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  Identification of a molecular defect in a stillborn fetus with perinatal lethal hypophosphatasia using a disease-associated genome sequencing approach

Olech, E. M., Zemojtel, T., Sowinska-Seidler, A., Mundlos, S., Robinson, P. N., Karczewski, M., et al. (2016). Identification of a molecular defect in a stillborn fetus with perinatal lethal hypophosphatasia using a disease-associated genome sequencing approach. Polish Journal of Pathology, 67(1), 78-83. doi:10.5114/pjp.2016.59480.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1A35-B Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002E-1A36-9
Genre: Journal Article

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© 2017 Polish Association of Pathologists and the Polish Branch of the International Academy of Pathology

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 Creators:
Olech, E. M., Author
Zemojtel, T., Author
Sowinska-Seidler, A., Author
Mundlos, S.1, Author              
Robinson, P. N.1, Author              
Karczewski, M., Author
Jamsheer, A., Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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Free keywords: Alkaline Phosphatase/*genetics High-Throughput Nucleotide Sequencing Humans Hypophosphatasia/*genetics Male Mutation, Missense Stillbirth/*genetics
 Abstract: Lethal skeletal disorders represent a heterogeneous and clinically variable group of genetic conditions, usually difficult to diagnose without post-mortem radiological assessment. Here we report on a stillborn patient delivered at 22 weeks of gestation who presented with severe skeletal symptoms comprising limb shortening and intrauterine fractures detected upon prenatal ultrasound and autopsy examination. Since post-mortem X-ray was refused and no phenotypic diagnosis could be attempted, we performed next-generation sequencing (NGS) of 2741 genes associated with all known Mendelian disorders. With this strategy, we were able to demonstrate the diagnosis at a molecular level, which turned out to be perinatal lethal hypophosphatasia (HPP). This severe form of HPP represents an inborn defect of ossification often resulting in stillbirth or postnatal death. The NGS panel revealed compound heterozygous ALPL missense mutations: c.1283G>C(p.Arg428Pro) and c.1363G>A(p.Gly455Ser). Mutations detected in our case, although previously described in other patients, have not been reported to co-occur in a single individual. The diagnosis established in our index using the NGS-based approach could have been successfully reached by standard radiography. Thus, our report points to the importance of X-ray examination in stillborn cases and highlights the emerging role of NGS strategies in the diagnostic process of prenatally manifesting skeletal disorders.

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Language(s): eng - English
 Dates: 2016-03
 Publication Status: Published in print
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 Identifiers: DOI: 10.5114/pjp.2016.59480
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Title: Polish Journal of Pathology
Source Genre: Journal
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Pages: - Volume / Issue: 67 (1) Sequence Number: - Start / End Page: 78 - 83 Identifier: ISSN: 1233-9687