Back to Search
Start Over
Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders
- Source :
- Orphanet Journal of Rare Diseases, Orphanet Journal of Rare Diseases, Vol 13, Iss 1, Pp 1-11 (2018)
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Background Many of the genetic childhood disorders leading to death in the pre- or neonatal period or during early childhood follow autosomal recessive modes of inheritance and bear specific challenges for genetic counseling and prenatal diagnostics. Parents are carriers but clinically unaffected, and diseases are rare but have recurrence risks of 25% in the same family. Often, affected children (or fetuses) die before a genetic diagnosis can be established, post-mortem analysis and phenotypic descriptions are insufficient and DNA from affected fetuses or children is not available for later analysis. A genetic diagnosis showing biallelic causative mutations is, however, the requirement for targeted carrier testing in parents and prenatal and preimplantation genetic diagnosis in further pregnancies. Methods We undertook targeted next-generation sequencing (NGS) for carrier screening of autosomal recessive lethal disorders in 8 consanguineous and 5 non-consanguineous couples with one or more affected children. We searched for heterozygous variants (non-synonymous coding or splice variants) in parents’ DNA, using a set of 430 genes known to be causative for rare autosomal recessive diseases with poor prognosis, and then filtering for variants present in genes overlapping in both partners. Putative pathogenic variants were tested for cosegregation in affected fetuses or children where material was available. Results The diagnosis for the premature death in children was established in 5 of the 13 couples. Out of the 8 couples in which no causative diagnosis could be established 4 consented to undergo further analysis, in two of those a potentially causative variant in a novel candidate gene was identified. Conclusions For the families in whom causative variants could be identified, these may now be used for prenatal and preimplantation genetic diagnostics. Our data show that NGS based gene panel sequencing of selected genes involved in lethal autosomal recessive disorders is an effective tool for carrier screening in parents and for the identification of recessive gene defects and offers the possibility of prenatal and preimplantation genetic diagnosis in further pregnancies in families that have experienced deaths in early childhood and /or multiple abortions. Electronic supplementary material The online version of this article (10.1186/s13023-018-0763-0) contains supplementary material, which is available to authorized users.
- Subjects :
- panel diagnostics
Male
0301 basic medicine
Candidate gene
Genetic counseling
lcsh:Medicine
carrier screening
Genes, Recessive
030105 genetics & heredity
Carrier testing
Preimplantation genetic diagnosis
DNA sequencing
03 medical and health sciences
Humans
Medicine
Pharmacology (medical)
Gene
Genetics (clinical)
next generation sequencing
Genetics
business.industry
Research
lcsh:R
High-Throughput Nucleotide Sequencing
autosomal recessive
General Medicine
Microarray Analysis
Phenotype
Human genetics
Pedigree
consanguineous
Female
business
Subjects
Details
- ISSN :
- 17501172
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Orphanet Journal of Rare Diseases
- Accession number :
- edsair.doi.dedup.....dbeb0525641bbb9da951c10d9b8e7702