scholarly journals Variable expressivity in a family with an aggrecanopathy

2021 ◽  
Author(s):  
Antoine Denis ◽  
Sami Chergui ◽  
Shuaa Basalom ◽  
Philippe M. Campeau ◽  
Chantal Janelle ◽  
...  
Keyword(s):  
Variable Expressivity

scholarly journals DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
L. C. Schenkel ◽  
E. Aref-Eshghi ◽  
K. Rooney ◽  
J. Kerkhof ◽  
M. A. Levy ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Critical Region ◽  
Deletion Syndrome ◽  
Genetic Defects ◽  
Chromosome 22 ◽  
Incomplete Penetrance ◽  
Variable Size ◽  
Variable Expressivity ◽  
Genome Wide ◽  
22Q13.3 Deletion Syndrome

Abstract Background Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. Results In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. Conclusion We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.

scholarly journals Variable Expressivity of the Beckwith-Wiedemann Syndrome in Four Pedigrees Segregating Loss-of-Function Variants of CDKN1C

Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 706
Author(s):  
Angela Sparago ◽  
Flavia Cerrato ◽  
Laura Pignata ◽  
Francisco Cammarata-Scalisi ◽  
Livia Garavelli ◽  
...  
Keyword(s):  
Cellular Proliferation ◽  
Missense Variant ◽  
Abdominal Wall Defects ◽  
Loss Of Function ◽  
Nonsense Mutations ◽  
Molecular Defects ◽  
Variable Expressivity ◽  
Imprinting Disorder ◽  
Perinatal Lethality ◽  
Intrafamilial Variability

Beckwith-Wiedemann syndrome (BWS) is an imprinting disorder characterized by prenatal and/or postnatal overgrowth, organomegaly, abdominal wall defects and tumor predisposition. CDKN1C is a maternally expressed gene of the 11p15.5 chromosomal region and is regulated by the imprinting control region IC2. It negatively controls cellular proliferation, and its expression or activity are frequently reduced in BWS. In particular, loss of IC2 methylation is associated with CDKN1C silencing in the majority of sporadic BWS cases, and maternally inherited loss-of-function variants of CDKN1C are the most frequent molecular defects of familial BWS. We have identified, using Sanger sequencing, novel CDKN1C variants in three families with recurrent cases of BWS, and a previously reported variant in a woman with recurrent miscarriages with exomphalos. Clinical evaluation of the patients showed variable manifestation of the disease. The frameshift and nonsense variants were consistently associated with exomphalos, while the missense variant caused a less severe phenotype. Pregnancy loss and perinatal lethality were found in the families segregating nonsense mutations. Intrafamilial variability of the clinical BWS features was observed, even between siblings. Our data are indicative of severe BWS phenotypes that, with variable expressivity, may be associated with both frameshift and nonsense variants of CDKN1C.

scholarly journals P38.08: Dehydrated hereditary stomatocytosis showing variable expressivity: Report of two cases and review of the literature

2008 ◽  
Vol 32 (3) ◽  
pp. 443-443
Author(s):  
O. Ami ◽  
A. Nguyen ◽  
L. Garcon ◽  
M. V. Senat ◽  
R. Frydman ◽  
...  
Keyword(s):  
Review Of The Literature ◽  
Variable Expressivity

scholarly journals Incomplete penetrance and variable expressivity: is there a microRNA connection?

BioEssays ◽  
2009 ◽  
Vol 31 (9) ◽  
pp. 981-992 ◽  
Author(s):  
Jasmine K. Ahluwalia ◽  
Manoj Hariharan ◽  
Rhishikesh Bargaje ◽  
Beena Pillai ◽  
Vani Brahmachari
Keyword(s):  
Incomplete Penetrance ◽  
Variable Expressivity

Variable Expressivity of rd-3 Retinal Degeneration Dependent on Background Strain

1993 ◽  
pp. 273-280 ◽  
Author(s):  
John R. Heckenlively ◽  
Bo Chang ◽  
Chen Peng ◽  
Norman L. Hawes ◽  
Thomas H. Roderick
Keyword(s):  
Retinal Degeneration ◽  
Variable Expressivity ◽  
Background Strain

scholarly journals Occurrence of Esophageal Atresia With Tracheoesophageal Fistula in Siblings From Three-Generation Family Affected by Variable Expressivity MYCN Mutation: A Case Report

