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.
Subject(s)
Genetic Testing/methods , Holoprosencephaly/diagnosis , Holoprosencephaly/genetics , Mutation , 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 SIX3ABSTRACT
UNLABELLED: Mutations in the human sonic hedgehog gene (SHH) are the most frequent cause of autosomal dominant inherited holoprosencephaly (HPE), a complex brain malformation resulting from incomplete cleavage of the developing forebrain into two separate hemispheres and ventricles. Here we report the clinical and molecular findings in five unrelated patients with HPE and their relatives with an identified SHH mutation. Three new and one previously reported SHH mutations were identified, a fifth proband was found to carry a reciprocal subtelomeric rearrangement involving the SHH locus in 7q36. An extremely wide intrafamilial phenotypic variability was observed, ranging from the classical phenotype with alobar HPE accompanied by typical severe craniofacial abnormalities to very mild clinical signs of choanal stenosis or solitary median maxillary central incisor (SMMCI) only. Two families were initially ascertained because of microcephaly in combination with developmental delay and/or mental retardation and SMMCI, the latter being a frequent finding in patients with an identified SHH mutation. In other affected family members a delay in speech acquisition and learning disabilities were the leading clinical signs. CONCLUSION: mutational analysis of the sonic hedgehog gene should not only be considered in patients presenting with the classical holoprosencephaly phenotype but also in those with two or more clinical signs of the wide phenotypic spectrum of associated abnormalities, especially in combination with a positive family history.
