (p = 1.07 × 10–14, β = 0.6606, CI95% = (0.4980, 0.8333), OR = 1.936) (Fig. 1). In other words: for a given region, the higher the male recombination rate is relative to the female rate, the more likely a CNV formed in that region will be paternal in origin. Stratified analyses on deletions and duplications separately lead to a nearly identical model (Deletions: p = 8.88 × 10–14, β = 0.6721, CI95% = (0.5009, 0.8546), OR = 1.9584; Duplications: p = 0.02, β = 0.8304, CI95% = (0.1508, 1.6017), OR = 2.2942) (Additional file 1: Figure S13–S14, Table S6–S7). Simple linear regression on the subset of CNV loci with more than 10 samples, shows the striking correlation between relative recombination rates and parental origin, where relative recombination rates explain 85% of the variance in parental bias (Additional file 1: Figure S15 and Table S8). Our logistic model can be used to predict paternal origin rates for any locus with estimable recombination in males and females, and we have done so (Additional file 1: Table S9). CNVs at the 15q13.3 and 17q23 both are predicted to have a paternal origin approximately 60% of the time, while at the 16p11.2 distal locus CNVs are predicted to have a maternal origin 76% of the time (Additional file 1: Table S9). If correct, our model would predict these loci exhibit a bias in parental origin.

Fig. 1
figure1

Recombination rates associate with parental origin. Predicted (curve) and observed paternal origin proportions for 1977 CNVs from 24 loci. Curated parent of origin data from 77 published studies are collapsed by loci into single data points; recombination rate ratios are the average of the metric for all CNVs within the data point. Data point size and color correspond to the number of CNV data collapsed into the data point. Recombination rate ratios predict parental origin for CNV mediated by NAHR (p = 1.07 × 10–14, β = 0.6606, CI95% = (0.4980, 0.8333), OR = 1.936)

Discussion

Parent of origin bias for de novo events at recurrent CNV loci has been well-documented but has lacked a compelling explanation. Our analysis of data gathered on 1977 CNVs from 77 published reports demonstrate that sex-specific variation in local meiotic recombination rates predicts parent of origin at recurrent CNV loci. Human male and female meiotic recombination rates and patterns differ greatly across the broad scale of human chromosomes. Recombination events are nearly uniformly distributed across the chromosome arms in females but tend to be clustered closer to the telomeres in males [108]. We note that this pattern has been previously recognized [26]. Here we have formally tested the hypothesis that recombination variation drives parent of origin variation using a rigorous, statistical framework (Fig. 1) and provided an estimate for the variance in parent of origin bias that is due to sex-specific recombination rates (Additional file 1: Figure S15).

Investigations into the mechanism by which recurrent CNVs arise have focused on LCRs and their makeup [1, 109]. These regions are composed of units of sequence repeats that vary in orientation, percent homology, length, and copy number. Consequently, LCRs are mosaics of varying units, imparting complexity to LCR architecture [23]. The frequency of NAHR events mediated by LCRs is a function of these characteristics and other features of the genomic architecture [21]. Specifically, the rate of NAHR is known to correlate positively with LCR length and percent homology and decrease as the distance between LCRs increases [19, 21]. However, because LCRs are challenging to study with short-read sequencing technology, the population-level variability of these regions is not well described [110]. Recent breakthroughs with long-read sequencing and optical mapping have revealed remarkable variation in LCRs [111,112,113], and haplotypes with higher risks for CNV formation have now been identified [114]. LCRs are substrates for NAHR [1], and thus are subject to the recombination process. Local recombination rates may influence how likely an NAHR event will happen between two LCRs. Therefore, when analyzing LCR haplotypes and their susceptibility to NAHR, one would need to take into account sex differences in recombination. For example, at loci with maternal biases, specific risk haplotypes may be required for males to form CNVs and vice versa. Greater enrichment of GC content, homologous core duplicons or the PRDM9 motifs, or other recombination-favoring factors may also be required [1, 19].

Variation in recombination rates between sexes is well established [108, 115,116,117,118]. Prediction of individual risk may also need to consider individual variation in meiotic recombination, particularly due to heritable variation and the presence or absence of inversion polymorphisms [117, 119]. Variants in several genes, including PRDM9, have been shown to affect recombination rates and the distribution of double-stranded breaks in mammals [120, 121]. Common alleles in PRDM9 are evidenced to affect the percentage of recombination events within individuals that take place at hotspots [120], and variants in RNF212 are associated with opposite effects on recombination rate between males and females [116, 121]. The unexplained variance in our study may be due to these additional factors, which are rich substrates for future study.

Many human genetic studies have observed correlations between inversion polymorphisms and genomic disorder loci [25, 122]. Because these inversions are copy-number neutral and often located in complex repeat regions, [123] they can be difficult to assay with current high-throughput strategies and their true impact remains to be explored. One model proposes that during meiosis these regions may fail to synapse properly and increase the probability of NAHR [124, 125]. Another theory suggests formation of inversions increases directly oriented content in LCRs leading to an NAHR-favorable haplotype [126]. Supporting these theories, inversion polymorphisms have been identified at the majority of recurrent CNV loci [24, 25, 30, 122, 124, 126, 127]. At the 7q11.23, 17q21.31, and 5q35 loci [24, 25, 127], compelling data indicts inversions as a highly associated marker of CNV formation. However, heterozygous inversions are known to suppress recombination perturbing the local pattern of recombination and altering the fate of chiasmata [119]. The analysis presented here strongly suggests that recombination is the driving force for CNV formation giving rise to an alternate explanation for the association between inversions and CNVs; they are both the consequence (and neither one the cause) of recombination between non-allelic homologous LCRs. Inversions and CNVs appear to be associated because both are being initiated by aberrant recombination. Viewing the system in this manner also explains the frequency of individual inversions at CNV loci. Inversions are arising via rare aberrant recombination, like CNVs, but subsequently being driven to higher frequency by natural selection, because they act to suppress recombination and “save offspring” from deleterious genomic disorders. Of course, frequent mutations leading to inversions and the details of LCR structure such as relative orientation and homology within a genomic region may promote or impede CNV formation in a locus-specific manner [128,129,130]. Further exploration of this relationship with improved genomic mapping can test these alternative models [131]. One testable prediction of the model described here is that inversions should be at higher frequency at loci giving rise to highly deleterious CNVs, as opposed to loci harboring recurrent benign CNVs.

