1. Further evidence for complex inheritance of holoprosencephaly: Lessons learned from pre- and postnatal diagnostic testing in Germany.
- Author
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Hinreiner S, Wieczorek D, Mueller D, Roedl T, Thiel G, Grasshoff U, Chaoui R, and Hehr U
- Subjects
- Brain abnormalities, Brain diagnostic imaging, Brain embryology, Branchial Region abnormalities, Branchial Region diagnostic imaging, Chromosome Deletion, Chromosomes, Human, Pair 1 genetics, Eye Proteins genetics, Facies, Female, Germany, Hedgehog Proteins genetics, High-Throughput Nucleotide Sequencing methods, Holoprosencephaly diagnostic imaging, Homeodomain Proteins genetics, Humans, Male, Microphthalmos diagnosis, Microphthalmos diagnostic imaging, Microphthalmos genetics, Nerve Tissue Proteins genetics, Nuclear Proteins genetics, Pedigree, Pregnancy, Prenatal Diagnosis, Transcription Factors genetics, Homeobox Protein SIX3, Genetic Testing methods, Holoprosencephaly diagnosis, Holoprosencephaly genetics, Mutation
- Abstract
Holoprosencephaly (HPE) has been defined as a distinct clinical entity with characteristic facial gestalt, which may-or may not-be associated with the true brain malformation observed postmortem in autopsy or in pre- or postnatal imaging. Affected families mainly show autosomal dominant inheritance with markedly reduced penetrance and extremely broad clinical variability even between mutation carriers within the same families. We here present advances in prenatal imaging over the last years, increasing the proportion of individuals with HPE identified prenatally including milder HPE forms and more frequently allowing to detect more severe forms already in early gestation. We report the results of diagnostic genetic testing of 344 unrelated patients for HPE at our lab in Germany since the year 2000, which currently with the application of next generation sequencing (NGS) panel sequencing identifies causal mutations for about 31% (12/38) of unrelated individuals with normal chromosomes when compared to about 15% (46/306) using conventional Sanger sequencing and Multiplex Ligation-dependent Probe Amplification (MLPA). More comprehensive genetic testing by our in house NGS panel sequencing of 10 HPE associated genes (MiSeq™ and NextSeq™500, Illumina, Inc., San Diego, CA) not only allowed to include genes with smaller contribution to the phenotype, but may also unravel additional low frequency or more common genetic variants potentially contributing to the observed large intrafamiliar variability and may ultimately guide our understanding of the individual clinical manifestation of this complex developmental disorder., (© 2018 Wiley Periodicals, Inc.)
- Published
- 2018
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