A potential founder variant in CARMIL2/RLTPR in three Norwegian families with warts, molluscum contagiosum, and T ‐cell dysfunction
ConclusionsWe report a novel primary immunodeficiency, and a differential molecular diagnosis to CXCR4‐, DOCK8‐, GATA2‐, MAGT1‐, MCM4‐, STK4‐, RHOH‐, TMC6‐, and TMC8‐related diseases. The specific variant may represent a Norwegian founder variant segregating on a population‐specific haplotype. A likely Norwegian founder variant was detected by exome sequencing in four patients from three different families. The patients had signs of primary immunodeficiency and common skin phenotype of warts, molluscs, and dermatitis since early childhood. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2016 Category: Genetics & Stem Cells Authors: Hanne S. Sorte, Liv T. Osnes, B ørre Fevang, Pål Aukrust, Hans C. Erichsen, Paul H. Backe, Tore G. Abrahamsen, Ole B. Kittang, Torstein Øverland, Shalini N. Jhangiani, Donna M. Muzny, Magnus D. Vigeland, Pubudu Samarakoon, Tomasz Gambin, Zeynep H. C. A Tags: Original Article Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2016 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Pitfalls in genetic testing: the story of missed SCN1A mutations
ConclusionWe illustrate the pitfalls of Sanger sequencing and most importantly provide evidence thatSCN1A mutations are an even more frequent cause of DS than already anticipated. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 18, 2016 Category: Genetics & Stem Cells Authors: Tania Dj émié, Sarah Weckhuysen, Sarah Spiczak, Gemma L. Carvill, Johanna Jaehn, Anna‐Kaisa Anttonen, Eva Brilstra, Hande S. Caglayan, Carolien G. Kovel, Christel Depienne, Eija Gaily, Elena Gennaro, Beatriz G. Giraldez, Padhraig Gormley, Tags: Original Article Source Type: research

A view on clinical genetics and genomics in Spain: of challenges and opportunities
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 18, 2016 Category: Genetics & Stem Cells Authors: Teresa Pàmpols, Feliciano J. Ramos, Pablo Lapunzina, Ignasi Gozalo‐Salellas, Luis A. Pérez‐Jurado, Aurora Pujol Tags: Genetics and Genomic Medicine around the World Source Type: research

Lessons learned from the search for genes responsible for rare Mendelian disorders
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 18, 2016 Category: Genetics & Stem Cells Authors: Nara L. Sobreira, David Valle Tags: Invited Commentary Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 18, 2016 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

A novel de novo TBX5 mutation in a patient with Holt –Oram syndrome leading to a dramatically reduced biological function
ConclusionThese results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient. We have identified a so far unpublished TBX5 mutation which occurs de novo in the patient diagnosed for HOS with healthy parents. The mutation is located in a highly conserved region of TBX5 and is predicted to be damaging. Functional experiments confirmed a dramatically reduced biological activity of the mutated TBX5 protein. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 14, 2016 Category: Genetics & Stem Cells Authors: Martina Dre ßen, Harald Lahm, Armin Lahm, Klaudia Wolf, Stefanie Doppler, Marcus‐André Deutsch, Julie Cleuziou, Jelena Pabst von Ohain, Patric Schön, Peter Ewert, Ivan Malcic, Rüdiger Lange, Markus Krane Tags: Original Article Source Type: research

A novel de novo TBX5 mutation in a patient with Holt–Oram syndrome leading to a dramatically reduced biological function
ConclusionThese results suggest that the dramatic functional alteration of the p.Pro85Thr mutation leads to the distinctive phenotype of the patient. We have identified a so far unpublished TBX5 mutation which occurs de novo in the patient diagnosed for HOS with healthy parents. The mutation is located in a highly conserved region of TBX5 and is predicted to be damaging. Functional experiments confirmed a dramatically reduced biological activity of the mutated TBX5 protein. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 14, 2016 Category: Genetics & Stem Cells Authors: Martina Dreßen, Harald Lahm, Armin Lahm, Klaudia Wolf, Stefanie Doppler, Marcus‐André Deutsch, Julie Cleuziou, Jelena Pabst von Ohain, Patric Schön, Peter Ewert, Ivan Malcic, Rüdiger Lange, Markus Krane Tags: Original Article Source Type: research

