Publications by authors named "Sau Wai Cheung"

162 Publications

Noninvasive prenatal screening for fetal sex chromosome aneuploidies.

Expert Rev Mol Diagn 2021 Apr 11:1-11. Epub 2021 Apr 11.

Medical Genetics Department/Prenatal Diagnostic Center, West China Second University Hospital, Sichuan University, Chengdu, China.

Introduction: Sex chromosome aneuploidies (SCAs) are among the most common chromosome abnormalities observed in humans. Manifestations include low fertility, infertility, delayed language development, and dysfunction in motor development. Noninvasive prenatal screening (NIPS) based on cell-free fetal DNA from the peripheral blood of pregnant women is increasingly used for the screening of fetal chromosome abnormalities, including screening for fetal gender and fetal sex chromosome aneuploidy. A systematic review of the literature about NIPS for SCAs is needed.

Areas Covered: This review evaluated a vast array of published studies focusing on the clinical significance, detection methods, performance of NIPS for SCAs, and the management of positive SCA results following screening with the aim of facilitating a comprehensive and systematic understanding of NIPS for SCAs.

Expert Commentary: Looking forward, NIPS is expected to become the primary screening test for common aneuploidies as well as other chromosome abnormalities, including some micro-deletions and micro-duplications, with the potential to transition from a screening test to a prenatal diagnosis method. Ultimately, the goal is to provide a safe and accurate method for increasing early diagnosis to improve long-term outcomes for the SCA patients and families by well- informed health care providers.
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http://dx.doi.org/10.1080/14737159.2021.1911651DOI Listing
April 2021

Deciphering the complexity of simple chromosomal insertions by genome sequencing.

Hum Genet 2021 Feb 29;140(2):361-380. Epub 2020 Jul 29.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.

Chromosomal insertions are thought to be rare structural rearrangements. The current understanding of the underlying mechanisms of their origin is still limited. In this study, we sequenced 16 cases with apparent simple insertions previously identified by karyotyping and/or chromosomal microarray analysis. Using mate-pair genome sequencing (GS), we identified all 16 insertions and revised previously designated karyotypes in 75.0% (12/16) of the cases. Additional cryptic rearrangements were identified in 68.8% of the cases (11/16). The incidence of additional cryptic rearrangements in chromosomal insertions was significantly higher compared to balanced translocations and inversions reported in other studies by GS. We characterized and classified the cryptic insertion rearrangements into four groups, which were not mutually exclusive: (1) insertion segments were fragmented and their subsegments rearranged and clustered at the insertion site (10/16, 62.5%); (2) one or more cryptic subsegments were not inserted into the insertion site (5/16, 31.3%); (3) segments of the acceptor chromosome were scattered and rejoined with the insertion segments (2/16, 12.5%); and (4) copy number gains were identified in the flanking regions of the insertion site (2/16, 12.5%). In addition to the observation of these chromothripsis- or chromoanasynthesis-like events, breakpoint sequence analysis revealed microhomology to be the predominant feature. However, no significant correlation was found between the number of cryptic rearrangements and the size of the insertion. Overall, our study provide molecular characterization of karyotypically apparent simple insertions, demonstrate previously underappreciated complexities, and evidence that chromosomal insertions are likely formed by nonhomologous end joining and/or microhomology-mediated replication-based DNA repair.
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http://dx.doi.org/10.1007/s00439-020-02210-xDOI Listing
February 2021

CNVs cause autosomal recessive genetic diseases with or without involvement of SNV/indels.

Genet Med 2020 10 24;22(10):1633-1641. Epub 2020 Jun 24.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Purpose: Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.

Methods: We retrospectively investigated the CNVs' contribution to AR conditions in cases subjected to chromosomal microarray analysis (CMA, N = ~70,000) and/or clinical exome sequencing (ES, N = ~12,000) at Baylor Genetics; most had pediatric onset neurodevelopmental disorders.

Results: CNVs contributed to biallelic variations in 87 cases, including 81 singletons and three affected sibling pairs. Seventy cases had CNVs affecting both alleles, and 17 had a CNV and a single-nucleotide variant (SNV)/indel in trans. In total, 94.3% of AR-CNVs affected one gene; among these 41.4% were single-exon and 35.0% were multiexon partial-gene events. Sixty-nine percent of homozygous AR-CNVs were embedded in homozygous genomic intervals. Five cases had large deletions unmasking an SNV/indel on the intact allele for a recessive condition, resulting in multiple molecular diagnoses.

Conclusions: AR-CNVs are often smaller in size, transmitted through generations, and underrecognized due to limitations in clinical CNV detection methods. Our findings from a large clinical cohort emphasized integrated CNV and SNV/indel analyses for precise clinical and molecular diagnosis especially in the context of genomic disorders.
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http://dx.doi.org/10.1038/s41436-020-0864-8DOI Listing
October 2020

Parental somatic mosaicism for CNV deletions - A need for more sensitive and precise detection methods in clinical diagnostics settings.