To our knowledge, this study is the first comprehensive investigation of parental origin of recurrent, NAHR-mediated CNV loci. Investigations of predominantly nonrecurrent CNVs show paternal bias [132,133,134]. Unlike recurrent CNVs, nonrecurrent CNVs are mostly formed via non-homologous end joining (NHEJ) and replicative mechanisms [1, 135, 136]. The standing hypothesis is that replication-based mechanisms of nonrecurrent CNV formation, which are known to accumulate errors in male germlines, contribute to this bias [132]. Our study reinforces the idea that the factors influencing recurrent CNVs differ from those impacting nonrecurrent CNVs. Future genome-wide analyses with larger sample sizes can further help refine our understanding of the divergent forces at play affecting recurrent and nonrecurrent CNV formation.

We conducted a comprehensive literature search at 38 loci and ultimately identified 1977 samples for analysis. We note that the majority of the data come from 7 well-studied loci (Table 1). While we thoroughly curated the data in a systematic way, it is possible that our data is subject to publication bias, where loci that exhibit parent of origin biases are more likely to have parental origin reported. Further exacerbating potential publication bias, genetic testing for the affected patient (and even more so for the parents) can be difficult to obtain due to concerns such as insurance coverage, potential future discrimination, and privacy concerns [137,138,139,140]. However, we note individuals with CNVs are generally not ascertained or recruited under the expectation that recombination affects parent of origin, and therefore, any potential publication or ascertainment bias is unlikely to confound the results of our analysis. Analysis of a larger cohort of CNV loci including benign CNVs will give greater insight into the role of recombination, and sex differences in recombination influencing parent of origin in CNVs.

Our estimates of recombination rates summarize CNV-scale (broad-scale) patterns of recombination, rather than fine-scale patterns near the sites of relevant recombination events that form these CNVs—LCRs. For example, local sex-specific hotspots within LCRs could be the underlying drivers behind the correlation between recombination rates and parental origin. Given the nature of repetitive regions like LCRs and our inability to adequately interrogate them with current sequencing technologies, accurate recombination data across and within the LCR regions is not available. In other words, the data is currently insufficient to conclude whether or not these broad-scale patterns are tightly correlated with fine-scale recombination rates in and around the LCRs. The best available data in the field allows us to infer the following: broad-scale patterns of recombination tightly predict patterns of parental origin.

Conclusions

In this study, we determined male and female differences in meiotic recombination rates significantly predict parent of origin for recurrent CNV loci. Combining the sex-specific recombination landscape and the mechanistic factors underlying it with a more detailed understanding of existing structural factors at genomic disorder loci can be expected to help guide standards used to identify and perform genetic counseling for individuals at risk of genomic rearrangement.

Availability of data and materials

The majority of the parent of origin data in our analyses was extracted from published sources, as in Table 1. The recombination rate datasets analyzed during the current study are available at https://doi.org/10.1126/science.aau1043 [106]. The SNP data generated and analyzed at the 3q29 locus is available in the NIMH Data Archive repository, (https://nda.nih.gov), collection ID #2614. The data will also be provided upon request to qualified investigators; please email the corresponding author (jmulle@emory.edu) for data access.

Abbreviations

CNV:

Copy number variant

LCR:

Low-copy repeat

NAHR:

Non-allelic homologous recombination

NCHS:

National Center for Health Statistics

References

  1. 1.

