Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing

@article{Mouden2016ComplexMO,
  title={Complex mode of inheritance in holoprosencephaly revealed by whole exome sequencing},
  author={Charlotte Mouden and Christ{\`e}le Dubourg and Wilfrid Carr{\'e} and Sophie Rose and Chlo{\'e} Qu{\'e}lin and Linda Akloul and Houda Hamdi-Roz{\'e} and G{\'e}raldine Viot and Houria Salhi and Pierre Darnault and Sylvie Odent and Val{\'e}rie Dup{\'e} and V{\'e}ronique David},
  journal={Clinical Genetics},
  year={2016},
  volume={89}
}
Holoprosencephaly (HPE) is the most common congenital cerebral malformation, characterized by impaired forebrain cleavage and midline facial anomalies. Heterozygous mutations in 14 genes have been associated with HPE and are often inherited from an unaffected parent, underlying complex genetic bases. It is now emerging that HPE may result from a combination of multiple genetic events, rather than from a single heterozygous mutation. To explore this hypothesis, we undertook whole exome… 
View on Wiley
hal-univ-rennes1.archives-ouvertes.fr
37 Citations
Highly Influential Citations
3
Background Citations
18
Methods Citations
2

37 Citations

Citation Type

Citation Type

Mutational Spectrum in Holoprosencephaly Shows That FGF is a New Major Signaling Pathway
TLDR
It is demonstrated that fibroblast growth factor signaling must now be considered a major pathway involved in HPE and supports that the implementation of NGS in HPe diagnosis is required to improve genetic counseling.
Further evidence for complex inheritance of holoprosencephaly: Lessons learned from pre‐ and postnatal diagnostic testing in Germany
TLDR
Advances in prenatal imaging over the last years are presented, 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.
Case report: a novel mutation in ZIC2 in an infant with microcephaly, holoprosencephaly, and arachnoid cyst
TLDR
This is the first identification of a mutated ZIC2 gene in a Han infant girl with mild microcephaly, semilobor HPE, and arachnoid cyst, and extensive bioinformatics analysis confirmed the pathogenicity of this extremely rare mutation.
New SHH and Known SIX3 Variants in a Series of Latin American Patients with Holoprosencephaly
TLDR
Nine patients, including 2 with SHH pathogenic variants, presented benign variants of the SHH, SIX3, ZIC2, and TGIF1 genes with potential alteration of splicing, a causal proposition in need of further studies.
Integrated Clinical and Omics Approach to Rare Diseases: Novel Genes and Oligogenic Inheritance in Holoprosencephaly
TLDR
This study reports novel HPE-relevant genes and reveals the existence of oligogenic cases resulting from several mutations in SHH-related genes, which underlines that integrating clinical phenotyping in genetic studies will improve the identification of causal variants in rare disorders.
Integrated clinical and omics approach to rare diseases: novel genes and oligogenic inheritance in holoprosencephaly
TLDR
It is hypothesized that distinction between different clinical manifestations of holoprosencephaly lies in the degree of overall functional impact on SHH signalling, and underline that integrating clinical phenotyping in genetic studies is a powerful tool to specify the clinical relevance of certain mutations.
Recent advances in understanding inheritance of holoprosencephaly
TLDR
The main purpose is to present different inheritance patterns that exist for HPE with a particular emphasis on oligogenic inheritance and its implications in genetic counseling.
BOC is a modifier gene in holoprosencephaly
TLDR
In addition to heterozygous loss‐of‐function mutations in specific SHH pathway genes and an ill‐defined environmental component, the findings identify a third variable in HPE: low‐frequency modifier genes, BOC being the first identified.
ZIC2 in Holoprosencephaly.
TLDR
Recent study of genotype-phenotype correlations in HPE cases has defined distinctive features of ZIC2-associated HPE presentation and genetics, revealing that Zic2 mutation does not produce the craniofacial abnormalities generally thought to characterise HPE but leads to a range of non-forebrain phenotypes.
Investigation of new candidate genes in a cohort of patients with familial congenital hypopituitarism and associated disorders
TLDR
This study identifies the first novel homozygous mutation in the LHX4 gene, p.T126M, in two deceased brothers from a pedigree with combined pituitary hormone deficiency with subsequent fatal consequences, and identifies six new candidate genes that were identified in phenotypically unique pedigrees submitted to GOSgene for exome sequencing.
...
1
2
3
4
...

References

SHOWING 1-10 OF 78 REFERENCES
Homozygous STIL Mutation Causes Holoprosencephaly and Microcephaly in Two Siblings
TLDR
In situ hybridization experiments using chick embryos demonstrated that expression of Stil was in accordance with a function during early patterning of the forebrain, supporting the genetic heterogeneity of HPE and increases the panel of genes to be tested for HPE diagnosis.
New findings for phenotype–genotype correlations in a large European series of holoprosencephaly cases
TLDR
An algorithm is proposed based on these new phenotype–genotype correlations, to facilitate molecular analysis and genetic counselling for HPE, and a significant correlation was found between renal/urinary defects and mutations of SHH and ZIC2.
Recurrent partial rhombencephalosynapsis and holoprosencephaly in siblings with a mutation of ZIC2
TLDR
Two half sisters with alobar or semi‐lobar holoprosencephaly (HPE) and partial RES were identified, suggesting that genes linked to HPE may also contribute to RES, and a deletion of seven base pairs in exon one of the ZIC2 gene (c.392_98del7) was identified in each of the two half sisters.
Mutations in the human Sonic Hedgehog gene cause holoprosencephaly
TLDR
The identification of human Sonic Hedgehog (SHH) as HPE3 — the first known gene to cause HPE is reported, and five families that segregate different heterozygous SHH mutations are found that predict premature termination of the SHH protein.
The mutational spectrum of the sonic hedgehog gene in holoprosencephaly: SHH mutations cause a significant proportion of autosomal dominant holoprosencephaly.
TLDR
It is suggested that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.
A Hypomorphic Allele in the FGF8 Gene Contributes to Holoprosencephaly and Is Allelic to Gonadotropin-Releasing Hormone Deficiency in Humans
TLDR
A total of 8 sequence variations in HPE patients are described, including a putative loss-of-function mutation in 3 members of a family with variable forms of classic HPE, and these findings are related to the phenotypes seen in other conditions.
Clinical spectrum of SIX3-associated mutations in holoprosencephaly: correlation between genotype, phenotype and function
TLDR
The data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype–phenotype correlation, as shown by functional studies using animal models.
Genotypic and phenotypic analysis of 396 individuals with mutations in Sonic Hedgehog
TLDR
HPE is more frequent in individuals with truncating mutations, but clinical predictions at the individual level remain elusive, and no specific genotype―phenotype correlations could be established regarding mutation location.
Holoprosencephaly due to mutations in ZIC2, a homologue of Drosophila odd-paired
TLDR
It is reported that human Z IC2 maps to this critical deletion region and that heterozygous mutations in ZIC2 are associated with HPE, and that Haploinsufficiency for Zic2 is likely to cause the brain malformations seen in 13q deletion patients.
Holoprosencephaly: new models, new insights
  • R. Krauss
  • Biology
    Expert Reviews in Molecular Medicine
  • 2007
TLDR
The new animal models described in this review suggest that human HPE arises from a complex interaction between the timing and strength of developmental signalling pathways, genetic variation and exposure to environmental agents.
...
1
2
3
4
5
...