Genomics 2020 09 6;112(5):2937-2941. Epub 2020 May 6.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address:

To further assess the scale and level of parental somatic mosaicism, we queried the CMA database at Baylor Genetics. We selected 50 unrelated families where clinically relevant apparent de novo CNV-deletions were found in the affected probands. Parental blood samples screening using deletion junction-specific PCR revealed four parents with somatic mosaicism. Droplet digital PCR (ddPCR), qPCR, and amplicon-based next-generation sequencing (NGS) were applied to validate these findings. Using ddPCR levels of mosaicism ranged from undetectable to 18.5%. Amplicon-based NGS and qPCR for the father with undetectable mosaicism was able to detect mosaicism at 0.39%. In one mother, ddPCR analysis revealed 15.6%, 10.6%, 8.2%, and undetectable levels of mosaicism in her blood, buccal cells, saliva, and urine samples, respectively. Our data suggest that more sensitive and precise methods, e.g. CNV junction-specific LR-PCR, ddPCR, or qPCR may allow for a more refined assessment of the potential disease recurrence risk for an identified variant.
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http://dx.doi.org/10.1016/j.ygeno.2020.05.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363577PMC
September 2020

Genome Sequencing Explores Complexity of Chromosomal Abnormalities in Recurrent Miscarriage.

Am J Hum Genet 2019 12 31;105(6):1102-1111. Epub 2019 Oct 31.

Centre for Reproductive Medicine, Shandong University, Jinan 250021, China; The Key laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan 250021, China; National Research Center for Assisted Reproductive Technology and Reproductive Genetics, Jinan 250021, China; Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200135, China; Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai 200135, China; Hong Kong Branches of Chinese National Engineering Research Centers - Center for Assisted Reproductive Technology and Reproductive Genetics, Hong Kong, China. Electronic address:

Recurrent miscarriage (RM) affects millions of couples globally, and half of them have no demonstrated etiology. Genome sequencing (GS) is an enhanced and novel cytogenetic tool to define the contribution of chromosomal abnormalities in human diseases. In this study we evaluated its utility in RM-affected couples. We performed low-pass GS retrospectively for 1,090 RM-affected couples, all of whom had routine chromosome analysis. A customized sequencing and interpretation pipeline was developed to identify chromosomal rearrangements and deletions/duplications with confirmation by fluorescence in situ hybridization, chromosomal microarray analysis, and PCR studies. Low-pass GS yielded results in 1,077 of 1,090 couples (98.8%) and detected 127 chromosomal abnormalities in 11.7% (126/1,077) of couples; both members of one couple were identified with inversions. Of the 126 couples, 39.7% (50/126) had received former diagnostic results by karyotyping characteristic of normal human male or female karyotypes. Low-pass GS revealed additional chromosomal abnormalities in 50 (4.0%) couples, including eight with balanced translocations and 42 inversions. Follow-up studies of these couples showed a higher miscarriage/fetal-anomaly rate of 5/10 (50%) compared to 21/93 (22.6%) in couples with normal GS, resulting in a relative risk of 2.2 (95% confidence interval, 1.1 to 4.6). In these couples, this protocol significantly increased the diagnostic yield of chromosomal abnormalities per couple (11.7%) in comparison to chromosome analysis (8.0%, chi-square test p = 0.000751). In summary, low-pass GS identified underlying chromosomal aberrations in 1 in 9 RM-affected couples, enabling identification of a subgroup of couples with increased risk of subsequent miscarriage who would benefit from a personalized intervention.
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http://dx.doi.org/10.1016/j.ajhg.2019.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904795PMC
December 2019

Xq22 deletions and correlation with distinct neurological disease traits in females: Further evidence for a contiguous gene syndrome.

Hum Mutat 2020 01 14;41(1):150-168. Epub 2019 Nov 14.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Xq22 deletions that encompass PLP1 (Xq22-PLP1-DEL) are notable for variable expressivity of neurological disease traits in females ranging from a mild late-onset form of spastic paraplegia type 2 (MIM# 312920), sometimes associated with skewed X-inactivation, to an early-onset neurological disease trait (EONDT) of severe developmental delay, intellectual disability, and behavioral abnormalities. Size and gene content of Xq22-PLP1-DEL vary and were proposed as potential molecular etiologies underlying variable expressivity in carrier females where two smallest regions of overlap (SROs) were suggested to influence disease. We ascertained a cohort of eight unrelated patients harboring Xq22-PLP1-DEL and performed high-density array comparative genomic hybridization and breakpoint-junction sequencing. Molecular characterization of Xq22-PLP1-DEL from 17 cases (eight herein and nine published) revealed an overrepresentation of breakpoints that reside within repeats (11/17, ~65%) and the clustering of ~47% of proximal breakpoints in a genomic instability hotspot with characteristic non-B DNA density. These findings implicate a potential role for genomic architecture in stimulating the formation of Xq22-PLP1-DEL. The correlation of Xq22-PLP1-DEL gene content with neurological disease trait in female cases enabled refinement of the associated SROs to a single genomic interval containing six genes. Our data support the hypothesis that genes contiguous to PLP1 contribute to EONDT.
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http://dx.doi.org/10.1002/humu.23902DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953250PMC
January 2020

Low-pass genome sequencing versus chromosomal microarray analysis: implementation in prenatal diagnosis.