Mentors without Borders
is a proposed international mentoring network that allows trainee geneticists to identify mentors from a list of volunteers who are not at one's own institution. It is an experiment, a matchmaker between a junior and a senior professional. These mentors do not replace the mentors at the home institution but allow the mentee, if desired, to identify mentors outside of their own institution. We envision that different ways of communicating and/or different mentor‐mentee relationships may prove beneficial to the trainee and the mentor. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2016 Category: Genetics & Stem Cells Authors: Maximilian Muenke Tags: Invited Commentary Source Type: research

Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients
ConclusionMutations in genes described in OMIM as, for example, intellectual disability gene can lead to phenotypes that get classified as EE in the clinic. We confirmed existing literature reports that de novo loss‐of‐function HNRNPUmutations lead to severe developmental delay and febrile seizures in the first year of life. Genes that were previously reported to have been found mutated in patients with epileptic encephalopathy were tested in a new patient cohort. Probably pathogenic variants were found in known genes for epileptic encephalopathy and in genes for intellectual disability syndromes. A de novo variant in...
Source: Molecular Genetics & Genomic Medicine - July 1, 2016 Category: Genetics & Stem Cells Authors: Carolien G.F. Kovel, Eva H. Brilstra, Marjan J.A. Kempen, Ruben Slot, Isaac J. Nijman, Zaid Afawi, Peter De Jonghe, Tania Dj émié, Renzo Guerrini, Katia Hardies, Ingo Helbig, Rik Hendrickx, Moine Kanaan, Uri Kramer, Anna‐Elina E. Lehesjoki, Johannes R Tags: Original Article Source Type: research

ADGRL3 (LPHN3) variants are associated with a refined phenotype of ADHD in the MTA study
ConclusionThe detection of susceptibility conferred by ADGRL3 variants in the extreme phenotype of continued diagnosis of ADHD‐C from childhood to adolescence provides additional support that the association of ADGRL3 and ADHD is not spurious. Exploring genetic effects in longitudinal cohorts, in which refined, age‐dependent phenotypes are documented, is crucial to understand the natural history of ADHD. ADGRL3 (LPHN3) variants are associated with ADHD susceptibility in cross‐sectional studies and in longitudinal studies. Evidence from a large longitudinal study is present in this publication. (Source: Molecular Gen...
Source: Molecular Genetics & Genomic Medicine - July 1, 2016 Category: Genetics & Stem Cells Authors: Maria T. Acosta, James Swanson, Annamarie Stehli, Brooke S. G. Molina, , Ariel F. Martinez, Mauricio Arcos‐Burgos, Maximilian Muenke Tags: Original Article Source Type: research

Population ‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans
ConclusionsWe found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population‐specific genetic risk factor for VTE in African Americans. We identified a novel association between a muta...
Source: Molecular Genetics & Genomic Medicine - June 21, 2016 Category: Genetics & Stem Cells Authors: Roxana Daneshjou, Larisa H. Cavallari, Peter E. Weeke, Konrad J. Karczewski, Katarzyna Drozda, Minoli A. Perera, Julie A. Johnson, Teri E. Klein, Carlos D. Bustamante, Dan M. Roden, Christian Shaffer, Joshua C. Denny, James L. Zehnder, Russ B. Altman Tags: Original Article Source Type: research

Erratum
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 12, 2016 Category: Genetics & Stem Cells Authors: Josephine Wincent, Aron Luthman, Martine Belzen, Christian Lans, Johanna Albert, Ann Nordgren, Britt‐Marie Anderlid Tags: Erratum Source Type: research

Medical genetics and genomic medicine in the Dominican Republic: challenges and opportunities
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 12, 2016 Category: Genetics & Stem Cells Authors: Juvianee I. Estrada‐Veras, Giselle A. Cabrera‐Peña, Ceila Pérez‐Estrella de Ferrán Tags: Genetics and Genomic Medicine around the World Source Type: research

