Further evidence for complex inheritance of holoprosencephaly: Lessons learned from pre‐ and postnatal diagnostic testing in Germany

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...

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Bibliographic Details
Published in:American journal of medical genetics. Part C, Seminars in medical genetics Seminars in medical genetics, 2018-06, Vol.178 (2), p.198-205
Main Authors: Hinreiner, Sophie, Wieczorek, Dagmar, Mueller, Dietmar, Roedl, Tanja, Thiel, Gundula, Grasshoff, Ute, Chaoui, Rabih, Hehr, Ute
Format: Article
Language:English
Subjects:
Autopsies
Autopsy
Autosomal dominant inheritance
Brain
Brain - abnormalities
Brain - diagnostic imaging
Brain - embryology
Branchial Region - abnormalities
Branchial Region - diagnostic imaging
Chromosome Deletion
Chromosomes
Chromosomes, Human, Pair 1 - genetics
Developmental disabilities
Diagnostic systems
Diagnostic tests
Eye Proteins - genetics
Facies
Female
Gene sequencing
Genes
Genetic diversity
Genetic screening
Genetic Testing - methods
Genetic variance
Genetics
Germany
Gestation
Hedgehog Proteins - genetics
Heredity
High-Throughput Nucleotide Sequencing - methods
Holoprosencephaly
Holoprosencephaly - diagnosis
Holoprosencephaly - diagnostic imaging
Holoprosencephaly - genetics
Homeobox Protein SIX3
Homeodomain Proteins - genetics
Humans
Male
Medical imaging
Microphthalmos - diagnosis
Microphthalmos - diagnostic imaging
Microphthalmos - genetics
Mutation
Nerve Tissue Proteins - genetics
Neuroimaging
Nuclear Proteins - genetics
Pedigree
Phenotypes
Pregnancy
Prenatal Diagnosis
Transcription Factors - genetics
Variability
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Description
Summary: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.
ISSN:1552-4868
1552-4876
DOI:10.1002/ajmg.c.31625