Genet Med 2020 03 26;22(3):500-510. Epub 2019 Aug 26.

Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: Emerging studies suggest that low-pass genome sequencing (GS) provides additional diagnostic yield of clinically significant copy-number variants (CNVs) compared with chromosomal microarray analysis (CMA). However, a prospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of low-pass GS compared with CMA is warranted.

Methods: A total of 1023 women undergoing prenatal diagnosis were enrolled. Each sample was subjected to low-pass GS and CMA for CNV analysis in parallel. CNVs were classified according to guidelines of the American College of Medical Genetics and Genomics.

Results: Low-pass GS not only identified all 124 numerical disorders or pathogenic or likely pathogenic (P/LP) CNVs detected by CMA in 121 cases (11.8%, 121/1023), but also defined 17 additional and clinically relevant P/LP CNVs in 17 cases (1.7%, 17/1023). In addition, low-pass GS significantly reduced the technical repeat rate from 4.6% (47/1023) for CMA to 0.5% (5/1023) and required less DNA (50 ng) as input.

Conclusion: In the context of prenatal diagnosis, low-pass GS identified additional and clinically significant information with enhanced resolution and increased sensitivity of detecting mosaicism as compared with the CMA platform used. This study provides strong evidence for applying low-pass GS as an alternative prenatal diagnostic test.
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http://dx.doi.org/10.1038/s41436-019-0634-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042067PMC
March 2020

Copy number variant and runs of homozygosity detection by microarrays enabled more precise molecular diagnoses in 11,020 clinical exome cases.

Genome Med 2019 05 17;11(1):30. Epub 2019 May 17.

Baylor Genetics Laboratories, Houston, TX, USA.

Background: Exome sequencing (ES) has been successfully applied in clinical detection of single nucleotide variants (SNVs) and small indels. However, identification of copy number variants (CNVs) using ES data remains challenging. The purpose of this study is to understand the contribution of CNVs and copy neutral runs of homozygosity (ROH) in molecular diagnosis of patients referred for ES.

Methods: In a cohort of 11,020 consecutive ES patients, an Illumina SNP array analysis interrogating mostly coding SNPs was performed as a quality control (QC) measurement and for CNV/ROH detection. Among these patients, clinical chromosomal microarray analysis (CMA) was performed at Baylor Genetics (BG) on 3229 patients, either before, concurrently, or after ES. We retrospectively analyzed the findings from CMA and the QC array.

Results: The QC array can detect ~ 70% of pathogenic/likely pathogenic CNVs (PCNVs) detectable by CMA. Out of the 11,020 ES cases, the QC array identified PCNVs in 327 patients and uniparental disomy (UPD) disorder-related ROH in 10 patients. The overall PCNV/UPD detection rate was 5.9% in the 3229 ES patients who also had CMA at BG; PCNV/UPD detection rate was higher in concurrent ES and CMA than in ES with prior CMA (7.2% vs 4.6%). The PCNVs/UPD contributed to the molecular diagnoses in 17.4% (189/1089) of molecularly diagnosed ES cases with CMA and were estimated to contribute in 10.6% of all molecularly diagnosed ES cases. Dual diagnoses with both PCNVs and SNVs were detected in 38 patients. PCNVs affecting single recessive disorder genes in a compound heterozygous state with SNVs were detected in 4 patients, and homozygous deletions (mostly exonic deletions) were detected in 17 patients. A higher PCNV detection rate was observed for patients with syndromic phenotypes and/or cardiovascular abnormalities.

Conclusions: Our clinical genomics study demonstrates that detection of PCNV/UPD through the QC array or CMA increases ES diagnostic rate, provides more precise molecular diagnosis for dominant as well as recessive traits, and enables more complete genetic diagnoses in patients with dual or multiple molecular diagnoses. Concurrent ES and CMA using an array with exonic coverage for disease genes enables most effective detection of both CNVs and SNVs and therefore is recommended especially in time-sensitive clinical situations.
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http://dx.doi.org/10.1186/s13073-019-0639-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525387PMC
May 2019

Interchromosomal template-switching as a novel molecular mechanism for imprinting perturbations associated with Temple syndrome.

Genome Med 2019 04 23;11(1):25. Epub 2019 Apr 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX, 77030-3498, USA.

Background: Intrachromosomal triplications (TRP) can contribute to disease etiology via gene dosage effects, gene disruption, position effects, or fusion gene formation. Recently, post-zygotic de novo triplications adjacent to copy-number neutral genomic intervals with runs of homozygosity (ROH) have been shown to result in uniparental isodisomy (UPD). The genomic structure of these complex genomic rearrangements (CGRs) shows a consistent pattern of an inverted triplication flanked by duplications (DUP-TRP/INV-DUP) formed by an iterative DNA replisome template-switching mechanism during replicative repair of a single-ended, double-stranded DNA (seDNA), the ROH results from an interhomolog or nonsister chromatid template switch. It has been postulated that these CGRs may lead to genetic abnormalities in carriers due to dosage-sensitive genes mapping within the copy-number variant regions, homozygosity for alleles at a locus causing an autosomal recessive (AR) disease trait within the ROH region, or imprinting-associated diseases.

