Variable expressivity and incomplete penetrance in a large family with non-classical Diamond-Blackfan anemia associated withribosomal protein L11splicing variant

2017 ◽  
Vol 173 (10) ◽  
pp. 2622-2627 ◽  
Author(s):  
Colleen M. Carlston ◽  
Zeinab A. Afify ◽  
Janice C. Palumbos ◽  
Heidi Bagley ◽  
Carlos Barbagelata ◽  
...  
Keyword(s):  
Large Family ◽  
Incomplete Penetrance ◽  
Variable Expressivity ◽  
Diamond Blackfan Anemia

scholarly journals Loss of coordinated expression between ribosomal and mitochondrial genes revealed by comprehensive characterization of a large family with a rare mendelian disorder

2020 ◽  
Author(s):  
Brendan Panici ◽  
Hosei Nakajima ◽  
Colleen M. Carlston ◽  
Hakan Ozadam ◽  
Can Cenik ◽  
...  
Keyword(s):  
Rna Splicing ◽  
Stop Codon ◽  
Ribosomal Subunit ◽  
Large Family ◽  
Transcript Abundance ◽  
Incomplete Penetrance ◽  
Variable Expressivity ◽  
Coordinated Expression ◽  
History Of

ABSTRACTNon-canonical intronic variants are a poorly characterized yet highly prevalent class of alterations associated with Mendelian disorders. Here, we report the first RNA expression and splicing analysis from a family whose members carry a non-canonical splice variant in an intron of RPL11 (c.396+3A>G). This mutation is causative for Diamond Blackfan Anemia (DBA) in this family despite incomplete penetrance and variable expressivity. Our analyses revealed a complex pattern of disruptions with many novel junctions of RPL11. These include an RPL11 transcript that is translated with a late stop codon in the 3’ untranslated region (3’UTR) of the main isoform. We observed that RPL11 transcript abundance is comparable among carriers regardless of symptom severity. Interestingly, both the small and large ribosomal subunit transcripts were significantly overexpressed in individuals with a history of anemia in addition to congenital abnormalities. Finally, we discovered that coordinated expression between mitochondrial components and RPL11 was lost in all carriers, which may lead to variable expressivity. Overall, this study highlights the importance of RNA splicing and expression analyses in families for molecular characterization of Mendelian diseases.

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

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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