2021 ◽  
Vol 9 ◽  
Author(s):  
Magdalena Klaniewska ◽  
Krystian Toczewski ◽  
Anna Rozensztrauch ◽  
Michal Bloch ◽  
Agata Dzielendziak ◽  
...  
Keyword(s):  
Esophageal Atresia ◽  
Neural Development ◽  
Tracheoesophageal Fistula ◽  
Phenotypic Expression ◽  
Loss Of Function ◽  
Variable Expressivity ◽  
Helix Loop Helix ◽  
Whole Exome ◽  
Generation Family ◽  
Specific Symptoms

The MYCN oncogene encodes a transcription factor belonging to the MYC family. It is primarily expressed in normal developing embryos and is thought to be critical in brain and other neural development. Loss-of-function variants resulting in haploinsufficiency of MYCN, which encodes a protein with a basic helix–loop–helix domain causes Feingold syndrome (OMIM 164280, ORPHA 391641). We present an occurrence of esophageal atresia (EA) with tracheoesophageal fistula in siblings from a three-generation family affected by variable expressivity of MYCN mutation p.(Ser90GlnfsTer176) as a diagnostic effect of searching the cause of familial esophageal atresia using NGS-based whole-exome sequencing (WES). All of our affected patients showed microcephaly and toe syndactyly, which were frequently reported in the literature. Just one patient exhibited clinodactyly. None of the patients exhibited brachymesophalangy or hypoplastic thumbs. The latest report noted that patients with EA and Feingold syndrome were also those with the more complex and severe phenotype. However, following a thorough review of the present literature, the same association was not found, which is also confirmed by the case we described. The variable phenotypic expression of the patients we described and the data from the literature guide a careful differential diagnosis of Feingold syndrome even in cases of poorly expressed and non-specific symptoms.

scholarly journals Inherited variants in CHD3 demonstrate variable expressivity in Snijders Blok-Campeau syndrome

2021 ◽  
Author(s):  
Jet van der Spek ◽  
Joery den Hoed ◽  
Lot Snijders Blok ◽  
Alexander J. M. Dingemans ◽  
Dick Schijven ◽  
...  
Keyword(s):  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Underlying Mechanism ◽  
Next Generation Sequencing Data ◽  
Sequencing Data ◽  
Human Phenotype ◽  
Variable Expressivity ◽  
Pathogenic Variants ◽  
Reduced Penetrance ◽  
Coding Variants

Interpretation of next-generation sequencing data of individuals with an apparent sporadic neurodevelopmental disorder (NDD) often focusses on pathogenic variants in genes associated with NDD, assuming full clinical penetrance with limited variable expressivity. Consequently, inherited variants in genes associated with dominant disorders may be overlooked when the transmitting parent is clinically unaffected. While de novo variants explain a substantial proportion of cases with NDDs, a significant number remains undiagnosed possibly explained by coding variants associated with reduced penetrance and variable expressivity. We characterized twenty families with inherited heterozygous missense or protein-truncating variants (PTVs) in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome, characterized by intellectual disability, speech delay and recognizable facial features (SNIBCPS). Notably, the majority of the inherited CHD3 variants were maternally transmitted. Computational facial and human phenotype ontology-based comparisons demonstrated that the phenotypic features of probands with inherited CHD3 variants overlap with the phenotype previously associated with de novo variants in the gene, while carrier parents are mildly or not affected, suggesting variable expressivity. Additionally, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of related healthy carriers with a CHD3 PTV, suggested that compensation of expression from the wildtype allele is unlikely to be an underlying mechanism. Our results point to a significant role of inherited variation in SNIBCPS, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation towards understanding the broader contributions of such variation to the landscape of human disease.

scholarly journals Two novel MYH7 proline substitutions cause Laing Distal Myopathy-like phenotypes with variable expressivity and neck extensor contracture

2016 ◽  
Vol 17 (1) ◽  
Author(s):  
Miora Feinstein-Linial ◽  
Massimo Buvoli ◽  
Ada Buvoli ◽  
Menachem Sadeh ◽  
Ron Dabby ◽  
...  
Keyword(s):  
Distal Myopathy ◽  
Variable Expressivity
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