Methods: Here, we report a family wherein the affected subject carries a de novo 2.2-Mb TRP followed by 42.2 Mb of ROH and manifests clinical features overlapping with those observed in association with chromosome 14 maternal UPD (UPD(14)mat). UPD(14)mat can cause clinical phenotypic features enabling a diagnosis of Temple syndrome. This CGR was then molecularly characterized by high-density custom aCGH, genome-wide single-nucleotide polymorphism (SNP) and methylation arrays, exome sequencing (ES), and the Oxford Nanopore long-read sequencing technology.

Results: We confirmed the postulated DUP-TRP/INV-DUP structure by multiple orthogonal genomic technologies in the proband. The methylation status of known differentially methylated regions (DMRs) on chromosome 14 revealed that the subject shows the typical methylation pattern of UPD(14)mat. Consistent with these molecular findings, the clinical features overlap with those observed in Temple syndrome, including speech delay.

Conclusions: These data provide experimental evidence that, in humans, triplication can lead to segmental UPD and imprinting disease. Importantly, genotype/phenotype analyses further reveal how a post-zygotically generated complex structural variant, resulting from a replication-based mutational mechanism, contributes to expanding the clinical phenotype of known genetic syndromes. Mechanistically, such events can distort transmission genetics resulting in homozygosity at a locus for which only one parent is a carrier as well as cause imprinting diseases.
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http://dx.doi.org/10.1186/s13073-019-0633-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480824PMC
April 2019

Phenotypic association of 15q11.2 CNVs of the region of breakpoints 1-2 (BP1-BP2) in a large cohort of samples referred for genetic diagnosis.

J Hum Genet 2019 Mar 12;64(3):253-255. Epub 2018 Dec 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX, 77030, USA.

In view of conflicting reports on the pathogenicity of 15q11.2 CNVs of the breakpoints 1-2 (BP1-BP2) region and lack of association with a specific phenotype, we collected phenotypic data on 51,462 patients referred for genetic testing at two centers (Magee-Womens Hospital of UPMC and Baylor Genetics Laboratories, Baylor College of Medicine). Using array CGH, 262 patients with deletions and 215 with duplications were identified and tested for their association with four phenotypes (developmental delay, dysmorphic features, autism group of disorders, and epilepsy/seizures). Only association of deletions with dysmorphic features was observed (P = 0.013) with low penetrance (3.8%). Our results, viewed in the context of other reports suggesting the lack of a clear phenotypic outcome, underscore the need for detailed phenotypic studies to better understand the pathogenicity of 15q11.2 (BP1-BP2) CNVs.
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http://dx.doi.org/10.1038/s10038-018-0543-7DOI Listing
March 2019

BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes.

Nat Commun 2018 11 20;9(1):4885. Epub 2018 Nov 20.

Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.

Coffin-Siris and Nicolaides-Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.
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http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018

Rare variants in the genetic background modulate cognitive and developmental phenotypes in individuals carrying disease-associated variants.

Genet Med 2019 04 7;21(4):816-825. Epub 2018 Sep 7.

Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.

Purpose: To assess the contribution of rare variants in the genetic background toward variability of neurodevelopmental phenotypes in individuals with rare copy-number variants (CNVs) and gene-disruptive variants.

Methods: We analyzed quantitative clinical information, exome sequencing, and microarray data from 757 probands and 233 parents and siblings who carry disease-associated variants.

Results: The number of rare likely deleterious variants in functionally intolerant genes ("other hits") correlated with expression of neurodevelopmental phenotypes in probands with 16p12.1 deletion (n=23, p=0.004) and in autism probands carrying gene-disruptive variants (n=184, p=0.03) compared with their carrier family members. Probands with 16p12.1 deletion and a strong family history presented more severe clinical features (p=0.04) and higher burden of other hits compared with those with mild/no family history (p=0.001). The number of other hits also correlated with severity of cognitive impairment in probands carrying pathogenic CNVs (n=53) or de novo pathogenic variants in disease genes (n=290), and negatively correlated with head size among 80 probands with 16p11.2 deletion. These co-occurring hits involved known disease-associated genes such as SETD5, AUTS2, and NRXN1, and were enriched for cellular and developmental processes.

Conclusion: Accurate genetic diagnosis of complex disorders will require complete evaluation of the genetic background even after a candidate disease-associated variant is identified.
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http://dx.doi.org/10.1038/s41436-018-0266-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405313PMC
April 2019

Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies.

Genet Med 2019 03 30;21(3):663-675. Epub 2018 Aug 30.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, 77030, USA.

Purpose: Defects in the cohesin pathway are associated with cohesinopathies, notably Cornelia de Lange syndrome (CdLS). We aimed to delineate pathogenic variants in known and candidate cohesinopathy genes from a clinical exome perspective.

Methods: We retrospectively studied patients referred for clinical exome sequencing (CES, N = 10,698). Patients with causative variants in novel or recently described cohesinopathy genes were enrolled for phenotypic characterization.

