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

Ewelina M. Olech; Tomasz Zemojtel; Anna Sowińska-Seidler; Peter N. Robinson; Stefan Mundlos; Marek Karczewski; Aleksander Jamsheer

doi:10.5114/pjp.2016.59480

eISSN: 2084-9869
ISSN: 1233-9687

Polish Journal of Pathology

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abstract:

Original paper

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

Ewelina M. Olech

,

Tomasz Zemojtel

,

Anna Sowińska-Seidler

,

Peter N. Robinson

,

Stefan Mundlos

,

Marek Karczewski

,

Aleksander Jamsheer

Pol J Pathol 2016; 67 (1): 78-83

DOI: https://doi.org/10.5114/pjp.2016.59480

Online publish date: 2016/05/10

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AMA

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

APA

Olech, E., Zemojtel, T., Sowińska-Seidler, A., Robinson, P., Mundlos, S.,  & 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. https://doi.org/10.5114/pjp.2016.59480

Chicago

Olech, Ewelina M., Tomasz Zemojtel, Anna Sowińska-Seidler, Peter N. Robinson, Stefan Mundlos, Marek Karczewski,  and Aleksander Jamsheer. 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.

Harvard

Olech, E., Zemojtel, T., Sowińska-Seidler, A., Robinson, P., Mundlos, S., Karczewski, M.,  and Jamsheer, A. (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), pp.78-83. https://doi.org/10.5114/pjp.2016.59480

MLA

Olech, Ewelina M. et al. "Identification of a molecular defect in a stillborn fetus with perinatal lethal hypophosphatasia using a disease-associated genome sequencing approach." Polish Journal of Pathology, vol. 67, no. 1, 2016, pp. 78-83. doi:10.5114/pjp.2016.59480.

Vancouver

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

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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.

keywords:

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

Ewelina M. Olech , Tomasz Zemojtel , Anna Sowińska-Seidler , Peter N. Robinson , Stefan Mundlos , Marek Karczewski , Aleksander Jamsheer

hypophosphatasia, ALPL, skeletal dysplasia, prenatal diagnosis, NGS

Ewelina M. Olech

,

Tomasz Zemojtel

,

Anna Sowińska-Seidler

,

Peter N. Robinson

,

Stefan Mundlos

,

Marek Karczewski

,

Aleksander Jamsheer