Clinical care models in the era of next‐generation sequencing
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 12, 2016 Category: Genetics & Stem Cells Authors: Anne Slavotinek Tags: Invited Commentary Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 12, 2016 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Concordance between whole ‐exome sequencing and clinical Sanger sequencing: implications for patient care
We report high concordance for well‐covered coding variants, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the use of supplementary Sanger sequencing for poorly‐covered genes when the clinical suspicion is high. Importantly, despite remaining difficulties with achieving complete coverage of the whole exome, 10 (38.5%) of the 26 compared patients were diagnosed through WES. The direct comparison of 391 coding and intronic variants identified by clinical Sanger sequencing to the whole‐exome sequencing (WES) results of 26 previously undiagnosed patients identified high concord...
Source: Molecular Genetics & Genomic Medicine - May 10, 2016 Category: Genetics & Stem Cells Authors: Alison Hamilton, Martine T étreault, David A. Dyment, Ruobing Zou, Kristin Kernohan, Michael T. Geraghty, , , Taila Hartley, Kym M. Boycott Tags: Original Article Source Type: research

The prevalence and distribution of the amyloidogenic transthyretin (TTR) V122I allele in Africa
ConclusionsOur data are consistent with a small number of founder carriers of the amyloidogenic TTR V122I (p.Val142Ile) allele in southern West Africa, with no apparent advantage or disadvantage of an allele carrying newborn reaching adulthood. In U.S. African Americans, the allele represents a significant risk for congestive heart failure late in life. If clinical penetrance is similar in African countries with high allele frequencies, then cardiac amyloidosis could also represent a significant cause of heart disease in the elderly in those populations. The substitution of isoleucine for valine at position 122 in the hum...
Source: Molecular Genetics & Genomic Medicine - May 1, 2016 Category: Genetics & Stem Cells Authors: Daniel R. Jacobson, Alice A. Alexander, Clement Tagoe, W. T. Garvey, Scott M. Williams, Sara Tishkoff, David Modiano, Sodiomon B. Sirima, Issa Kalidi, Amadou Toure, Joel N. Buxbaum Tags: Original Article Source Type: research

Usher syndrome in Denmark: mutation spectrum and some clinical observations
ConclusionMutations that lead to USH1 were predominantly identified in MYO7A (75%), whereas all mutations in USH2 cases were identified in USH2A. The MYO7A mutation c.93C>A, p.(Cys31*) accounted for 33% of all USH1 mutations and the USH2A c.2299delG, p.(Glu767Serfs*21) variant accounted for 45% of all USH2 mutations in the Danish cohort. We combined new mutation data in Usher syndrome (USH) with previously published. In total, we present a comprehensive overview of mutations identified in 100 patients wiith USH from Denmark. The Myo7a mutation p.Cys31* accounted for 33% of all USH1 mutations and the USH2A mutation p.Gl...
Source: Molecular Genetics & Genomic Medicine - May 1, 2016 Category: Genetics & Stem Cells Authors: Shzeena Dad, Nanna Dahl Rendtorff, Lisbeth Tranebjærg, Karen Grønskov, Helena Gásdal Karstensen, Vigdis Brox, Øivind Nilssen, Anne‐Françoise Roux, Thomas Rosenberg, Hanne Jensen, Lisbeth Birk Møller Tags: Original Article Source Type: research

Population‐specific single‐nucleotide polymorphism confers increased risk of venous thromboembolism in African Americans
ConclusionsWe found a variant, PROS1 V510M, in an African American family with VTE and clinical laboratory abnormalities in Protein S. Additionally, we found that this variant conferred increased risk of VTE in a case–control study of African Americans. In the ESP cohort, the variant is nearly absent in ESP European descent subjects (n = 3, allele frequency: 0.03%). Additionally, in 1000 Genomes Phase 3 data, the variant only appears in African descent populations. Thus, PROS1 V510M is a population‐specific genetic risk factor for VTE in African Americans. We identified a novel association between a muta...
Source: Molecular Genetics & Genomic Medicine - May 1, 2016 Category: Genetics & Stem Cells Authors: Roxana Daneshjou, Larisa H. Cavallari, Peter E. Weeke, Konrad J. Karczewski, Katarzyna Drozda, Minoli A. Perera, Julie A. Johnson, Teri E. Klein, Carlos D. Bustamante, Dan M. Roden, Christian Shaffer, Joshua C. Denny, James L. Zehnder, Russ B. Altman Tags: Original Article Source Type: research

