scholarly journals Ten points to consider when providing genetic counseling for variants of incomplete penetrance and variable expressivity detected in a prenatal setting

2020 ◽  
Vol 99 (11) ◽  
pp. 1427-1429
Author(s):  
Idit Maya ◽  
Rivka Sukenik‐Halevy ◽  
Lina Basel‐Salmon ◽  
Lena Sagi‐Dain
Keyword(s):  
Genetic Counseling ◽  
Incomplete Penetrance ◽  
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 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

scholarly journals Phenotype and Genotype Correlations in Inherited Retinal Diseases: Population-Guided Variant Interpretation, Variable Expressivity and Incomplete Penetrance

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1274
Author(s):  
Jamie M. Ellingford ◽  
Robert B. Hufnagel ◽  
Gavin Arno
Keyword(s):  
Incomplete Penetrance ◽  
Retinal Diseases ◽  
Variant Interpretation ◽  
Variable Expressivity ◽  
Human Disorders ◽  
Variable Group

Inherited retinal diseases (IRDs) are a diverse and variable group of rare human disorders [...]

scholarly journals Novel Insights into the Pathogenesis of Monogenic Congenital Anomalies of the Kidney and Urinary Tract

2017 ◽  
Vol 29 (1) ◽  
pp. 36-50 ◽  
Author(s):  
Amelie T. van der Ven ◽  
Asaf Vivante ◽  
Friedhelm Hildebrandt
Keyword(s):  
Urinary Tract ◽  
Vesicoureteral Reflux ◽  
Congenital Anomalies ◽  
Congenital Malformations ◽  
Renal Agenesis ◽  
Incomplete Penetrance ◽  
Variable Expressivity ◽  
Genetic Causes ◽  
Shed Light ◽  
Lines Of Evidence

Congenital anomalies of the kidneys and urinary tract (CAKUT) comprise a large spectrum of congenital malformations ranging from severe manifestations, such as renal agenesis, to potentially milder conditions, such as vesicoureteral reflux. CAKUT causes approximately 40% of ESRD that manifests within the first three decades of life. Several lines of evidence indicate that CAKUT is often caused by recessive or dominant mutations in single (monogenic) genes. To date, approximately 40 monogenic genes are known to cause CAKUT if mutated, explaining 5%–20% of patients. However, hundreds of different monogenic CAKUT genes probably exist. The discovery of novel CAKUT-causing genes remains challenging because of this pronounced heterogeneity, variable expressivity, and incomplete penetrance. We here give an overview of known genetic causes for human CAKUT and shed light on distinct renal morphogenetic pathways that were identified as relevant for CAKUT in mice and humans.

scholarly journals Incomplete penetrance, variable expressivity, or dosage insensitivity in four families with directly transmitted unbalanced chromosome abnormalities

2017 ◽  
Vol 176 (2) ◽  
pp. 319-329 ◽  
Author(s):  
Mark S. Bateman ◽  
Morag N. Collinson ◽  
David J. Bunyan ◽  
Amanda L. Collins ◽  
Philippa Duncan ◽  
...  
Keyword(s):  
Chromosome Abnormalities ◽  
Incomplete Penetrance ◽  
Variable Expressivity

Genetic Counseling in Hereditary Non-Polyposis Colorectal Cancer

1996 ◽  
Vol 82 (2) ◽  
pp. 136-142
Author(s):  
Abdelhamid Heouaine ◽  
Cristina Mareni ◽  
Liliana Varesco ◽  
Maurizio Genuardi ◽  
Giovanni Neri
Keyword(s):  
Colorectal Cancer ◽  
Genetic Counseling ◽  
Cancer Susceptibility ◽  
Mutant Gene ◽  
Incomplete Penetrance ◽  
Pilot Studies ◽  
Dna Mismatch ◽  
Molecular Tests ◽  
Probability Estimates ◽  
Hereditary Conditions

