An exome sequencing strategy to diagnose lethal autosomal recessive disorders

2.50
Hdl Handle:
http://hdl.handle.net/11287/593948
Title:
An exome sequencing strategy to diagnose lethal autosomal recessive disorders
Authors:
Ellard, Sian ( 0000-0002-7620-5526 ) ; Kivuva, Emma; Turnpenny, Peter D.; Stals, Karen; Johnson, Matthew; Xie, W.; Caswell, R.; Lango Allen, H.
Abstract:
Rare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies.
Citation:
Eur J Hum Genet. 2015 Mar;23(3):401-4.
Publisher:
Nature
Journal:
European journal of human genetics : EJHG
Issue Date:
1-Mar-2015
URI:
http://hdl.handle.net/11287/593948
DOI:
10.1038/ejhg.2014.120
PubMed ID:
24961629
Additional Links:
http://dx.doi.org/10.1038/ejhg.2014.120
Note:
This article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.
Type:
Journal Article
Language:
eng
ISSN:
1476-5438
Appears in Collections:
2015 RD&E publications; Clinical Genetics (Peninsula Genetics); Molecular Genetics; Molecular Genetics

Full metadata record

DC FieldValue Language
dc.contributor.authorEllard, Sianen
dc.contributor.authorKivuva, Emmaen
dc.contributor.authorTurnpenny, Peter D.en
dc.contributor.authorStals, Karenen
dc.contributor.authorJohnson, Matthewen
dc.contributor.authorXie, W.en
dc.contributor.authorCaswell, R.en
dc.contributor.authorLango Allen, H.en
dc.date.accessioned2016-01-19T12:37:51Zen
dc.date.available2016-01-19T12:37:51Zen
dc.date.issued2015-03-01en
dc.identifier.citationEur J Hum Genet. 2015 Mar;23(3):401-4.en
dc.identifier.issn1476-5438en
dc.identifier.pmid24961629en
dc.identifier.doi10.1038/ejhg.2014.120en
dc.identifier.urihttp://hdl.handle.net/11287/593948en
dc.description.abstractRare disorders resulting in prenatal or neonatal death are genetically heterogeneous. For some conditions, affected fetuses can be diagnosed by ultrasound scan, but this is not usually possible until mid-gestation. There is often limited fetal DNA available for investigation. We investigated a strategy for diagnosing autosomal recessive lethal disorders in non-consanguineous pedigrees with multiple affected fetuses. Exome sequencing was performed to identify genes where each parent is heterozygous for a rare non-synonymous-coding or splicing variant. Putative pathogenic variants were tested for cosegregation in affected fetuses and unaffected siblings. In eight couples of European ancestry, we found on average 1.75 genes (range 0-4) where both parents were heterozygous for rare potentially deleterious variants. A proof-of-principle study detected heterozygous DYNC2H1 variants in a couple whose five fetuses had short-rib polydactyly. Prospective analysis of two couples with multiple pregnancy terminations for fetal akinesia syndrome was performed and a diagnosis was obtained in both the families. The first couple were each heterozygous for a previously reported GLE1 variant, p.Arg569His or p.Val617Met; both were inherited by their two affected fetuses. The second couple were each heterozygous for a novel RYR1 variant, c.14130-2A>G or p.Ser3074Phe; both were inherited by their three affected fetuses but not by their unaffected child. Biallelic GLE1 and RYR1 disease-causing variants have been described in other cases with fetal akinesia syndrome. We conclude that exome sequencing of parental samples can be an effective tool for diagnosing lethal recessive disorders in outbred couples. This permits early prenatal diagnosis in future pregnancies.en
dc.language.isoengen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/ejhg.2014.120en
dc.titleAn exome sequencing strategy to diagnose lethal autosomal recessive disordersen
dc.typeJournal Articleen
dc.identifier.journalEuropean journal of human genetics : EJHGen
dc.description.noteThis article is available via Open Access. Please click on the 'Additional Link' above to access the full-text.en

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