Results: Pathogenic or likely pathogenic single-nucleotide and insertion/deletion variants (SNVs/indels) were identified in established disease genes including NIPBL (N = 5), SMC1A (N = 14), SMC3 (N = 4), RAD21 (N = 2), and HDAC8 (N = 8). The phenotypes in this genetically defined cohort skew towards the mild end of CdLS spectrum as compared with phenotype-driven cohorts. Candidate or recently reported cohesinopathy genes were supported by de novo SNVs/indels in STAG1 (N = 3), STAG2 (N = 5), PDS5A (N = 1), and WAPL (N = 1), and one inherited SNV in PDS5A. We also identified copy-number deletions affecting STAG1 (two de novo, one of unknown inheritance) and STAG2 (one of unknown inheritance). Patients with STAG1 and STAG2 variants presented with overlapping features yet without characteristic facial features of CdLS.

Conclusion: CES effectively identified disease-causing alleles at the mild end of the cohensinopathy spectrum and enabled characterization of candidate disease genes.
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http://dx.doi.org/10.1038/s41436-018-0085-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395558PMC
March 2019

Prenatal diagnosis of Wolf-Hirschhorn syndrome: from ultrasound findings, diagnostic technology to genetic counseling.

Arch Gynecol Obstet 2018 08 28;298(2):289-295. Epub 2018 May 28.

Department of Fetal Medicine and Prenatal Diagnosis center, Shanghai First Maternity and Infant Hospital, Tongji University School of Medicine, 2699 West Gaoke Rd, Pudong New District, Shanghai, 201204, China.

Purpose: Wolf-Hirschhorn syndrome (WHS) is a contiguous gene syndrome due to terminal chromosome 4p deletions. We explored prenatal diagnosis of WHS by ultrasound as well as karyotype and single nucleotide polymorphism array (SNP array) to characterize the structural variants of WHS prenatally.

Methods: Ten prenatal cases of WHS were evaluated for the indication of the invasive testing, the ultrasound features, and cytogenetic and microarray results.

Results: Eight cases were diagnosed by karyotyping and SNP array, while two cases were detected only by SNP array. Combining our cases with 37 prenatal cases from the literature, the most common sonographic features were IUGR (97.7%) and typical facial appearance (82.9%). Other less common phenotypes included renal hypoplasia (36.2%), cardiac malformation (29.8%), cleft lip and palate (25.5%), cerebral abnormalities (25.5%), skeletal anomalies (21.3%), and increased nuchal translucency/nuchal fold thickness (NT/NF) (19%).

Conclusions: The most common intrauterine phenotypes of WHS were severe IUGR and typical facial appearance with other less consistent ultrasound findings. Noninvasive prenatal testing (NIPT) is one very promising screening tool for WHS. SNP array can improve diagnostic precision for detecting WHS, especially for the cryptic aberrations that cannot be identified by the traditional karyotyping. Ectopic kidney may be a previously unrecognized phenotype of WHS.
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http://dx.doi.org/10.1007/s00404-018-4798-1DOI Listing
August 2018

Balanced Chromosomal Rearrangement Detection by Low-Pass Whole-Genome Sequencing.

Curr Protoc Hum Genet 2018 01 24;96:8.18.1-8.18.16. Epub 2018 Jan 24.

Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.

Balanced chromosomal rearrangements (or balanced chromosome abnormalities, BCAs) are common chromosomal structural variants. Emerging studies have demonstrated the feasibility of using whole-genome sequencing (WGS) for detection of BCA-associated breakpoints, but the requirement for a priori knowledge of the rearranged regions from G-banded chromosome analysis limits its application. The protocols described here are based on low-pass WGS for detecting BCA events independent from chromosome analysis, and has been validated using genomic data from the 1000 Genomes Project. This approach adopts non-size-selected mate-pair library (3∼8 kb) with 2∼3 μg DNA as input, and requires only 30 million read-pairs (50 bp, equivalent to 1-fold base-coverage) for each sample. The complete procedure takes 13 days and the total cost is estimated to be less than $600 (USD) per sample. © 2018 by John Wiley & Sons, Inc.
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http://dx.doi.org/10.1002/cphg.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5924704PMC
January 2018

Targeted gene panel sequencing prenatally detects two novel mutations of DYNC2H1 in a fetus with increased biparietal diameter and polyhydramnios.

Birth Defects Res 2018 03 23;110(4):364-371. Epub 2018 Jan 23.

Department of Fetal Medicine Unit and Prenatal Diagnosis Center, Shanghai First Maternity and Infant Hospital of Tongji University, Shanghai, China.

Background: Genetic skeletal disorders (GSDs) are clinically and genetically heterogeneous with more than 350 genes accounting for the diversity of disease phenotypes. Prenatal diagnosis of these disorders has been challenging because of the limited but variable prenatal phenotypes, highlighting the need of a novel genetic approach. Short-rib polydactyly syndrome (SRPS) Type III is an autosomal recessive GSD characterized by extreme narrowness of the thorax, severely shortened tubular bones, polydactyly and multiple malformations.

Methods: Cytogenetic and molecular analyses using GTG-banding, single nucleotide polymorphism array and a novel GSDs targeted gene panel sequencing were performed in a 24 weeks fetus with increased biparietal diameter (BPD), short limbs, narrow thorax and polyhydramnios.