The effect of parental age on the presence of de novo mutations – Lessons from neurofibromatosis type I
Abstract BackgroundNeurofibromatosis type 1 (NF1) is the most common autosomal dominant neurocutaneous disease with a prevalence of 1:2500. Approximately, 50% of the cases are sporadic. Advanced paternal age is associated with germline mutations and autosomal diseases. We aimed to use NF1 as a paradigm to study the effect of parental age on sporadic mutation rates for both advanced and younger parental ages. MethodsThe medical charts of 118 NF1 pediatric patients followed in a specialized Israeli NF1 clinic were evaluated. Thirty‐one cases were diagnosed by genetic tests and 87 by NIH clinical criteria. Sixty‐four case...
Source: Molecular Genetics & Genomic Medicine - May 1, 2016 Category: Genetics & Stem Cells Authors: Tom Dubov, Hagit Toledano‐Alhadef, Felix Bokstein, Shlomi Constantini, Shay Ben‐Shachar Tags: Original Article Source Type: research

Founder mutation in KCNJ10 in Pakistani patients with EAST syndrome
ConclusionBy knowing the prevalent mutation in a given population more efficient diagnostics can be performed and the families can benefit from specific counseling. Providing genetic evidence for a founder mutation in a rare kidney, brain, and inner ear disease in a Pakistani population. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 1, 2016 Category: Genetics & Stem Cells Authors: Ola Abdelhadi, Daniela Iancu, Mehmet Tekman, Horia Stanescu, Detlef Bockenhauer, Robert Kleta Tags: Original Article Source Type: research

A 2.5 ‐year snapshot of Mendelian discovery
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - April 3, 2016 Category: Genetics & Stem Cells Authors: Benjamin D. Solomon, Teresa Lee, Anh ‐Dao Nguyen, Tyra G. Wolfsberg Tags: Editorial Source Type: research

Novel de novo EEF1A2 missense mutations causing epilepsy and intellectual disability
ConclusionsEEF1A2 should be considered as a causative gene not only in cases of epileptic encephalopathy but also in children with less severe epilepsy and intellectual disability. The emergence of a possible discernible phenotype, a broad nasal bridge, tented upper lip, everted lower lip and downturned corners of the mouth may help in identifying patients with mutations in EEF1A2. Exome sequencing has led to the discovery of mutations in novel causative genes for epilepsy. One such gene is EEF1A2, which has been found to be mutated de novo in five cases of severe epilepsy. We now report on a further seven cases, each wit...
Source: Molecular Genetics & Genomic Medicine - April 3, 2016 Category: Genetics & Stem Cells Authors: Wayne W.K. Lam, John J. Millichap, Dinesh C. Soares, Richard Chin, Ailsa McLellan, David R. FitzPatrick, Frances Elmslie, Melissa M. Lees, G. Bradley Schaefer, , Catherine M. Abbott Tags: Original Article Source Type: research

GATA5 mutation homozygosity linked to a double outlet right ventricle phenotype in a Lebanese patient
ConclusionOur results do prove that p.Y142H is associated with DORV and suggests includingGATA5 as a potential gene to be screened in patients with this phenotype. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 17, 2016 Category: Genetics & Stem Cells Authors: Kameel Kassab, Hadla Hariri, Lara Gharibeh, Akl C. Fahed, Manal Zein, Inaam El ‐Rassy, Mona Nemer, Issam El‐Rassi, Fadi Bitar, Georges Nemer Tags: Original Article Source Type: research

Genetics and genomic medicine in Mali: challenges and future perspectives
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 17, 2016 Category: Genetics & Stem Cells Authors: Guida Landouré, Oumar Samassékou, Mahamadou Traoré, Katherine G. Meilleur, Cheick Oumar Guinto, Barrington G. Burnett, Charlotte J. Sumner, Kenneth H. Fischbeck Tags: Genetics and Genomic Medicine around the World Source Type: research