    Carvalho CM, Lupski JR. Mechanisms underlying structural variant formation in genomic disorders. Nat Rev Genet. 2016;17(4):224–38.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, et al. Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med. 2012;367(14):1321–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Harel T, Lupski JR. Genomic disorders 20 years on-mechanisms for clinical manifestations. Clin Genet. 2018;93(3):439–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Mefford HC. Genotype to phenotype-discovery and characterization of novel genomic disorders in a “genotype-first” era. Genet Med. 2009;11(12):836–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Feuk L, Carson AR, Scherer SW. Structural variation in the human genome. Nat Rev Genet. 2006;7(2):85–97.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Girirajan S, Campbell CD, Eichler EE. Human copy number variation and complex genetic disease. Annu Rev Genet. 2011;45:203–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Coe BP, Witherspoon K, Rosenfeld JA, van Bon BW, Vulto-van Silfhout AT, Bosco P, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet. 2014;46(10):1063–71.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, et al. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities. Genet Med. 2011;13(9):777–84.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Lifton RP, Dluhy RG, Powers M, Rich GM, Cook S, Ulick S, et al. A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992;355(6357):262–5.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Mulle JG, Dodd AF, McGrath JA, Wolyniec PS, Mitchell AA, Shetty AC, et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am J Hum Genet. 2010;87(2):229–36.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerriere A, Vital A, et al. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38(1):24–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Walters RG, Jacquemont S, Valsesia A, de Smith AJ, Martinet D, Andersson J, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature. 2010;463(7281):671–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Pinto D, Delaby E, Merico D, Barbosa M, Merikangas A, Klei L, et al. Convergence of genes and cellular pathways dysregulated in autism spectrum disorders. Am J Hum Genet. 2014;94(5):677–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Sebat J, Lakshmi B, Malhotra D, Troge J, Lese-Martin C, Walsh T, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316(5823):445–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Marshall CR, Howrigan DP, Merico D, Thiruvahindrapuram B, Wu W, Greer DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet. 2017;49(1):27–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, Cooper GM, et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science. 2008;320(5875):539–43.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Girirajan S, Brkanac Z, Coe BP, Baker C, Vives L, Vu TH, et al. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet. 2011;7(11):e1002334.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Dittwald P, Gambin T, Szafranski P, Li J, Amato S, Divon MY, et al. NAHR-mediated copy-number variants in a clinical population: mechanistic insights into both genomic disorders and Mendelizing traits. Genome Res. 2013;23(9):1395–409.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006;38(9):1038–42.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Liu P, Carvalho CM, Hastings PJ, Lupski JR. Mechanisms for recurrent and complex human genomic rearrangements. Curr Opin Genet Dev. 2012;22(3):211–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Liu P, Lacaria M, Zhang F, Withers M, Hastings PJ, Lupski JR. Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over. Am J Hum Genet. 2011;89(4):580–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Stankiewicz P, Lupski JR. Structural variation in the human genome and its role in disease. Annu Rev Med. 2010;61:437–55.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Marques-Bonet T, Eichler EE. The evolution of human segmental duplications and the core duplicon hypothesis. Cold Spring Harb Symp Quant Biol. 2009;74:355–62.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Hobart HH, Morris CA, Mervis CB, Pani AM, Kistler DJ, Rios CM, et al. Inversion of the Williams syndrome region is a common polymorphism found more frequently in parents of children with Williams syndrome. Am J Med Genet C Semin Med Genet. 2010;154C(2):220–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006;38(9):999–1001.

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Duyzend MH, Nuttle X, Coe BP, Baker C, Nickerson DA, Bernier R, et al. Maternal modifiers and parent-of-origin bias of the autism-associated 16p11.2 CNV. Am J Hum Genet. 2016;98(1):45–57.

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Lazaro C, Gaona A, Ainsworth P, Tenconi R, Vidaud D, Kruyer H, et al. Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet. 1996;98(6):696–9.

    CAS  PubMed  Article  Google Scholar 

  28. 28.

    Neuhausler L, Summerer A, Cooper DN, Mautner VF, Kehrer-Sawatzki H. Pronounced maternal parent-of-origin bias for type-1 NF1 microdeletions. Hum Genet. 2018;137(5):365–73.

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, et al. Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet. 1998;102(5):591–7.

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Delio M, Guo T, McDonald-McGinn DM, Zackai E, Herman S, Kaminetzky M, et al. Enhanced maternal origin of the 22q11.2 deletion in velocardiofacial and DiGeorge syndromes. Am J Hum Genet. 2013;92(3):439–47.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31.

    Miyake N, Kurotaki N, Sugawara H, Shimokawa O, Harada N, Kondoh T, et al. Preferential paternal origin of microdeletions caused by prezygotic chromosome or chromatid rearrangements in Sotos syndrome. Am J Hum Genet. 2003;72(5):1331–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Tatton-Brown K, Douglas J, Coleman K, Baujat G, Chandler K, Clarke A, et al. Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome. J Med Genet. 2005;42(4):307–13.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Page SL, Hawley RS. Chromosome choreography: the meiotic ballet. Science. 2003;301(5634):785–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Hunt PA, Hassold TJ. Sex matters in meiosis. Science. 2002;296(5576):2181–3.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Christiansen J, Dyck JD, Elyas BG, Lilley M, Bamforth JS, Hicks M, et al. Chromosome 1q21.1 contiguous gene deletion is associated with congenital heart disease. Circ Res. 2004;94(11):1429–35.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359(16):1685–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Sanders SJ, He X, Willsey AJ, Ercan-Sencicek AG, Samocha KE, Cicek AE, et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron. 2015;87(6):1215–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Smajlagic D, Lavrichenko K, Berland S, Helgeland O, Knudsen GP, Vaudel M, et al. Population prevalence and inheritance pattern of recurrent CNVs associated with neurodevelopmental disorders in 12,252 newborns and their parents. Eur J Hum Genet. 2021;29(1):205–15.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Soemedi R, Wilson IJ, Bentham J, Darlay R, Topf A, Zelenika D, et al. Contribution of global rare copy-number variants to the risk of sporadic congenital heart disease. Am J Hum Genet. 2012;91(3):489–501.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Kirov G, Pocklington AJ, Holmans P, Ivanov D, Ikeda M, Ruderfer D, et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol Psychiatry. 2012;17(2):142–53.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  41. 41.

    Malt EA, Juhasz K, Frengen A, Wangensteen T, Emilsen NM, Hansen B, et al. Neuropsychiatric phenotype in relation to gene variants in the hemizygous allele in 3q29 deletion carriers: a case series. Mol Genet Genomic Med. 2019;7(9):e889.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Quintero-Rivera F, Sharifi-Hannauer P, Martinez-Agosto JA. Autistic and psychiatric findings associated with the 3q29 microdeletion syndrome: case report and review. Am J Med Genet A. 2010;152A(10):2459–67.

    PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Baumer A, Dutly F, Balmer D, Riegel M, Tukel T, Krajewska-Walasek M, et al. High level of unequal meiotic crossovers at the origin of the 22q11.2 and 7q11.23 deletions. Hum Mol Genet. 1998;7(5):887–94.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Bayes M, Magano LF, Rivera N, Flores R, Perez Jurado LA. Mutational mechanisms of Williams–Beuren syndrome deletions. Am J Hum Genet. 2003;73(1):131–51.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Codina-Sola M, Costa-Roger M, Perez-Garcia D, Flores R, Palacios-Verdu MG, Cusco I, et al. Genetic factors contributing to autism spectrum disorder in Williams–Beuren syndrome. J Med Genet. 2019;56(12):801–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Depienne C, Heron D, Betancur C, Benyahia B, Trouillard O, Bouteiller D, et al. Autism, language delay and mental retardation in a patient with 7q11 duplication. J Med Genet. 2007;44(7):452–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Dutra RL, Pieri Pde C, Teixeira AC, Honjo RS, Bertola DR, Kim CA. Detection of deletions at 7q11.23 in Williams–Beuren syndrome by polymorphic markers. Clinics (Sao Paulo). 2011;66(6):959–64.

    Article  Google Scholar 

  48. 48.

    Ghaffari M, Tahmasebi Birgani M, Kariminejad R, Saberi A. Genotype–phenotype correlation and the size of microdeletion or microduplication of 7q11.23 region in patients with Williams–Beuren syndrome. Ann Hum Genet. 2018;82(6):469–76.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Masson J, Demily C, Chatron N, Labalme A, Rollat-Farnier PA, Schluth-Bolard C, et al. Molecular investigation, using chromosomal microarray and whole exome sequencing, of six patients affected by Williams Beuren syndrome and Autism Spectrum Disorder. Orphanet J Rare Dis. 2019;14(1):121.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Morris CA, Mervis CB, Paciorkowski AP, Abdul-Rahman O, Dugan SL, Rope AF, et al. 7q11.23 duplication syndrome: physical characteristics and natural history. Am J Med Genet A. 2015;167A(12):2916–35.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. 51.

    Perez-Garcia D, Flores R, Brun-Gasca C, Perez-Jurado LA. Lateral preference in Williams–Beuren syndrome is associated with cognition and language. Eur Child Adolesc Psychiatry. 2015;24(9):1025–33.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Robinson WP, Waslynka J, Bernasconi F, Wang M, Clark S, Kotzot D, et al. Delineation of 7q11.2 deletions associated with Williams–Beuren syndrome and mapping of a repetitive sequence to within and to either side of the common deletion. Genomics. 1996;34(1):17–23.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Thomas NS, Durkie M, Potts G, Sandford R, Van Zyl B, Youings S, et al. Parental and chromosomal origins of microdeletion and duplication syndromes involving 7q11.23, 15q11-q13 and 22q11. Eur J Hum Genet. 2006;14(7):831–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Wu YQ, Sutton VR, Nickerson E, Lupski JR, Potocki L, Korenberg JR, et al. Delineation of the common critical region in Williams syndrome and clinical correlation of growth, heart defects, ethnicity, and parental origin. Am J Med Genet. 1998;78(1):82–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Barber JC, Rosenfeld JA, Foulds N, Laird S, Bateman MS, Thomas NS, et al. 8p23.1 duplication syndrome; common, confirmed, and novel features in six further patients. Am J Med Genet A. 2013;161A(3):487–500.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  56. 56.

    Shimokawa O, Miyake N, Yoshimura T, Sosonkina N, Harada N, Mizuguchi T, et al. Molecular characterization of del(8)(p23.1p23.1) in a case of congenital diaphragmatic hernia. Am J Med Genet A. 2005;136(1):49–51.

    PubMed  Article  PubMed Central  Google Scholar 

  57. 57.

    Wischmeijer A, Magini P, Giorda R, Gnoli M, Ciccone R, Cecconi L, et al. Olfactory receptor-related duplicons mediate a microdeletion at 11q13.2q13.4 associated with a syndromic phenotype. Mol Syndromol. 2011;1(4):176–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, et al. A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet. 2008;40(3):322–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Chen CP, Wang LK, Chern SR, Wu PS, Chen SW, Wu FT, et al. Prenatal diagnosis and molecular cytogenetic characterization of a chromosome 15q24 microdeletion. Taiwan J Obstet Gynecol. 2020;59(3):432–6.

    PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Gao X, Gotway G, Rathjen K, Johnston C, Sparagana S, Wise CA. Genomic analyses of patients with unexplained early-onset scoliosis. Spine Deform. 2014;2(5):324–32.

    PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Huynh MT, Lambert AS, Tosca L, Petit F, Philippe C, Parisot F, et al. 15q24.1 BP4–BP1 microdeletion unmasking paternally inherited functional polymorphisms combined with distal 15q24.2q24.3 duplication in a patient with epilepsy, psychomotor delay, overweight, ventricular arrhythmia. Eur J Med Genet. 2018;61(8):459–64.

    PubMed  Article  PubMed Central  Google Scholar 

  62. 62.

    McInnes LA, Nakamine A, Pilorge M, Brandt T, Jimenez Gonzalez P, Fallas M, et al. A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region. Mol Autism. 2010;1(1):5.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    Mefford HC, Rosenfeld JA, Shur N, Slavotinek AM, Cox VA, Hennekam RC, et al. Further clinical and molecular delineation of the 15q24 microdeletion syndrome. J Med Genet. 2012;49(2):110–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Sharp AJ, Selzer RR, Veltman JA, Gimelli S, Gimelli G, Striano P, et al. Characterization of a recurrent 15q24 microdeletion syndrome. Hum Mol Genet. 2007;16(5):567–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Burgess T, Brown NJ, Stark Z, Bruno DL, Oertel R, Chong B, et al. Characterization of core clinical phenotypes associated with recurrent proximal 15q25.2 microdeletions. Am J Med Genet A. 2014;164A(1):77–86.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  66. 66.