Results: No chromosomal abnormalities and pathogenic copy number variations (CNVs) were detected in the fetus. Two novel compound heterozygous mutations c.2992C > T and c.12836G > C in the DYNC2H1 gene were identified by targeted genes panel sequencing. A literature review was performed to delineate the prenatal phenotype of SRPS Type III.

Conclusion: This is the first report of prenatal diagnosis of DYNC2H1 mutations causing SRPS Type III in a fetus with increased BPD associated with polyhydramnios in China. Our findings expand the mutation spectrum of DYNC2H1 in this rare disease and demonstrate that targeted gene panel capture followed by next-generation sequencing (NGS) is an efficient and cost-effective method to perform a molecular prenatal diagnosis of a rare genetic skeletal disorder.
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http://dx.doi.org/10.1002/bdr2.1146DOI Listing
March 2018

Identification of balanced chromosomal rearrangements previously unknown among participants in the 1000 Genomes Project: implications for interpretation of structural variation in genomes and the future of clinical cytogenetics.

Genet Med 2018 07 2;20(7):697-707. Epub 2017 Nov 2.

Department of Obstetrics & Gynaecology, The Chinese University of Hong Kong, Hong Kong, China.

Purpose: Recent studies demonstrate that whole-genome sequencing enables detection of cryptic rearrangements in apparently balanced chromosomal rearrangements (also known as balanced chromosomal abnormalities, BCAs) previously identified by conventional cytogenetic methods. We aimed to assess our analytical tool for detecting BCAs in the 1000 Genomes Project without knowing which bands were affected.

Methods: The 1000 Genomes Project provides an unprecedented integrated map of structural variants in phenotypically normal subjects, but there is no information on potential inclusion of subjects with apparent BCAs akin to those traditionally detected in diagnostic cytogenetics laboratories. We applied our analytical tool to 1,166 genomes from the 1000 Genomes Project with sufficient physical coverage (8.25-fold).

Results: With this approach, we detected four reciprocal balanced translocations and four inversions, ranging in size from 57.9 kb to 13.3 Mb, all of which were confirmed by cytogenetic methods and polymerase chain reaction studies. One of these DNAs has a subtle translocation that is not readily identified by chromosome analysis because of the similarity of the banding patterns and size of exchanged segments, and another results in disruption of all transcripts of an OMIM gene.

Conclusion: Our study demonstrates the extension of utilizing low-pass whole-genome sequencing for unbiased detection of BCAs including translocations and inversions previously unknown in the 1000 Genomes Project.
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http://dx.doi.org/10.1038/gim.2017.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5932280PMC
July 2018

Positive predictive value estimates for cell-free noninvasive prenatal screening from data of a large referral genetic diagnostic laboratory.

Am J Obstet Gynecol 2017 12 13;217(6):691.e1-691.e6. Epub 2017 Oct 13.

Baylor Genetics, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX. Electronic address:

Background: Since its debut in 2011, cell-free fetal DNA screening has undergone rapid expansion with respect to both utilization and coverage. However, conclusive data regarding the clinical validity and utility of this screening tool, both for the originally included common autosomal and sex-chromosomal aneuploidies as well as the more recently added chromosomal microdeletion syndromes, have lagged behind. Thus, there is a continued need to educate clinicians and patients about the current benefits and limitations of this screening tool to inform pre- and posttest counseling, pre/perinatal decision making, and medical risk assessment/management.

Objective: The objective of this study was to determine the positive predictive value and false-positive rates for different chromosomal abnormalities identified by cell-free fetal DNA screening using a large data set of diagnostic testing results on invasive samples submitted to the laboratory for confirmatory studies.

Study Design: We tested 712 patient samples sent to our laboratory to confirm a cell-free fetal DNA screening result, indicating high risk for a chromosome abnormality. We compiled data from all cases in which the indication for confirmatory testing was a positive cell-free fetal DNA screen, including the common trisomies, sex chromosomal aneuploidies, microdeletion syndromes, and other large genome-wide copy number abnormalities. Testing modalities included fluorescence in situ hybridization, G-banded karyotype, and/or chromosomal microarray analysis performed on chorionic villus samples, amniotic fluid, or postnatally obtained blood samples. Positive predictive values and false-positive rates were calculated from tabulated data.

Results: The positive predictive values for trisomy 13, 18, and 21 were consistent with previous reports at 45%, 76%, and 84%, respectively. For the microdeletion syndrome regions, positive predictive values ranged from 0% for detection of Cri-du-Chat syndrome and Prader-Willi/Angelman syndrome to 14% for 1p36 deletion syndrome and 21% for 22q11.2 deletion syndrome. Detection of sex chromosomal aneuploidies had positive predictive values of 26% for monosomy X, 50% for 47,XXX, and 86% for 47,XXY.