Invited commentary: The need for human genetics and genomics in dental school curricula
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 17, 2016 Category: Genetics & Stem Cells Authors: P. Suzanne Hart, Thomas C. Hart Tags: Invited Commentary Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 17, 2016 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Computational assessment of feature combinations for pathogenic variant prediction
ConclusionExisting pathogenicity prediction methods can be further improved. We investigated which combination of existing methods, variant features, and gene features archived the best performance in the prediction of pathogenic variants. We found that combining the number of “biological process” Gene Ontology annotations of a gene with the methods PON‐P2 and PROVEAN significantly improved prediction of pathogenic variants, outperforming all individual methods. Analysis of the Gene Ontology feature suggests that it is not a variant‐dependent annotation bias but reflects the multifunctional nature of disea...
Source: Molecular Genetics & Genomic Medicine - March 14, 2016 Category: Genetics & Stem Cells Authors: Eva König, Johannes Rainer, Francisco S. Domingues Tags: Original Article Source Type: research

Importance of nonsynonymous OCA2 variants in human eye color prediction
ConclusionOur data showed that rs74653330:A>T (p.Ala481Thr) and rs121918166:G>A (p.Val443Ile) have a measurable effect on normal pigmentation variation. We showed that the two variants, rs7465330 and rs129119166 had a measurable effect on eye color variation. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 11, 2016 Category: Genetics & Stem Cells Authors: Jeppe D. Andersen, Carlotta Pietroni, Peter Johansen, Mikkel M. Andersen, Vania Pereira, Claus Børsting, Niels Morling Tags: Original Article Source Type: research

The limitations of qPCR telomere length measurement in diagnosing dyskeratosis congenita
Abstract BackgroundTelomere length
Source: Molecular Genetics & Genomic Medicine - March 1, 2016 Category: Genetics & Stem Cells Authors: Shahinaz M. Gadalla, Payal P. Khincha, Hormuzd A. Katki, Neelam Giri, Jason Y. Y. Wong, Stephen Spellman, Jack A. Yanovski, Joan C. Han, Immaculata De Vivo, Blanche P. Alter, Sharon A. Savage Tags: Original Article Source Type: research

Concordance between whole‐exome sequencing and clinical Sanger sequencing: implications for patient care
We report high concordance for well‐covered coding variants, supporting the use of WES as a screening tool for heterogeneous disorders, and recommend the use of supplementary Sanger sequencing for poorly‐covered genes when the clinical suspicion is high. Importantly, despite remaining difficulties with achieving complete coverage of the whole exome, 10 (38.5%) of the 26 compared patients were diagnosed through WES. The direct comparison of 391 coding and intronic variants identified by clinical Sanger sequencing to the whole‐exome sequencing (WES) results of 26 previously undiagnosed patients identified high concord...
Source: Molecular Genetics & Genomic Medicine - March 1, 2016 Category: Genetics & Stem Cells Authors: Alison Hamilton, Martine Tétreault, David A. Dyment, Ruobing Zou, Kristin Kernohan, Michael T. Geraghty, , , Taila Hartley, Kym M. Boycott Tags: Original Article Source Type: research

Pitfalls in genetic testing: the story of missed SCN1A mutations
ConclusionWe illustrate the pitfalls of Sanger sequencing and most importantly provide evidence that SCN1A mutations are an even more frequent cause of DS than already anticipated. We explored to what extent inconsistencies between Sanger sequencing and next‐generation sequencing affect the molecular diagnosis of patients. Hereto we focused on the analysis of mutations in SCN1A, the major gene implicated in Dravet syndrome and epilepsy. We illustrate the pitfalls of genetic screening technologies and most importantly provide evidence that SCN1A mutations are an even more frequent cause of Dravet syndrome than already an...
Source: Molecular Genetics & Genomic Medicine - March 1, 2016 Category: Genetics & Stem Cells Authors: Tania Djémié, Sarah Weckhuysen, Sarah Spiczak, Gemma L. Carvill, Johanna Jaehn, Anna‐Kaisa Anttonen, Eva Brilstra, Hande S. Caglayan, Carolien G. Kovel, Christel Depienne, Eija Gaily, Elena Gennaro, Beatriz G. Giraldez, Padhraig Gormley, Rosa Guerrero Tags: Original Article Source Type: research