    Palumbo O, Palumbo P, Palladino T, Stallone R, Miroballo M, Piemontese MR, et al. An emerging phenotype of interstitial 15q25.2 microdeletions: clinical report and review. Am J Med Genet A. 2012;158A(12):3182–9.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  67. 67.

    Wagenstaller J, Spranger S, Lorenz-Depiereux B, Kazmierczak B, Nathrath M, Wahl D, et al. Copy-number variations measured by single-nucleotide-polymorphism oligonucleotide arrays in patients with mental retardation. Am J Hum Genet. 2007;81(4):768–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Egolf LE, Vaksman Z, Lopez G, Rokita JL, Modi A, Basta PV, et al. Germline 16p11.2 microdeletion predisposes to neuroblastoma. Am J Hum Genet. 2019;105(3):658–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Karolak JA, Gambin T, Honey EM, Slavik T, Popek E, Stankiewicz P. A de novo 2.2 Mb recurrent 17q23.1q23.2 deletion unmasks novel putative regulatory non-coding SNVs associated with lethal lung hypoplasia and pulmonary hypertension: a case report. BMC Med Genomics. 2020;13(1):34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Redaelli S, Maitz S, Crosti F, Sala E, Villa N, Spaccini L, et al. Refining the phenotype of recurrent rearrangements of chromosome 16. Int J Mol Sci. 2019;20(5):1–17.

    Article  CAS  Google Scholar 

  71. 71.

    Tabet AC, Pilorge M, Delorme R, Amsellem F, Pinard JM, Leboyer M, et al. Autism multiplex family with 16p11.2p12.2 microduplication syndrome in monozygotic twins and distal 16p11.2 deletion in their brother. Eur J Hum Genet. 2012;20(5):540–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Greenberg F, Guzzetta V, Montes de Oca-Luna R, Magenis RE, Smith AC, Richter SF, et al. Molecular analysis of the Smith–Magenis syndrome: a possible contiguous-gene syndrome associated with del(17)(p11.2). Am J Hum Genet. 1991;49(6):1207–18.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Nakamine A, Ouchanov L, Jimenez P, Manghi ER, Esquivel M, Monge S, et al. Duplication of 17(p11.2p11.2) in a male child with autism and severe language delay. Am J Med Genet A. 2008;146A(5):636–43.

    PubMed  Article  PubMed Central  Google Scholar 

  74. 74.

    Potocki L, Shaw CJ, Stankiewicz P, Lupski JR. Variability in clinical phenotype despite common chromosomal deletion in Smith–Magenis syndrome [del(17)(p11.2p11.2)]. Genet Med. 2003;5(6):430–4.

    PubMed  Article  PubMed Central  Google Scholar 

  75. 75.

    Shaw CJ, Bi W, Lupski JR. Genetic proof of unequal meiotic crossovers in reciprocal deletion and duplication of 17p11.2. Am J Hum Genet. 2002;71(5):1072–81.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Yang SP, Bidichandani SI, Figuera LE, Juyal RC, Saxon PJ, Baldini A, et al. Molecular analysis of deletion (17)(p11.2p11.2) in a family segregating a 17p paracentric inversion: implications for carriers of paracentric inversions. Am J Hum Genet. 1997;60(5):1184–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Steinmann K, Kluwe L, Cooper DN, Brems H, De Raedt T, Legius E, et al. Copy number variations in the NF1 gene region are infrequent and do not predispose to recurrent type-1 deletions. Eur J Hum Genet. 2008;16(5):572–80.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Palumbo P, Antona V, Palumbo O, Piccione M, Nardello R, Fontana A, et al. Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case. Gene. 2014;538(2):373–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Digilio MC, Bernardini L, Capolino R, Digilio M, Dentici ML, Novelli A, et al. Hypopigmented skin patches in 17q21.31 microdeletion syndrome: expanding the spectrum of cutaneous findings. Clin Dysmorphol. 2014;23(1):32–4.

    PubMed  Article  PubMed Central  Google Scholar 

  80. 80.

    Dubourg C, Sanlaville D, Doco-Fenzy M, Le Caignec C, Missirian C, Jaillard S, et al. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur J Med Genet. 2011;54(2):144–51.

    PubMed  Article  PubMed Central  Google Scholar 

  81. 81.

    Grisart B, Willatt L, Destree A, Fryns JP, Rack K, de Ravel T, et al. 17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction. J Med Genet. 2009;46(8):524–30.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  82. 82.

    Kirchhoff M, Bisgaard AM, Duno M, Hansen FJ, Schwartz M. A 17q21.31 microduplication, reciprocal to the newly described 17q21.31 microdeletion, in a girl with severe psychomotor developmental delay and dysmorphic craniofacial features. Eur J Med Genet. 2007;50(4):256–63.

    PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008;45(11):710–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Vlckova M, Hancarova M, Drabova J, Slamova Z, Koudova M, Alanova R, et al. Monozygotic twins with 17q21.31 microdeletion syndrome. Twin Res Hum Genet. 2014;17(5):405–10.

    PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Karolak JA, Vincent M, Deutsch G, Gambin T, Cogne B, Pichon O, et al. Complex compound inheritance of lethal lung developmental disorders due to disruption of the TBX-FGF pathway. Am J Hum Genet. 2019;104(2):213–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Bassett AS, Marshall CR, Lionel AC, Chow EW, Scherer SW. Copy number variations and risk for schizophrenia in 22q11.2 deletion syndrome. Hum Mol Genet. 2008;17(24):4045–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Baumer A, Riegel M, Schinzel A. Non-random asynchronous replication at 22q11.2 favours unequal meiotic crossovers leading to the human 22q11.2 deletion. J Med Genet. 2004;41(6):413–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Brondum-Nielsen K, Christensen K. Chromosome 22q11 deletion and other chromosome aberrations in cases with cleft palate, congenital heart defects and/or mental disability. A survey based on the Danish Facial Cleft Register. Clin Genet. 1996;50(3):116–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Chakraborty D, Bernal AJ, Schoch K, Howard TD, Ip EH, Hooper SR, et al. Dysregulation of DGCR6 and DGCR6L: psychopathological outcomes in chromosome 22q11.2 deletion syndrome. Transl Psychiatry. 2012;2:e105.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    Demczuk S, Levy A, Aubry M, Croquette MF, Philip N, Prieur M, et al. Excess of deletions of maternal origin in the DiGeorge/velo-cardio-facial syndromes. A study of 22 new patients and review of the literature. Hum Genet. 1995;96(1):9–13.

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Fokstuen S, Arbenz U, Artan S, Dutly F, Bauersfeld U, Brecevic L, et al. 22q11.2 deletions in a series of patients with non-selective congenital heart defects: incidence, type of defects and parental origin. Clin Genet. 1998;53(1):63–9.

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Glaser B, Mumme DL, Blasey C, Morris MA, Dahoun SP, Antonarakis SE, et al. Language skills in children with velocardiofacial syndrome (deletion 22q11.2). J Pediatr. 2002;140(6):753–8.

    PubMed  Article  Google Scholar 

  93. 93.

    Guo T, Diacou A, Nomaru H, McDonald-McGinn DM, Hestand M, Demaerel W, et al. Deletion size analysis of 1680 22q11.2DS subjects identifies a new recombination hotspot on chromosome 22q11.2. Hum Mol Genet. 2018;27(7):1150–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Michaelovsky E, Gothelf D, Korostishevsky M, Frisch A, Burg M, Carmel M, et al. Association between a common haplotype in the COMT gene region and psychiatric disorders in individuals with 22q11.2DS. Int J Neuropsychopharmacol. 2008;11(3):351–63.

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Molck MC, Vieira TP, Simioni M, Sgardioli IC, dos Santos AP, Xavier AC, et al. Distal 22q11.2 microduplication combined with typical 22q11.2 proximal deletion: a case report. Am J Med Genet A. 2015;167A(1):215–20.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Morrow B, Goldberg R, Carlson C, Das Gupta R, Sirotkin H, Collins J, et al. Molecular definition of the 22q11 deletions in velo-cardio-facial syndrome. Am J Hum Genet. 1995;56(6):1391–403.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Saitta SC, Harris SE, Gaeth AP, Driscoll DA, McDonald-McGinn DM, Maisenbacher MK, et al. Aberrant interchromosomal exchanges are the predominant cause of the 22q11.2 deletion. Hum Mol Genet. 2004;13(4):417–28.

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Saitta SC, Harris SE, McDonald-McGinn DM, Emanuel BS, Tonnesen MK, Zackai EH, et al. Independent de novo 22q11.2 deletions in first cousins with DiGeorge/velocardiofacial syndrome. Am J Med Genet A. 2004;124A(3):313–7.

    PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Sandrin-Garcia P, Abramides DV, Martelli LR, Ramos ES, Richieri-Costa A, Passos GA. Typical phenotypic spectrum of velocardiofacial syndrome occurs independently of deletion size in chromosome 22q11.2. Mol Cell Biochem. 2007;303(1–2):9–17.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  100. 100.

    Sandrin-Garcia P, Macedo C, Martelli LR, Ramos ES, Guion-Almeida ML, Richieri-Costa A, et al. Recurrent 22q11.2 deletion in a sibship suggestive of parental germline mosaicism in velocardiofacial syndrome. Clin Genet. 2002;61(5):380–3.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Vervoort L, Demaerel W, Rengifo LY, Odrzywolski A, Vergaelen E, Hestand MS, et al. Atypical chromosome 22q11.2 deletions are complex rearrangements and have different mechanistic origins. Hum Mol Genet. 2019;28(22):3724–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Vittorini S, Sacchelli M, Iascone MR, Collavoli A, Storti S, Giusti A, et al. Molecular characterization of chromosome 22 deletions by short tandem repeat polymorphism (STRP) in patients with conotruncal heart defects. Clin Chem Lab Med. 2001;39(12):1249–58.

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Murphy MM, Lindsey Burrell T, Cubells JF, Espana RA, Gambello MJ, Goines KCB, et al. Study protocol for The Emory 3q29 Project: evaluation of neurodevelopmental, psychiatric, and medical symptoms in 3q29 deletion syndrome. BMC Psychiatry. 2018;18(1):183.

    PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Team RC. R: a language and environment for statistical computing. Vienna: Team RC; 2014.

    Google Scholar 

  106. 106.

    Halldorsson BV, Palsson G, Stefansson OA, Jonsson H, Hardarson MT, Eggertsson HP, et al. Characterizing mutagenic effects of recombination through a sequence-level genetic map. Science. 2019;363(6425):eaau1043.

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    McDonald-McGinn DM, Hain HS, Emanuel BS, Zackai EH, et al. 22q11.2 deletion syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, et al., editors. GeneReviews((R)). University of Washington; 1993.

    Google Scholar 

  108. 108.

    Broman KW, Murray JC, Sheffield VC, White RL, Weber JL. Comprehensive human genetic maps: individual and sex-specific variation in recombination. Am J Hum Genet. 1998;63(3):861–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Sharp AJ, Cheng Z, Eichler EE. Structural variation of the human genome. Nature Rev Genet. 2006;7:85–97.

    Google Scholar 

  110. 110.

