Dataset Information

Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.

ABSTRACT:

Purpose

Mendelian phenotypes in humans vary from benign variants to lethal disorders. Embryonic lethal phenotypes that are similar to what has been known for a long time in mice have remained largely unknown because of the difficulty in arriving at a molecular diagnosis. The purpose of this study is to test whether next generation sequencing can reveal the underlying etiology of recurrent fetal loss.

Methods

We hypothesized that exome sequencing combined with autozygome analysis can reveal the underlying mutation in a family in which recurrent fetal loss was likely to be autosomal recessive in origin.

Results

A novel mutation in CHRNA1 was identified. This gene is known to cause multiple pterygium and fetal akinesia syndrome.

Conclusion

This is the first report of exome sequencing to identify the cause of recurrent fetal loss and reveal the diagnosis of a lethal human phenotype. Our results should inspire a systematic examination of the extent of "unborn" Mendelian phenotypes in humans using next-generation sequencing.

SUBMITTER: Shamseldin HE

PROVIDER: S-EPMC3908556 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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Publications

Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.

Shamseldin Hanan E HE Swaid Abdulrahman A Alkuraya Fowzan S FS

Genetics in medicine : official journal of the American College of Medical Genetics 20121004 4

<h4>Purpose</h4>Mendelian phenotypes in humans vary from benign variants to lethal disorders. Embryonic lethal phenotypes that are similar to what has been known for a long time in mice have remained largely unknown because of the difficulty in arriving at a molecular diagnosis. The purpose of this study is to test whether next generation sequencing can reveal the underlying etiology of recurrent fetal loss.<h4>Methods</h4>We hypothesized that exome sequencing combined with autozygome analysis c ...[more]

PMID: 23037934

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Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

Dataset Information

Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.

Purpose

Methods

Results

Conclusion

Publications

Lifting the lid on unborn lethal Mendelian phenotypes through exome sequencing.

Similar Datasets

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