Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

Riggs, Erin Rooney; Nelson, Tristan; Merz, Andrew; Ackley, Todd; Bunke, Brian; Collins, Christin; Collinson, Morag N.; Fan, Yao Shan; Goodenberger, McKinsey L.; Golden, Denae M.; Haglund-Hazy, Linda; Krgovic, Danijela; Lamb, Allen N.; Lewis, Zoe K; Li, Guang; Liu, Yajuan; Meck, Jeanne; Neufeld-Kaiser, Whitney; Runke, Cassandra; Sanmann, Jennifer N.; Stavropoulos, Dimitri J.; Strong, Emma; Su, Meng; Tayeh, Marwan K.; Vokač, Nadja Kokalj; Thorland, Erik C.; Andersen, Erica; Martin, Christa Lese

doi:10.1002/humu.23610

Cited by 26 publications

(34 citation statements)

References 39 publications

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“…These reported copy number aberrations indicate that HAND2 is dosage sensitive, which is consistent with its DECIPHER haploinsufficiency index of 1.56% (0–10% score = more likely to exhibit haploinsufficiency) (Huang, Lee, Marcotte, & Hurles, 2010). However, haplosensitivity and triplosensitivity scores have yet to be defined by ClinGen (Riggs et al, 2018), and the Human Mutation Database (HGMD) currently only includes two disease causing (p.Leu47Pro, p.Ser65Ile) and three likely disease causing (p.Pro11Arg, p.Val83Leu, p.Ala31_Ala32dup) HAND2 sequence variants.…”

Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the basic helix–loop–helix transcription factorHAND2causes congenital heart defects

Cohen

Simotas

Webb

et al. 2020

American J of Med Genetics Pt A

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Congenital heart defects (CHDs) are caused by a disruption in heart morphogenesis, which is dependent, in part, on a network of transcription factors (TFs) that regulate myocardial development. Heterozygous sequence variants in the basic helix-loophelix TF gene heart and neural crest derivatives expressed 2 (HAND2) have been reported among some patients with CHDs; however, HAND2 has not yet been established as a Mendelian disease gene. We report a 31-month-old male with unicommissural unicuspid aortic valve, moderate aortic stenosis, and mild pulmonic stenosis. Chromosome analysis revealed a normal 46,XY karyotype, and a CHD sequencing panel was negative for pathogenic variants in NKX2.5, GATA4, TBX5, and CHD7. However, chromosomal microarray (CMA) testing identified a heterozygous 546.0-kb deletion on chromosome 4q34.1 (174364195_174910239[GRCh37/hg19]) that included exons 1 and 2 of SCRG1, HAND2, and HAND2-AS1. Familial CMA testing determined that the deletion was paternally inherited, which supported a likely pathogenic classification as the proband's father had previously undergone surgery for Tetralogy of Fallot. The family history was also notable for a paternal uncle who had previously died from complications related to an unknown heart defect. Taken together, this first report of a HAND2 and HAND2-AS1 deletion in a family with CHDs strongly supports haploinsufficiency of HAND2 as an autosomal dominant cause of CHD. K E Y W O R D S chromosomal microarray, congenital heart defects, HAND2, stenosis, Tetralogy of Fallot

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Section: Discussionmentioning

confidence: 99%

Haploinsufficiency of the basic helix–loop–helix transcription factorHAND2causes congenital heart defects

Cohen

Simotas

Webb

et al. 2020

American J of Med Genetics Pt A

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“…(i) The stop sites of predicted uORFs are significantly more conserved than all UTR bases matched on gene and distance from the CDS (Fisher's P =1.8x10 -17 ). uORF stop bases are most highly conserved when (ii) the uORF has evidence of translation, (iii) the variant results in an oORF, (iv) the uORF start site has a strong/moderate Kozak The increased power of this analysis enables us to convincingly demonstrate that uORF stop sites upstream of (1) LoF intolerant genes, (2) genes manually curated as haploinsufficient 24 , and (3) developmental disorder genes with a dominant LoF mechanism, are all highly conserved. Stop sites upstream of genes in these groups have 21.9%, 29.6% and 31.6% of bases with PhyloP >2, respectively (Fisher's P =8.2x10 -250 , 4.7x10 -43 and 1.4x10 -52 compared to all stop site bases, respectively; Figure 2c), suggesting that removing these stop sites is likely to be deleterious.…”

Section: Variants That Disrupt Stop Codons Of Existing Uorfs Also Shomentioning

confidence: 94%

“…(iii) The deleteriousness of uAUG-creating variants depends on the context into which they are created, with stronger selection against uAUG-creation close to the CDS, and with a stronger Kozak consensus sequence. (iv) uAUG-creating variants are under strong negative selection upstream of genes manually curated as haploinsufficient 24…”

Section: Uaug-creating Variants Are Under Strong Negative Selectionmentioning

confidence: 99%

Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals

Whiffin¹,

Kj²,

Zhang³

et al. 2019

Preprint

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Upstream open reading frames (uORFs) are important tissue-specific cis -regulators of protein translation. Although isolated case reports have shown that variants that create or disrupt uORFs can cause disease, genetic sequencing approaches typically focus on protein-coding regions and ignore these variants. Here, we describe a systematic genome-wide study of variants that create and disrupt human uORFs, and explore their role in human disease using 15,708 whole genome sequences collected by the Genome Aggregation Database (gnomAD) project. We show that 14,897 variants that create new start codons upstream of the canonical coding sequence (CDS), and 2,406 variants disrupting the stop site of existing uORFs, are under strong negative selection. Furthermore, variants creating uORFs that overlap the CDS show signals of selection equivalent to coding loss-of-function variants, and uORF-perturbing variants are under strong selection when arising upstream of known disease genes and genes intolerant to loss-of-function variants. Finally, we identify specific genes where perturbation of uORFs is likely to represent an important disease mechanism, and report a novel uORF frameshift variant upstream of NF2 in families with neurofibromatosis. Our results highlight uORF-perturbing variants as an important and under-recognised functional class that can contribute to penetrant human disease, and demonstrate the power of large-scale population sequencing data to study the deleteriousness of specific classes of non-coding variants.

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“…CNVs were called using CNVnator (v.0.2.7) 51 and structural variations with Breakdancer 52 and CREST 53 . A secondary, overlapping CNV discovery analysis was performed by binning into 10 kb windows, filtering by calling loss of heterozygosity (LoH) in more than 95% of variants in flagged regions 54,55 and annotating using ClinGen Gene Dosage Sensitivity (27-09-2017 release). Structural variations were called and included in the analysis using Breakdancer 52 .…”

Section: Methodsmentioning

confidence: 99%

Genome sequencing of human in vitro fertilisation embryos for pathogenic variation screening

Murphy

Samarasekera

Macaskill

et al. 2020

Sci Rep

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Whole-genome sequencing of preimplantation human embryos to detect and screen for genetic diseases is a technically challenging extension to preconception screening. combining preconception genetic screening with preimplantation testing of human embryos facilitates the detection of de novo mutations and self-validates transmitted variant detection in both the reproductive couple and the embryo's samples. Here we describe a trio testing workflow that involves whole-genome sequencing of amplified DNA from biopsied embryo trophectoderm cells and genomic DNA from both parents. Variant prediction software and annotation databases were used to assess variants of unknown significance and previously not described de novo variants in five single-gene preimplantation genetic testing couples and eleven of their embryos. Pathogenic variation, tandem repeat, copy number and structural variations were examined against variant calls for compound heterozygosity and predicted disease status was ascertained. Multiple trio testing showed complete concordance with known variants ascertained by single-nucleotide polymorphism array and uncovered de novo and transmitted pathogenic variants. this pilot study describes a method of whole-genome sequencing and analysis for embryo selection in high-risk couples to prevent early life fatal genetic conditions that adversely affect the quality of life of the individual and families. Whole-genome sequencing in the iVf clinic. For over two decades, preimplantation genetic testing (PGT) has been available for couples who are aware they carry a genetic condition or have had a child affected by a genetic disease. In vitro fertilisation (IVF) used in conjunction with monogenic PGT is available for couples to prevent transmission of known hereditary monogenic disorders. PGT for aneuploidy screens embryos for large segmental or whole-chromosome copy number changes and is commonly used for older women (>35 years) who have a history of infertility, miscarriages or chromosomally abnormal conceptions 1-3. The most recent developments in clinical PGT are low-coverage next-generation sequencing and Karyomapping, which uses a highly polymorphic single-nucleotide polymorphism (SNP) microarray to identify disease-causing haplotypes. Nextgeneration sequencing PGT for aneuploidy (typically <0.1× depth) is useful for high-throughput screening at a reasonable cost for detecting chromosomal aneuploidies, structural variations and large copy-number variations (CNVs) 4-6. In addition to pedigree analysis for monogenic disorders, Karyomapping has been reported to identify partial chromosomal aneuploidies as small as 1.8 Mb 7. For couples seeking to ascertain their risk of having an affected child, around 6,000 diseases exist that may be genetically screened for 8. A mutation or disease-causing variant in one or both copies of approximately 5,000 human genes can cause a syndromic disease or phenotype 9-14. Between 0.5-5% of infants are born with a genetic condition or disorder 15,16. The preconception genetic screening...

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Copy number variant discrepancy resolution using the ClinGen dosage sensitivity map results in updated clinical interpretations in ClinVar

Cited by 26 publications

References 39 publications

Haploinsufficiency of the basic helix–loop–helix transcription factorHAND2causes congenital heart defects

Haploinsufficiency of the basic helix–loop–helix transcription factorHAND2causes congenital heart defects

Characterising the loss-of-function impact of 5’ untranslated region variants in whole genome sequence data from 15,708 individuals

Genome sequencing of human in vitro fertilisation embryos for pathogenic variation screening

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