Conclusion: The positive predictive values for detection of common autosomal and sex chromosomal aneuploidies by cell-free fetal DNA screening were comparable with other studies. Identification of microdeletions was associated with lower positive predictive values and higher false-positive rates, likely because of the low prevalence of the individual targeted microdeletion syndromes in the general population. Although the obtained positive predictive values compare favorably with those seen in traditional screening approaches for common aneuploidies, they highlight the importance of educating clinicians and patients on the limitations of cell-free fetal DNA screening tests. Improvement of the cell-free fetal DNA screening technology and continued monitoring of its performance after introduction into clinical practice will be important to fully establish its clinical utility. Nonetheless, our data provide valuable information that may aid result interpretation, patient counseling, and clinical decision making/management.
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http://dx.doi.org/10.1016/j.ajog.2017.10.005DOI Listing
December 2017

Identification of novel candidate disease genes from de novo exonic copy number variants.

Genome Med 2017 09 21;9(1):83. Epub 2017 Sep 21.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030-3411, USA.

Background: Exon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype-phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.

Methods: We retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.

Results: In this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.

Conclusions: Together, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.
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http://dx.doi.org/10.1186/s13073-017-0472-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607840PMC
September 2017

Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X-linked intellectual disability.

PLoS One 2017 17;12(4):e0175962. Epub 2017 Apr 17.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

By searching a clinical database of over 60,000 individuals referred for array-based CNV analyses and online resources, we identified four males from three families with intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly who carried small, overlapping deletions of Xp11.22. The maximum region of overlap between their deletions spanned ~430 kb and included two pseudogenes, CENPVL1 and CENPVL2, whose functions are not known, and two protein coding genes-the G1 to S phase transition 2 gene (GSPT2) and the MAGE family member D1 gene (MAGED1). Deletions of this ~430 kb region have not been previously implicated in human disease. Duplications of GSPT2 have been documented in individuals with intellectual disability, but the phenotypic consequences of a loss of GSPT2 function have not been elucidated in humans or mouse models. Changes in MAGED1 have not been associated with intellectual disability in humans, but loss of MAGED1 function is associated with neurocognitive and neurobehavioral phenotypes in mice. In all cases, the Xp11.22 deletion was inherited from an unaffected mother. Studies performed on DNA from one of these mothers did not show evidence of skewed X-inactivation. These results suggest that deletions of an ~430 kb region on chromosome Xp11.22 that encompass CENPVL1, CENPVL2, GSPT2 and MAGED1 cause a distinct X-linked syndrome characterized by intellectual disability, developmental delay, hypotonia, joint hypermobility and relative macrocephaly. Loss of GSPT2 and/or MAGED1 function may contribute to the intellectual disability and developmental delay seen in males with these deletions.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175962PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393878PMC
April 2017

Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features.

Hum Genet 2017 04 1;136(4):377-386. Epub 2017 Mar 1.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.
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http://dx.doi.org/10.1007/s00439-017-1763-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5543723PMC
April 2017

Characterization of chromosomal abnormalities in pregnancy losses reveals critical genes and loci for human early development.

Hum Mutat 2017 06 29;38(6):669-677. Epub 2017 Mar 29.

Human Genome Sequencing Center, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas.

Detailed characterization of chromosomal abnormalities, a common cause for congenital abnormalities and pregnancy loss, is critical for elucidating genes for human fetal development. Here, 2,186 product-of-conception samples were tested for copy-number variations (CNVs) at two clinical diagnostic centers using whole-genome sequencing and high-resolution chromosomal microarray analysis. We developed a new gene discovery approach to predict potential developmental genes and identified 275 candidate genes from CNVs detected from both datasets. Based on Mouse Genome Informatics (MGI) and Zebrafish model organism database (ZFIN), 75% of identified genes could lead to developmental defects when mutated. Genes involved in embryonic development, gene transcription, and regulation of biological processes were significantly enriched. Especially, transcription factors and gene families sharing specific protein domains predominated, which included known developmental genes such as HOX, NKX homeodomain genes, and helix-loop-helix containing HAND2, NEUROG2, and NEUROD1 as well as potential novel developmental genes. We observed that developmental genes were denser in certain chromosomal regions, enabling identification of 31 potential genomic loci with clustered genes associated with development.
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http://dx.doi.org/10.1002/humu.23207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5671119PMC
June 2017

An Organismal CNV Mutator Phenotype Restricted to Early Human Development.

Cell 2017 02;168(5):830-842.e7

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

De novo copy number variants (dnCNVs) arising at multiple loci in a personal genome have usually been considered to reflect cancer somatic genomic instabilities. We describe a multiple dnCNV (MdnCNV) phenomenon in which individuals with genomic disorders carry five to ten constitutional dnCNVs. These CNVs originate from independent formation incidences, are predominantly tandem duplications or complex gains, exhibit breakpoint junction features reminiscent of replicative repair, and show increased de novo point mutations flanking the rearrangement junctions. The active CNV mutation shower appears to be restricted to a transient perizygotic period. We propose that a defect in the CNV formation process is responsible for the "CNV-mutator state," and this state is dampened after early embryogenesis. The constitutional MdnCNV phenomenon resembles chromosomal instability in various cancers. Investigations of this phenomenon may provide unique access to understanding genomic disorders, structural variant mutagenesis, human evolution, and cancer biology.
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http://dx.doi.org/10.1016/j.cell.2017.01.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407901PMC
February 2017

Mechanisms for Complex Chromosomal Insertions.

