scholarly journals Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

2015 ◽  
Author(s):  
Jessica X. Chong ◽  
Joon-Ho Yu ◽  
Peter Lorentzen ◽  
Karen M. Park ◽  
Seema M. Jamal ◽  
...  
Keyword(s):  
Social Networking ◽  
Developmental Delay ◽  
De Novo ◽  
Gene Discovery ◽  
Pathogenic Variant ◽  
Facial Features ◽  
Variants Of Unknown Significance ◽  
Mendelian Gene ◽  
Unknown Significance ◽  
Share Data

ABSTRACTPurpose:The pace of Mendelian gene discovery is slowed by the “n-of-1 problem” – the difficulty of establishing causality of a putatively pathogenic variant in a single person or family. Identification of an unrelated person with an overlapping phenotype and suspected pathogenic variant in the same gene can overcome this barrier but is often impeded by lack of a convenient or widely-available way to share data on candidate variants / genes among families, clinicians and researchers.Methods:Social networking among families, clinicians and researchers was used to identify three children with variants of unknown significance in KDM1A and similar phenotypes.Results:De novo variants in KDM1A underlie a new syndrome characterized by developmental delay and distinctive facial features.Conclusion:Social networking is a potentially powerful strategy to discover genes for rare Mendelian conditions, particularly those with non-specific phenotypic features. To facilitate the efforts of families to share phenotypic and genomic information with each other, clinicians, and researchers, we developed the Repository for Mendelian Genomics Family Portal (RMD-FP). Design and development of a web-based tool, MyGene2, that enables families, clinicians and researchers to search for gene matches based on analysis of phenotype and exome data deposited into the RMD-FP is underway.

scholarly journals Gene discovery for Mendelian conditions via social networking: de novo variants in KDM1A cause developmental delay and distinctive facial features

2015 ◽  
Vol 18 (8) ◽  
pp. 788-795 ◽  
Author(s):  
Jessica X. Chong ◽  
◽  
Joon-Ho Yu ◽  
Peter Lorentzen ◽  
Karen M. Park ◽  
...  
Keyword(s):  
Social Networking ◽  
Developmental Delay ◽  
De Novo ◽  
Gene Discovery ◽  
Facial Features

scholarly journals Recurrent de novo pathogenic variant of WASF1 in a Japanese patient with neurodevelopmental disorder with absent language and variable seizures

2021 ◽  
Vol 8 (1) ◽  
Author(s):  
Keiko Shimojima Yamamoto ◽  
Tomoe Yanagishita ◽  
Hisako Yamamoto ◽  
Yusaku Miyamoto ◽  
Miho Nagata ◽  
...  
Keyword(s):  
Developmental Delay ◽  
Neurodevelopmental Disorders ◽  
Japanese Patient ◽  
De Novo ◽  
Neurodevelopmental Disorder ◽  
Pathogenic Variant ◽  
Adult Patients ◽  
Facial Features ◽  
Initial Report

AbstractA recurrent de novo pathogenic variant of WASF1, NM_003931:c.1516C>T [p.Arg506*], was identified in a 6-year-old female Japanese patient with severe developmental delay, hypotonia, hyperkinetic behavior, and distinctive facial features. The initial report of five adult patients with WASF1 variants was the only previous report regarding variants of this gene; this is the second such report, reaffirming that rare but recurrent truncating variants of WASF1 are associated with severe neurodevelopmental disorders.

Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features

2018 ◽  
Vol 176 (12) ◽  
pp. 2548-2553 ◽  
Author(s):  
Caleb P. Bupp ◽  
Chad R. Schultz ◽  
Katie L. Uhl ◽  
Surender Rajasekaran ◽  
André S. Bachmann
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Pathogenic Variant ◽  
Dysmorphic Features

scholarly journals Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 698 ◽  
Author(s):  
Rossella Elisei ◽  
Alessia Tacito ◽  
Teresa Ramone ◽  
Raffaele Ciampi ◽  
Valeria Bottici ◽  
...  
Keyword(s):  
Genetic Screening ◽  
De Novo ◽  
Germline Mutations ◽  
Pathogenic Role ◽  
Medullary Thyroid ◽  
Variants Of Unknown Significance ◽  
The Family ◽  
Unknown Significance ◽  
Hereditary Medullary Thyroid Carcinoma ◽  
Sporadic Cases

Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were “de novo” and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC; b) the prevalence of different mutations varies with V804M being the most frequent; c) the association genotype–phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

2q23 de novo microdeletion involving the MBD5 gene in a patient with developmental delay, postnatal microcephaly and distinct facial features

2011 ◽  
Vol 155 (2) ◽  
pp. 424-429 ◽  
Author(s):  
Brian H.Y. Chung ◽  
James Stavropoulos ◽  
Christian R. Marshall ◽  
Rosanna Weksberg ◽  
Stephen W. Scherer ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Facial Features

De novo pathogenic variant in TUBB2A presenting with arthrogryposis multiplex congenita, brain abnormalities, and severe developmental delay

2017 ◽  
Vol 173 (10) ◽  
pp. 2725-2730 ◽  
Author(s):  
Resham Ejaz ◽  
Anath C. Lionel ◽  
Susan Blaser ◽  
Susan Walker ◽  
Stephen W. Scherer ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Pathogenic Variant ◽  
Arthrogryposis Multiplex Congenita ◽  
Brain Abnormalities

scholarly journals De novo triplication of 11q12.3 in a patient with developmental delay and distinctive facial features

2013 ◽  
Vol 6 (1) ◽  
pp. 15 ◽  
Author(s):  
Toshiyuki Yamamoto ◽  
Mari Matsuo ◽  
Shino Shimada ◽  
Noriko Sangu ◽  
Keiko Shimojima ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Facial Features

A de novo interstitial deletion of 8p11.2 including ANK1 identified in a patient with spherocytosis, psychomotor developmental delay, and distinctive facial features

Gene ◽  
2012 ◽  
Vol 506 (1) ◽  
pp. 146-149 ◽  
Author(s):  
Kazushi Miya ◽  
Keiko Shimojima ◽  
Midori Sugawara ◽  
Shino Shimada ◽  
Hiroyuki Tsuri ◽  
...  
Keyword(s):  
Developmental Delay ◽  
De Novo ◽  
Interstitial Deletion ◽  
Facial Features

scholarly journals ExACtly zero or once

2017 ◽  
Vol 3 (4) ◽  
pp. e163 ◽  
Author(s):  
Caitlin A. Bennett ◽  
Slavé Petrovski ◽  
Karen L. Oliver ◽  
Samuel F. Berkovic
Keyword(s):  
General Population ◽  
Autosomal Dominant ◽  
De Novo ◽  
Clinical Role ◽  
Variants Of Unknown Significance ◽  
Neurologic Disorders ◽  
Exome Aggregation Consortium ◽  
Unknown Significance ◽  
Strong Segregation

Objective:To assist the interpretation of genomic data for common epilepsies, we asked whether variants implicated in mild epilepsies in autosomal dominant families are present in the general population.Methods:We studied 12 genes for the milder epilepsies and identified published variants with strong segregation support (de novo germline mutation or ≥4 affected family members). These variants were checked in the Exome Aggregation Consortium (ExAC), a database of genetic variation in over 60,000 individuals. We subsequently evaluated variants in these epilepsy genes that lacked strong segregation support. To determine whether the findings in epilepsies were representative of other diseases, we also assessed the presence of variants in other dominant neurologic disorders (e.g., CADASIL).Results:Published epilepsy variants with strong segregation support (n = 65) were absent (n = 61) or present once (n = 4) in ExAC. By contrast, of 46 published epilepsy variants without strong segregation support, 8 occurred recurrently (2–186 times). Similarly, none of the 45 disease-associated variants from other neurologic disorders with strong segregation support occurred more than once in ExAC. Reanalysis using the larger ExAC V2 plus gnomAD reference cohort showed consistent results.Conclusions:Variants causing autosomal dominant epilepsies are ultra-rare in the general population. Variants observed more than once in ExAC were only found among reports without strong segregation support, suggesting that they may be benign. Clinicians are increasingly faced with the interpretation of genetic variants of unknown significance. These data illustrate that variants present more than once in ExAC are less likely to be pathogenic, reinforcing the valuable clinical role of ExAC.

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