Genetic counseling is a medical process aimed at providing information about disease risks for hereditary conditions. For adult-onset diseases, such as cancer, the main purpose consists in formulating probability estimates of disease appearance, along with details on preventive or follow-up measures. The process of genetic counseling has been substantially modified by the availability of molecular tests to identify mutant gene carriers. So far, 16 autosomal dominant genes associated with cancer susceptibility have been cloned. Four of these, which encode for components of the DNA mismatch repair machinery, have been implicated in hereditary non-polyposis colorectal cancer, one of the most common hereditary cancer syndromes. Genetic counseling and testing in hereditary non-polyposis colorectal cancer is associated with several problems that are common to other hereditary conditions (psychologic consequences, confidentiality, genetic “discrimination”, testing of minors, prenatal diagnosis) and peculiar to the specific condition (incomplete penetrance, genotypic and phenotypic heterogeneity, limits of currently available tests). For such reasons, genetic testing should be performed in qualified research laboratories and restricted to highly selected families. In this way, pilot studies, involving both clinicians and researchers, can be undertaken with the aim of providing comprehensive results, potentially applicable to other cancer-predisposing conditions.

FAMILIAL HEARING LOSS ASSOCIATED WITH BRANCHIAL FISTULAS

PEDIATRICS ◽  
1969 ◽  
Vol 44 (6) ◽  
pp. 978-985
Author(s):  
Peter T. Rowley
Keyword(s):  
Hearing Loss ◽  
Early Diagnosis ◽  
Young Children ◽  
Autosomal Dominant ◽  
Normal Development ◽  
Incomplete Penetrance ◽  
Congenital Hearing Loss ◽  
Dominant Trait ◽  
Autosomal Dominant Trait ◽  
Variable Expressivity

A family is presented with cervical and preauricular branchial fistulas and congenital hearing loss. The hearing loss is unusual in having both conductive and sensorineural components. The basis of the conductive defect in the propositus was demonstrated at surgery to be a malformation of the ossicles. Hypoplasia of the mandible was present in two individuals. The syndrome was inherited as an autosomal dominant trait with variable expressivity and apparently incomplete penetrance. The occurrence of branchial fistulas should precipitate a search for defective hearing among relatives, especially in young children where early diagnosis and correction may permit the normal development of speech.

scholarly journals Partial Lipodystrophy and LMNA p.R545H Variant

2021 ◽  
Vol 10 (5) ◽  
pp. 1142
Author(s):  
Silvia Magno ◽  
Giovanni Ceccarini ◽  
Andrea Barison ◽  
Iacopo Fabiani ◽  
Alessandro Giacomina ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Subcutaneous Fat ◽  
Gene Mutations ◽  
In Silico Analysis ◽  
Missense Variant ◽  
Fat Distribution ◽  
Incomplete Penetrance ◽  
Partial Lipodystrophy ◽  
Variable Expressivity ◽  
Organ Systems

Laminopathies are disorders caused by LMNA gene mutations, which selectively affect different tissues and organ systems, and present with heterogeneous clinical and pathological traits. The molecular mechanisms behind these clinical differences and tissue specificity have not been fully clarified. We herein examine the case of a patient carrying a heterozygous LMNA c.1634G>A (p.R545H) variant with a mild, transient myopathy, who was referred to our center for the suspicion of lipodystrophy. At physical examination, an abnormal distribution of subcutaneous fat was noticed, with fat accumulation in the anterior regions of the neck, resembling the fat distribution pattern of familial partial lipodystrophy type 2 (FPLD2). The R545H missense variant has been found at very low allelic frequency in public databases, and in silico analysis showed that this amino acid substitution is predicted to have a damaging role. Other patients carrying the heterozygous LMNA p.R545H allele have shown a marked clinical heterogeneity in terms of phenotypic body fat distribution and severity of organ system involvement. These findings indicate that the LMNA p.R545H heterozygous variant exhibits incomplete penetrance and highly variable expressivity. We hypothesized that additional genetic factors, epigenetic mechanisms, or environmental triggers might explain the variable expressivity of phenotypes among various patients.

scholarly journals Incomplete Penetrance and Variable Expressivity: Hallmarks in Channelopathies Associated with Sudden Cardiac Death

Biology ◽  
2017 ◽  
Vol 7 (1) ◽  
pp. 3 ◽  
Author(s):  
Monica Coll ◽  
Alexandra Pérez-Serra ◽  
Jesus Mates ◽  
Bernat del Olmo ◽  
Marta Puigmulé ◽  
...  
Keyword(s):  
Sudden Cardiac Death ◽  
Cardiac Death ◽  
Incomplete Penetrance ◽  
Variable Expressivity
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