Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness
ConclusionOur study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions. This study uniquely compares the diagnostic yield, cost effectiveness, and clinical utility of the exome diagnostic model over the standard diagnostic model...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Elizabeth E. Palmer, Deborah Schofield, Rupendra Shrestha, Tejaswi Kandula, Rebecca Macintosh, John A. Lawson, Ian Andrews, Hugo Sampaio, Alexandra M. Johnson, Michelle A. Farrar, Michael Cardamone, David Mowat, George Elakis, William Lo, Ying Zhu, Kevin Tags: ORIGINAL ARTICLE Source Type: research

A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy
ConclusionOur study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification. We identified a novel indel mutation in DES, encoding the intermediate filament protein desmin, in a patient with skeletal and cardiac myopathy. