Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families

Genome Biology - Tập 16 - Trang 1-7 - 2015
Hanan E. Shamseldin1, Maha Tulbah2, Wesam Kurdi2, Maha Nemer2, Nada Alsahan2, Elham Al Mardawi3, Ola Khalifa4,5, Amal Hashem6, Ahmed Kurdi7, Zainab Babay8, Dalal K. Bubshait4,9, Niema Ibrahim1, Firdous Abdulwahab1, Zuhair Rahbeeni4, Mais Hashem1, Fowzan S. Alkuraya1,10
1Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
3Department of Obstetrics and Gynecology, Security Forces Hospital, Riyadh, Saudi Arabia
4Department of Medical Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
5Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
6Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
7Department of Obstetrics and Gynecology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia;
8Department of Obstetrics and Gynecology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
9Department of Pediatrics, King Fahd Hospital of the University, University of Dammam, Dammam, Saudi Arabia
10Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia

Tóm tắt

Identifying genetic variants that lead to discernible phenotypes is the core of Mendelian genetics. An approach that considers embryonic lethality as a bona fide Mendelian phenotype has the potential to reveal novel genetic causes, which will further our understanding of early human development at a molecular level. Consanguineous families in which embryonic lethality segregates as a recessive Mendelian phenotype offer a unique opportunity for high throughput novel gene discovery as has been established for other recessive postnatal phenotypes. We have studied 24 eligible families using autozygosity mapping and whole-exome sequencing. In addition to revealing mutations in genes previously linked to embryonic lethality in severe cases, our approach revealed seven novel candidate genes (THSD1, PIGC, UBN1, MYOM1, DNAH14, GALNT14, and FZD6). A founder mutation in one of these genes, THSD1, which has been linked to vascular permeability, accounted for embryonic lethality in three of the study families. Unlike the other six candidate genes, we were able to identify a second mutation in THSD1 in a family with a less severe phenotype consisting of hydrops fetalis and persistent postnatal edema, which provides further support for the proposed link between this gene and embryonic lethality. Our study represents an important step towards the systematic analysis of “embryonic lethal genes” in humans.

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Genome Biology

Tập 16

1-7

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