A 2.5‐year snapshot of Mendelian discovery
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 1, 2016 Category: Genetics & Stem Cells Authors: Benjamin D. Solomon, Teresa Lee, Anh‐Dao Nguyen, Tyra G. Wolfsberg Tags: Editorial Source Type: research

Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy
ConclusionThere is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype–phenotype correlations. Choroideremia is an X‐linked inherited retinal degeneration that causes nyctalopia, progressive loss of visual fields leading to loss of central visual acuity. This natural history study describes the onset and progression of these factors with respect to age and causative mutation in the CHM gene. No genotype–phenotype correlations existed within this study suggesting all genotypes could be included in future clinical trials of gene therapy in ch...
Source: Molecular Genetics & Genomic Medicine - February 28, 2016 Category: Genetics & Stem Cells Authors: Paul R. Freund, Yuri V. Sergeev, Ian M. MacDonald Tags: Original Article Source Type: research

A novel approach for next ‐generation sequencing of circulating tumor cells
ConclusionThese spiking experiments provide proof of concept of a clinically applicable workflow for real‐time monitoring of patient tumor using noninvasive liquid biopsies. The application of solid tumor next‐generation sequencing (NGS) approaches to circulating tumor samples has been hampered by the low‐input DNA available from rare circulating tumor cells (CTCs), and whole genome amplification (WGA) approaches used to generate sufficient input DNA are often incompatible with blood collection tube preservatives used to facilitate clinical sample batching. We developed a novel approach combining tumor cell isolatio...
Source: Molecular Genetics & Genomic Medicine - February 28, 2016 Category: Genetics & Stem Cells Authors: Stephanie S. Yee, David B. Lieberman, Tatiana Blanchard, JulieAnn Rader, Jianhua Zhao, Andrea B. Troxel, Daniel DeSloover, Alan J. Fox, Robert D. Daber, Bijal Kakrecha, Shrey Sukhadia, George K. Belka, Angela M. DeMichele, Lewis A. Chodosh, Jennifer J. D. Tags: Method Source Type: research

Mosaic ratio quantification of isochromosome 12p in Pallister–Killian syndrome using droplet digital PCR
ConclusionDroplet digital PCR should be considered as an effective tool for both clinical and research analytics to precisely quantify mosaic genomic copy number alterations or mosaic mutations. We report the utility of the droplet digital PCR system in quantifying the mosaic ratio of isochromosome 12p in Pallister–Killian syndrome. Droplet digital PCR should be considered as an effective tool for both clinical and research analytics to precisely quantify mosaic genomic copy number alterations or mosaic mutations. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 20, 2016 Category: Genetics & Stem Cells Authors: Katsunori Fujiki, Katsuhiko Shirahige, Maninder Kaur, Matthew A. Deardorff, Laura K. Conlin, Ian D. Krantz, Kosuke Izumi Tags: Original Article Source Type: research

Development of a diagnostic DNA chip to screen for 30 autosomal recessive disorders in the Hutterite population
ConclusionsOur analysis indicates that the chip is a sensitive and specific means of carrier testing in the Hutterite population and can serve as a model for other founder populations. Hutterites, a religious isolate located in North America, have a number of genetic disorders that are unique and/or over‐represented. A diagnostic chip that simultaneously tests for 30 autosomal recessive disorders of significance to this population was developed and validated in partnership with Asper Biotech. We have determined that this diagnostic chip provides a sensitive and specific means for carrier testing and has the potential to...
Source: Molecular Genetics & Genomic Medicine - January 19, 2016 Category: Genetics & Stem Cells Authors: Barbara Triggs‐Raine, Tamara Dyck, Kym M. Boycott, A. Micheil Innes, Carole Ober, Jillian S. Parboosingh, Alexis Botkin, Cheryl R. Greenberg, Elizabeth L. Spriggs Tags: Original Article Source Type: research

