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01.12.2018 | Research | Ausgabe 1/2018 Open Access

Orphanet Journal of Rare Diseases 1/2018

Targeted next-generation sequencing analysis in couples at increased risk for autosomal recessive disorders

Orphanet Journal of Rare Diseases > Ausgabe 1/2018
Katalin Komlosi, Stefan Diederich, Desiree Lucia Fend-Guella, Oliver Bartsch, Jennifer Winter, Ulrich Zechner, Michael Beck, Peter Meyer, Susann Schweiger
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13023-018-0763-0) contains supplementary material, which is available to authorized users.



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.


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.


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.


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.
Additional file 1: Table S1. List of the 430 genes investigated in the couples. Additional file listing the 430 genes for severe AR and XL disorders investigated in the couples (XLS 142 kb)
Additional file 2: Table S2. Additional variants in the couples. Additional file describing additional possibly pathogenic variants in the couples and sequencing quality of the variants (DOCX 21 kb)
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