Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation

Handle URI:
http://hdl.handle.net/10754/623796
Title:
Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation
Authors:
Monies, Dorota ( 0000-0001-5785-6799 ) ; Maddirevula, Sateesh; Kurdi, Wesam ( 0000-0001-7958-8123 ) ; Alanazy, Mohammed H. ( 0000-0001-5177-8283 ) ; Alkhalidi, Hisham ( 0000-0002-7094-5646 ) ; Al-Owain, Mohammed; Sulaiman, Raashda A. ( 0000-0002-6868-9823 ) ; Faqeih, Eissa; Goljan, Ewa; Ibrahim, Niema; Abdulwahab, Firdous; Hashem, Mais; Abouelhoda, Mohamed; Shaheen, Ranad ( 0000-0002-2590-1759 ) ; Arold, Stefan T. ( 0000-0001-5278-0668 ) ; Alkuraya, Fowzan S.
Abstract:
The purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.Our results show that, in the era of genomic sequencing and
KAUST Department:
Biological and Environmental Sciences and Engineering (BESE) Division; Computational Bioscience Research Center (CBRC)
Citation:
Monies D, Maddirevula S, Kurdi W, Alanazy MH, Alkhalidi H, et al. (2017) Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genetics in Medicine. Available: http://dx.doi.org/10.1038/gim.2017.22.
Publisher:
Springer Nature
Journal:
Genetics in Medicine
Issue Date:
6-Apr-2017
DOI:
10.1038/gim.2017.22
Type:
Article
ISSN:
1098-3600; 1530-0366
Additional Links:
http://www.nature.com/gim/journal/vaop/ncurrent/full/gim201722a.html
Appears in Collections:
Articles; Computational Bioscience Research Center (CBRC); Biological and Environmental Sciences and Engineering (BESE) Division

Full metadata record

DC FieldValue Language
dc.contributor.authorMonies, Dorotaen
dc.contributor.authorMaddirevula, Sateeshen
dc.contributor.authorKurdi, Wesamen
dc.contributor.authorAlanazy, Mohammed H.en
dc.contributor.authorAlkhalidi, Hishamen
dc.contributor.authorAl-Owain, Mohammeden
dc.contributor.authorSulaiman, Raashda A.en
dc.contributor.authorFaqeih, Eissaen
dc.contributor.authorGoljan, Ewaen
dc.contributor.authorIbrahim, Niemaen
dc.contributor.authorAbdulwahab, Firdousen
dc.contributor.authorHashem, Maisen
dc.contributor.authorAbouelhoda, Mohameden
dc.contributor.authorShaheen, Ranaden
dc.contributor.authorArold, Stefan T.en
dc.contributor.authorAlkuraya, Fowzan S.en
dc.date.accessioned2017-05-31T11:23:06Z-
dc.date.available2017-05-31T11:23:06Z-
dc.date.issued2017-04-06en
dc.identifier.citationMonies D, Maddirevula S, Kurdi W, Alanazy MH, Alkhalidi H, et al. (2017) Autozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretation. Genetics in Medicine. Available: http://dx.doi.org/10.1038/gim.2017.22.en
dc.identifier.issn1098-3600en
dc.identifier.issn1530-0366en
dc.identifier.doi10.1038/gim.2017.22en
dc.identifier.urihttp://hdl.handle.net/10754/623796-
dc.description.abstractThe purpose of this study is to describe recessive alleles in strictly dominant genes. Identifying recessive mutations in genes for which only dominant disease or risk alleles have been reported can expand our understanding of the medical relevance of these genes both phenotypically and mechanistically. The Saudi population is enriched for autozygosity, which enhances the homozygous occurrence of alleles, including pathogenic alleles in genes that have been associated only with a dominant inheritance pattern.Exome sequencing of patients from consanguineous families with likely recessive phenotypes was performed. In one family, the genotype of the deceased children was inferred from their parents due to lack of available samples.We describe the identification of 11 recessive variants (5 of which are reported here for the first time) in 11 genes for which only dominant disease or risk alleles have been reported. The observed phenotypes for these recessive variants were novel (e.g., FBN2-related myopathy and CSF1R-related brain malformation and osteopetrosis), typical (e.g., ACTG2-related visceral myopathy), or an apparently healthy state (e.g., PDE11A), consistent with the corresponding mouse knockout phenotypes.Our results show that, in the era of genomic sequencing anden
dc.publisherSpringer Natureen
dc.relation.urlhttp://www.nature.com/gim/journal/vaop/ncurrent/full/gim201722a.htmlen
dc.titleAutozygosity reveals recessive mutations and novel mechanisms in dominant genes: implications in variant interpretationen
dc.typeArticleen
dc.contributor.departmentBiological and Environmental Sciences and Engineering (BESE) Divisionen
dc.contributor.departmentComputational Bioscience Research Center (CBRC)en
dc.identifier.journalGenetics in Medicineen
dc.contributor.institutionSaudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Obstetrics and Gynecology, King Faisal Specialist Hospital, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Internal Medicine, King Saud University Medical City and College of Medicine, King Saud University, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Pathology, King Saud University Medical City and College of Medicine, King Saud University, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.en
dc.contributor.institutionDepartment of Pediatric Subspecialties, Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.en
kaust.authorArold, Stefan T.en
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