Panel testing reveals nonsense and missense CDH1 mutations in families without hereditary diffuse gastric cancer
ConclusionsOur study demonstrates the need for further analysis of CDH1 mutation penetrance in order to better counsel asymptomatic CDH1 mutation carriers on preventative measures and general care. Here, we present two families with pathogenic CDH1 mutations. The first family carries a novel truncating, nonsense CDH1 mutation that we were able to trace for three generations, but reports no family history of diffuse gastric cancer. The occurrence of cancer in this family deviates significantly from the expectation for hereditary diffuse gastric cancer. The proband from the second family presents with breast cancer and carr...
Source: Molecular Genetics & Genomic Medicine - January 13, 2016 Category: Genetics & Stem Cells Authors: Julie M. Huynh, Christina M. Laukaitis Tags: Clinical Report Source Type: research

Johann Gregor Mendel: paragon of experimental science
This is a foreword on the life and work of one of the greatest minds of the 20th century, the father of modern genetics, Johann Gregor Mendel. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2016 Category: Genetics & Stem Cells Authors: Mauricio De Castro Tags: Invited Commentary Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2016 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas
ConclusionOur linkage study of BE/EAC pedigrees identified linkage regions on chromosomes 2, 4, 12, and 15, with some reported associations located within our linkage peaks. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to BE and EAC. We identified linkage regions on chromosomes 2q31, 12q23, and 15q26. Some of our linkage regions are consistent with reported genomic associations to BE and EAC. Our linkage results can help prioritize association tests to delineate the genetic determinants underlying susceptibility to Barrett's esophagus and esophag...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Xiangqing Sun, Robert Elston, Gary W. Falk, William M. Grady, Ashley Faulx, Sumeet K. Mittal, Marcia I. Canto, Nicholas J. Shaheen, Jean S. Wang, Prasad G. Iyer, Julian A. Abrams, Joseph E. Willis, Kishore Guda, Sanford Markowitz, Jill S. Barnholtz‐Sloa Tags: Original Article Source Type: research

Identification of genetic variants of LGI1 and RTN4R (NgR1) linked to schizophrenia that are defective in NgR1–LGI1 signaling
ConclusionVariants in NgR1 and LGI1 may be associated with schizophrenia and variants in NgR1 found in schizophrenic patients have impaired LGI1–NgR1 signaling. Impaired LGI1–NgR1 signaling may contribute to disease progression. We screened two unrelated schizophrenic populations for variants in RTN4R and LGI1, and observed a previously reported rare coding variant in RTN4R (c.1195C>T, pR399W) and three novel LGI1 mutations were found, two missense mutations (c.205G>A, p.V69I) and (c.313G>A, V105M) and an intronic variant (g.897T>C) that likely leads to a protein truncation. Using cell‐based assa...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Rhalena A. Thomas, Amirthagowri Ambalavanan, Guy A. Rouleau, Philip A. Barker Tags: Original Article Source Type: research

Behavioral and transcriptomic profiling of mice null for Lphn3, a gene implicated in ADHD and addiction
ConclusionsTranscriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development. LPHN3 has been associated with both ADHD and vulnerability to addiction. We evaluated a Lphn3 null mouse and observed changes in behavior that encompass both activity levels and reward motivation. We also observe altered serum calcium levels; neurite outgrowth...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Caitlin A. Orsini, Barry Setlow, Michael DeJesus, Stacy Galaviz, Kimberly Loesch, Thomas Ioerger, Deeann Wallis Tags: Original Article Source Type: research

A novel approach for next‐generation sequencing of circulating tumor cells
ConclusionThese spiking experiments provide proof of concept of a clinically applicable workflow for real‐time monitoring of patient tumor using noninvasive liquid biopsies. The application of solid tumor next‐generation sequencing (NGS) approaches to circulating tumor samples has been hampered by the low‐input DNA available from rare circulating tumor cells (CTCs), and whole genome amplification (WGA) approaches used to generate sufficient input DNA are often incompatible with blood collection tube preservatives used to facilitate clinical sample batching. We developed a novel approach combining tumor cell isolatio...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Stephanie S. Yee, David B. Lieberman, Tatiana Blanchard, JulieAnn Rader, Jianhua Zhao, Andrea B. Troxel, Daniel DeSloover, Alan J. Fox, Robert D. Daber, Bijal Kakrecha, Shrey Sukhadia, George K. Belka, Angela M. DeMichele, Lewis A. Chodosh, Jennifer J. D. Tags: Method Source Type: research