    Eichler EE. Masquerading repeats: paralogous pitfalls of the human genome. Genome Res. 1998;8(8):758–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Lam ET, Hastie A, Lin C, Ehrlich D, Das SK, Austin MD, et al. Genome mapping on nanochannel arrays for structural variation analysis and sequence assembly. Nat Biotechnol. 2012;30(8):771–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  112. 112.

    Levy-Sakin M, Pastor S, Mostovoy Y, Li L, Leung AKY, McCaffrey J, et al. Genome maps across 26 human populations reveal population-specific patterns of structural variation. Nat Commun. 2019;10(1):1025.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  113. 113.

    Mak AC, Lai YY, Lam ET, Kwok TP, Leung AK, Poon A, et al. Genome-wide structural variation detection by genome mapping on nanochannel arrays. Genetics. 2016;202(1):351–62.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  114. 114.

    Demaerel W, Mostovoy Y, Yilmaz F, Vervoort L, Pastor S, Hestand MS, et al. The 22q11 low copy repeats are characterized by unprecedented size and structural variability. Genome Res. 2019;29(9):1389–401.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Agarwal I, Przeworski M. Signatures of replication timing, recombination, and sex in the spectrum of rare variants on the human X chromosome and autosomes. Proc Natl Acad Sci U S A. 2019;116(36):17916–24.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Chowdhury R, Bois PR, Feingold E, Sherman SL, Cheung VG. Genetic analysis of variation in human meiotic recombination. PLoS Genet. 2009;5(9):e1000648.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Coop G, Wen X, Ober C, Pritchard JK, Przeworski M. High-resolution mapping of crossovers reveals extensive variation in fine-scale recombination patterns among humans. Science. 2008;319(5868):1395–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Kong A, Gudbjartsson DF, Sainz J, Jonsdottir GM, Gudjonsson SA, Richardsson B, et al. A high-resolution recombination map of the human genome. Nat Genet. 2002;31(3):241–7.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  119. 119.

    Crown KN, Miller DE, Sekelsky J, Hawley RS. Local inversion heterozygosity alters recombination throughout the genome. Curr Biol. 2018;28(18):2984-90.e3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Kong A, Thorleifsson G, Gudbjartsson DF, Masson G, Sigurdsson A, Jonasdottir A, et al. Fine-scale recombination rate differences between sexes, populations and individuals. Nature. 2010;467(7319):1099–103.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  121. 121.

    Kong A, Thorleifsson G, Stefansson H, Masson G, Helgason A, Gudbjartsson DF, et al. Sequence variants in the RNF212 gene associate with genome-wide recombination rate. Science. 2008;319(5868):1398–401.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  122. 122.

    Antonacci F, Kidd JM, Marques-Bonet T, Ventura M, Siswara P, Jiang Z, et al. Characterization of six human disease-associated inversion polymorphisms. Hum Mol Genet. 2009;18(14):2555–66.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Puig M, Casillas S, Villatoro S, Caceres M. Human inversions and their functional consequences. Brief Funct Genomics. 2015;14(5):369–79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Osborne LR, Li M, Pober B, Chitayat D, Bodurtha J, Mandel A, et al. A 1.5 million-base pair inversion polymorphism in families with Williams–Beuren syndrome. Nat Genet. 2001;29(3):321–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Rao PN, Li W, Vissers LE, Veltman JA, Ophoff RA. Recurrent inversion events at 17q21.31 microdeletion locus are linked to the MAPT H2 haplotype. Cytogenet Genome Res. 2010;129(4):275–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Gimelli G, Pujana MA, Patricelli MG, Russo S, Giardino D, Larizza L, et al. Genomic inversions of human chromosome 15q11-q13 in mothers of Angelman syndrome patients with class II (BP2/3) deletions. Hum Mol Genet. 2003;12(8):849–58.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  127. 127.

    Visser R, Shimokawa O, Harada N, Kinoshita A, Ohta T, Niikawa N, et al. Identification of a 3.0-kb major recombination hotspot in patients with Sotos syndrome who carry a common 1.9-Mb microdeletion. Am J Hum Genet. 2005;76(1):52–67.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  128. 128.

    Antonarakis SE, Rossiter JP, Young M, Horst J, de Moerloose P, Sommer SS, et al. Factor VIII gene inversions in severe hemophilia A: results of an international consortium study. Blood. 1995;86(6):2206–12.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  129. 129.

    Tam E, Young EJ, Morris CA, Marshall CR, Loo W, Scherer SW, et al. The common inversion of the Williams–Beuren syndrome region at 7q11.23 does not cause clinical symptoms. Am J Med Genet A. 2008;146A(14):1797–806.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Zody MC, Jiang Z, Fung HC, Antonacci F, Hillier LW, Cardone MF, et al. Evolutionary toggling of the MAPT 17q21.31 inversion region. Nat Genet. 2008;40(9):1076–83.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Giner-Delgado C, Villatoro S, Lerga-Jaso J, Gaya-Vidal M, Oliva M, Castellano D, et al. Evolutionary and functional impact of common polymorphic inversions in the human genome. Nat Commun. 2019;10(1):4222.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  132. 132.

    Hehir-Kwa JY, Rodriguez-Santiago B, Vissers LE, de Leeuw N, Pfundt R, Buitelaar JK, et al. De novo copy number variants associated with intellectual disability have a paternal origin and age bias. J Med Genet. 2011;48(11):776–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  133. 133.

    Kloosterman WP, Francioli LC, Hormozdiari F, Marschall T, Hehir-Kwa JY, Abdellaoui A, et al. Characteristics of de novo structural changes in the human genome. Genome Res. 2015;25(6):792–801.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  134. 134.

