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Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

ABSTRACT: Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group of 14 patients, we determined sex chromosome dosage, copy number variation, and gene mutations. In the patients with a known genetic diagnosis (obtained either on a clinical or research basis), this test identified the molecular cause in 100% (7/7) of patients. In patients in whom no molecular diagnosis had been made, this tool identified a genetic diagnosis in two of seven patients. Targeted sequencing of genes representing a specific spectrum of disorders can result in a higher rate of genetic diagnoses than current diagnostic approaches. Our DSD diagnostic tool provides for first time, in a single blood test, a comprehensive genetic diagnosis in patients presenting with a wide range of urogenital anomalies.

SUBMITTER: Arboleda VA

PROVIDER: S-EPMC4052834 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

Arboleda V A VA Lee H H Sánchez F J FJ Délot E C EC Sandberg D E DE Grody W W WW Nelson S F SF Vilain E E

Clinical genetics 20120501 1

Disorders of sex development (DSD) are rare disorders in which there is discordance between chromosomal, gonadal, and phenotypic sex. Only a minority of patients clinically diagnosed with DSD obtains a molecular diagnosis, leaving a large gap in our understanding of the prevalence, management, and outcomes in affected patients. We created a novel DSD-genetic diagnostic tool, in which sex development genes are captured using RNA probes and undergo massively parallel sequencing. In the pilot group ...[more]

PMID: 22435390

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Project description:There have been two major eras in the history of gene discovery. The first was the era of linkage analysis, with approximately 1,300 disease-related genes identified by positional cloning by the turn of the millennium. The second era has been powered by two major breakthroughs: the publication of the human genome and the development of massively parallel sequencing (MPS). MPS has greatly accelerated disease gene identification, such that disease genes that would have taken years to map previously can now be determined in a matter of weeks. Additionally, the number of affected families needed to map a causative gene and the size of such families have fallen: de novo mutations, previously intractable by linkage analysis, can be identified through sequencing of the parent-child trio, and genes for recessive disease can be identified through MPS even of a single affected individual. MPS technologies include whole exome sequencing (WES), whole genome sequencing (WGS), and panel sequencing, each with their strengths. While WES has been responsible for most gene discoveries through MPS, WGS is superior in detecting copy number variants, chromosomal rearrangements, and repeat-rich regions. Panels are commonly used for diagnostic purposes as they are extremely cost-effective and generate manageable quantities of data, with no risk of unexpected findings. However, in instances of diagnostic uncertainty, it can be challenging to choose the right panel, and in these circumstances WES has a higher diagnostic yield. MPS has ethical, social, and legal implications, many of which are common to genetic testing generally but amplified due to the magnitude of data (e.g., relationship misattribution, identification of variants of uncertain significance, and genetic discrimination); others are unique to WES and WGS technologies (e.g., incidental or secondary findings). Nonetheless, MPS is rapidly translating into clinical practice as an extremely useful part of the clinical armamentarium.

Project description:Although the primary objective of forensic DNA analyses of unidentified human remains is positive identification, cases involving historical or archaeological skeletal remains often lack reference samples for comparison. Massively parallel sequencing (MPS) offers an opportunity to provide biometric data in such cases, and these cases provide valuable data on the feasibility of applying MPS for characterization of modern forensic casework samples. In this study, MPS was used to characterize 140-year-old human skeletal remains discovered at a historical site in Deadwood, South Dakota, United States. The remains were in an unmarked grave and there were no records or other metadata available regarding the identity of the individual. Due to the high throughput of MPS, a variety of biometric markers could be typed using a single sample.Using MPS and suitable forensic genetic markers, more relevant information could be obtained from a limited quantity and quality sample. Results were obtained for 25/26 Y-STRs, 34/34 Y SNPs, 166/166 ancestry-informative SNPs, 24/24 phenotype-informative SNPs, 102/102 human identity SNPs, 27/29 autosomal STRs (plus amelogenin), and 4/8 X-STRs (as well as ten regions of mtDNA). The Y-chromosome (Y-STR, Y-SNP) and mtDNA profiles of the unidentified skeletal remains are consistent with the R1b and H1 haplogroups, respectively. Both of these haplogroups are the most common haplogroups in Western Europe. Ancestry-informative SNP analysis also supported European ancestry. The genetic results are consistent with anthropological findings that the remains belong to a male of European ancestry (Caucasian). Phenotype-informative SNP data provided strong support that the individual had light red hair and brown eyes.This study is among the first to genetically characterize historical human remains with forensic genetic marker kits specifically designed for MPS. The outcome demonstrates that substantially more genetic information can be obtained from the same initial quantities of DNA as that of current CE-based analyses.

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Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

Publications

Targeted massively parallel sequencing provides comprehensive genetic diagnosis for patients with disorders of sex development.

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