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Additional file 1. Bibliographical Information of Analysed Publications. A list providing full bibliographical information of all 87 publications included in the analysis of this systematic review.

TA-SWISS / Zentrum für Technologiefolgen-Abschätzung, 63/2016, ISBN:978-37281-3749-4, ISBN:978-3-7281-3748-7

Sequencing results of GARNL3 in 192 patients with ID/DD.

Sequencing results of GARNL3 in 192 patients with ID/DD.

OBJECTIVE The aim of this study is to assess the rate of prenatal detection of multiple congenital contractures to identify reasons for the failure of prenatal diagnosis and to propose the first guidelines to improve prenatal diagnosis. METHOD We evaluated records on 107 individuals recognized at birth to have Amyoplasia. We reviewed the literature on the onset and development of fetal activity antenatal clinical signs in fetal movement disorders prenatal studies of fetal movement and contractures by ultrasound and magnetic resonance imaging (MRI) and existing guidelines. RESULT In 73.8 the diagnosis was missed prenatally. Correct diagnosis was achieved by the identification of bilateral clubfeet on ultrasound or because mothers perceived reduced fetal movement. Ultrasound would be able to visualize contractures joint positioning the quality of fetal movements lung size muscle tissue and bone growth in the first or early second trimester. MRI results are promising. Guidelines for assessing early fetal movement do not exist. CONCLUSION Prenatal detection rate of multiple congenital contractures is appalling. Failure of diagnosis precludes further etiologic and diagnostic workup and deprives families of making informed pregnancy choices. Standards for prenatal diagnosis are lacking but on the basis of current knowledge and expert opinion we propose the first guidelines for a prenatal diagnostic strategy discuss future directions and the need for multicentric studies.

The extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified. Polish National Science Centre [UMO-2016/22/E/NZ5/00270]; Deutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [SP1532/3-1, SP1532/4-1, SP1532/5-1]; Max Planck FoundationFoundation CELLEX; Deutsches Zentrum fur Luft-und Raumfahrt (DLR)Helmholtz AssociationGerman Aerospace Centre (DLR) [01GM1925]; Projekt DEAL Open Access funding enabled and organized by Projekt DEAL. A.J. was supported by the grant from the Polish National Science Centre UMO-2016/22/E/NZ5/00270. M.S. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SP1532/31, SP1532/4-1 and SP1532/5-1), the Max Planck Foundation and the Deutsches Zentrum fur Luft-und Raumfahrt (DLR 01GM1925).