PLoS Genet 2016 Nov 23;12(11):e1006446. Epub 2016 Nov 23.

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

Chromosomal insertions are genomic rearrangements with a chromosome segment inserted into a non-homologous chromosome or a non-adjacent locus on the same chromosome or the other homologue, constituting ~2% of nonrecurrent copy-number gains. Little is known about the molecular mechanisms of their formation. We identified 16 individuals with complex insertions among 56,000 individuals tested at Baylor Genetics using clinical array comparative genomic hybridization (aCGH) and fluorescence in situ hybridization (FISH). Custom high-density aCGH was performed on 10 individuals with available DNA, and breakpoint junctions were fine-mapped at nucleotide resolution by long-range PCR and DNA sequencing in 6 individuals to glean insights into potential mechanisms of formation. We observed microhomologies and templated insertions at the breakpoint junctions, resembling the breakpoint junction signatures found in complex genomic rearrangements generated by replication-based mechanism(s) with iterative template switches. In addition, we analyzed 5 families with apparently balanced insertion in one parent detected by FISH analysis and found that 3 parents had additional small copy-number variants (CNVs) at one or both sides of the inserting fragments as well as at the inserted sites. We propose that replicative repair can result in interchromosomal complex insertions generated through chromothripsis-like chromoanasynthesis involving two or three chromosomes, and cause a significant fraction of apparently balanced insertions harboring small flanking CNVs.
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http://dx.doi.org/10.1371/journal.pgen.1006446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120786PMC
November 2016

Prenatal detection of 10q22q23 duplications: dilemmas in phenotype prediction.

Prenat Diagn 2016 Dec 29;36(13):1211-1216. Epub 2016 Nov 29.

Department of Obstetrics and Gynecology, The Chinese University of Hong Kong, Hong Kong.

Objectives: The phenotype for 10q22q23 duplication is diverse, ranging from intellectual disability and dysmorphism to normal development. Interpreting the clinical significance of the duplication identified in this region is difficult, especially in the prenatal setting. This study aimed to characterize the prenatal findings associated with this submicroscopic imbalance and discuss the dilemmas in predicting the phenotype of 10q22q23 duplications.

Methods: This is a retrospective study of three cases of 10q22q23 duplications diagnosed prenatally by chromosomal microarray analysis. Detailed pregnancy outcome and pediatric follow-up were documented.

Results: The genotypic and phenotypic features of the reported cases were discussed. 10q22q23 duplications are associated with an unpredictable and variable phenotypic outcome. Despite there was no phenotype found to be shared by 50% of the duplication cases, congenital heart defects, hypotelorism, and developmental delays including speech and motor delay seem to be more common.

Conclusions: The phenotype of 10q22q23 duplication is highly variable prenatally and postnatally. Identification of additional affected individuals with similar duplications is needed to provide further insights into the pathogenesis of this microduplication. © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/pd.4959DOI Listing
December 2016

DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome.

Am J Hum Genet 2016 09 25;99(3):555-566. Epub 2016 Aug 25.

Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. Electronic address:

Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed across ∼1.9 Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.
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http://dx.doi.org/10.1016/j.ajhg.2016.06.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5011056PMC
September 2016

4p16.3 microdeletions and microduplications detected by chromosomal microarray analysis: New insights into mechanisms and critical regions.

Am J Med Genet A 2016 10 10;170(10):2540-50. Epub 2016 Jun 10.

Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas.

Deletions in the 4p16.3 region cause Wolf-Hirschhorn syndrome, a well known contiguous microdeletion syndrome with the critical region for common phenotype mapped in WHSCR2. Recently, duplications in 4p16.3 were reported in three patients with developmental delay and dysmorphic features. Through chromosomal microarray analysis, we identified 156 patients with a deletion (n = 109) or duplication (n = 47) in 4p16.3 out of approximately 60,000 patients analyzed by Baylor Miraca Genetics Laboratories. Seventy-five of the postnatally detected deletions encompassed the entire critical region, 32 (43%) of which were associated with other chromosome rearrangements, including six patients (8%) that had a duplication adjacent to the terminal deletion. Our data indicate that Wolf-Hirschhorn syndrome deletions with an adjacent duplication occur at a higher frequency than previously appreciated. Pure deletions (n = 14) or duplications (n = 15) without other copy number changes distal to or inside the WHSCR2 were identified for mapping of critical regions. Our data suggest that deletion of the segment from 0.6 to 0.9 Mb from the terminus of 4p causes a seizure phenotype and duplications of a region distal to the previously defined smallest region of overlap for 4p16.3 microduplication syndrome are associated with neurodevelopmental problems. We detected seven Wolf-Hirschhorn syndrome deletions and one 4p16.3 duplication prenatally; all of the seven are either >8 Mb in size and/or associated with large duplications. In conclusion, our study provides deeper insight into the molecular mechanisms, the critical regions and effective prenatal diagnosis for 4p16.3 deletions/ duplications. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37796DOI Listing
October 2016