    Ma R, Deng L, Xia Y, Wei X, Cao Y, Guo R, et al. A clear bias in parental origin of de novo pathogenic CNVs related to intellectual disability, developmental delay and multiple congenital anomalies. Sci Rep. 2017;7:44446.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    Lee JA, Carvalho CM, Lupski JR. A DNA replication mechanism for generating nonrecurrent rearrangements associated with genomic disorders. Cell. 2007;131(7):1235–47.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  136. 136.

    Zhang F, Khajavi M, Connolly AM, Towne CF, Batish SD, Lupski JR. The DNA replication FoSTeS/MMBIR mechanism can generate genomic, genic and exonic complex rearrangements in humans. Nat Genet. 2009;41(7):849–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Barton KS, Tabor HK, Starks H, Garrison NA, Laurino M, Burke W. Pathways from autism spectrum disorder diagnosis to genetic testing. Genet Med. 2018;20(7):737–44.

    PubMed  Article  PubMed Central  Google Scholar 

  138. 138.

    Glassford MR, Rosenfeld JA, Freedman AA, Zwick ME, Mulle JG, Unique Rare Chromosome Disorder Support G. Novel features of 3q29 deletion syndrome: results from the 3q29 registry. Am J Med Genet A. 2016;170A(4):999–1006.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  139. 139.

    Phillips KA, Trosman JR, Deverka PA, Quinn B, Tunis S, Neumann PJ, et al. Insurance coverage for genomic tests. Science. 2018;360(6386):278–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Stiles D, Appelbaum PS. Cases in precision medicine: concerns about privacy and discrimination after genomic sequencing. Ann Intern Med. 2019;170(10):717–21.

    PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

The authors wish to acknowledge the grace and generosity of our study participants and the contributions of the members of the Emory 3q29 Project: Jennifer Mulle, Hallie Averbach, Katrina Aberizk, Emily Black, Gary J. Bassell, T. Lindsey Burrell, Grace Carlock, Shanthi Cambala, Tamara Caspary, Joseph F. Cubells, David Cutler, Paul A. Dawson, Michael P. Epstein, Roberto Espana, Michael J. Gambello, Katrina Goines, Ryan Guest, Henry R. Johnston, Cheryl Klaiman, Sookyong Koh, Elizabeth J. Leslie, Longchuan Li, Bryan Mak, Tamika Malone, Michael Mortillo, Trenell Mosley, Melissa M. Murphy, Derek Novacek, Becky Pollak, Ryan Purcell, Timothy Rutkowski, Rossana Sanchez, Celine A. Saulnier, Jason Schroeder, Esra Sefik, Sarah Shultz, Nikisha Sisodiya, Steven Sloan, Elaine F. Walker, Stephen T. Warren, David Weinshenker, Zhexing Wen, Michael E. Zwick.

Funding

This study was supported in part by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities. Additional support was provided by the Georgia Clinical & Translational Science Alliance of the National Institutes of Health under Award Number UL1TR002378. The content is solely the responsibility of the authors and does not necessarily reflect the official views of the National Institutes of Health. Funding support includes Emory University, Grant/Award Number: Treasure Your Exceptions Project; National Institutes of Health, Grant/Award Numbers: 1R01MH110701-01A1, F31GM131609, T32GM008490. The funding bodies played no role in the design of the study nor in the collection, analysis, and interpretation of the data, nor the writing of the manuscript.

Author information

Affiliations

Authors

Contributions

TJM participated in the conception and design of the study, acquisition, and analysis of data, interpretation of results, and drafting of the manuscript. HRJ participated in study design, data acquisition, interpretation of results, and drafting of the manuscript. DJC participated substantially in study design, interpretation of results, and drafting of the manuscript. MEZ participated substantially in study design, interpretation of results, and drafting of the manuscript. JGM participated substantially in the study design, data acquisition, interpretation of results, and drafting of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Jennifer G. Mulle.

Ethics declarations

Ethics approval and consent to participate

The majority of data analyzed in this paper was derived from peer-reviewed manuscripts that are in the public domain, and no additional permissions were required for access to the data. For data generated by our team (parent of origin for de novo deletions at the 3q29 locus), all study subjects provided written informed consent before participating in this study and submitting samples for research. For study subjects younger than 16, assent was obtained from the study subjects themselves, and written informed consent was obtained from their parent or legal guardian. This process was approved by Emory University’s Institutional Review Board (IRB000088012).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Figure S1.

Schematic of recombination rate calculation method; Figures S2–S12. Recombination rates of 24 loci analyzed; Figure S13. Logistic regression with deletions only; Figure S14. Logistic regression with duplications only; Figure S15. Linear regression with combined CNV parent of origin data; Table S3. LCR22 recombination rate data; Table S5. Demographic data for 3q29 cohort; Table S6. Summarized data for logistic regression with deletions only; Table S7. Summarized data for logistic regression with duplications only; Table S8. Sensitivity analysis results for linear regression analysis with deletions and duplications combined; Table S9. Predicted paternal origin probability for loci with small sample sizes or missing from analysis; Supplemental Materials and Methods; Supplemental References.

Additional file 2: Table S1.

Exclusion/Inclusion statuses and literature search results of genomic disorder loci conducted January 2021.

Additional file 3: Table S2.

List of 1268 search results curated from literature search.

Additional file 4: Table S4.

Logistic regression data for 1977 CNVs.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Mosley, T.J., Johnston, H., Cutler, D.J. et al. Sex-specific recombination patterns predict parent of origin for recurrent genomic disorders. BMC Med Genomics 14, 154 (2021). https://doi.org/10.1186/s12920-021-00999-8

Download citation

Keywords

  • Copy number variants
  • Meiotic recombination
  • Parent of origin
  • 3q29 deletion