Rothmund–Thomson Syndrome: novel pathogenic mutations and frequencies of variants in the RECQL4 and USB1 (C16orf57) gene
ConclusionThe current study contributes to the improvement of genetic diagnostic strategies and interpretation in RTS and PN that is relevant in order to assess the patients' cancer risk, to avoid continuous and inconclusive clinical evaluations and to clarify the recurrence risk in the families. Additionally, it shows that the phenotype of more than 50% of the patients with suspected Rothmund–Thomson disease may be due to mutations in other genes raising the need for further extended genetic analyses. We report on genotype and phenotype data of a cohort of 44 index patients with clinically suspected Rothmund&n...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Aude‐Annick Suter, Peter Itin, Karl Heinimann, Munaza Ahmed, Tazeen Ashraf, Helen Fryssira, Usha Kini, Pablo Lapunzina, Peter Miny, Mette Sommerlund, Mohnish Suri, Signe Vaeth, Pradeep Vasudevan, Sabina Gallati Tags: Original Article Source Type: research

Variable expressivity and co‐occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy
ConclusionThe p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon. Familial hypercholesterolemia in Lebanon is more frequent than other parts of the world because of high rates of consanguineous marriages. We hereby report that the p.Q136* LDLRAP1 variant is the second “Lebanese Allele” in our country. In addition, we report the first family with both LDLR and LDLRAP1 variants with different phenotypes between family members unexplained by their corresponding genotypes. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Akl C. Fahed, Ruby Khalaf, Rony Salloum, Rabih R. Andary, Raya Safa, Inaam El‐Rassy, Elie Moubarak, Sami T. Azar, Fadi F. Bitar, Georges Nemer Tags: Original Article Source Type: research

Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families
ConclusionATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population. We identified the molecular defects in...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Laura I. Escobar, Christopher Simian, Cyrielle Treard, Donia Hayek, Carolina Salvador, Norma Guerra, Mario Matos, Mara Medeiros, Sandra Enciso, María Dolores Camargo, Rosa Vargas‐Poussou Tags: Original Article Source Type: research

Carrier screening by next‐generation sequencing: health benefits and cost effectiveness
ConclusionThis study demonstrated that NGS‐based carrier screening offers the greater benefit in clinical outcomes and lower total healthcare cost as compared with genotyping. We evaluated the cost effectiveness of carrier screening via next‐generation DNA sequencing (NGS) versus the traditional genotyping approach by using a robust mathematical model to estimate carefully selected health and other outcomes associated with 14 genetic diseases that major medical societies recommend for screening. The model accounts for all decisions considered by available medical opinion and outcomes relevant to carrier screening and ...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Mohammad Azimi, Kyle Schmaus, Valerie Greger, Dana Neitzel, Robert Rochelle, Tuan Dinh Tags: Original Article Source Type: research

Chromosome loci vary by juvenile myoclonic epilepsy subsyndromes: linkage and haplotype analysis applied to epilepsy and EEG 3.5–6.0 Hz polyspike waves
Abstract Juvenile myoclonic epilepsy (JME), the most common genetic epilepsy, remains enigmatic because it is considered one disease instead of several diseases. We ascertained three large multigenerational/multiplex JME pedigrees from Honduras with differing JME subsyndromes, including Childhood Absence Epilepsy evolving to JME (CAE/JME; pedigree 1), JME with adolescent onset pyknoleptic absence (JME/pA; pedigree 2), and classic JME (cJME; pedigree 3). All phenotypes were validated, including symptomatic persons with various epilepsies, asymptomatic persons with EEG 3.5–6.0 Hz polyspike waves, and asymptomatic ...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Jenny E. Wight, Viet‐Huong Nguyen, Marco T. Medina, Christopher Patterson, Reyna M. Durón, Yolly Molina, Yu‐Chen Lin, Iris E. Martínez‐Juárez, Adriana Ochoa, Aurelio Jara‐Prado, Miyabi Tanaka, Dongsheng Bai, Sumaya Aftab, Julia N. Bailey, Anton Tags: Original Article Source Type: research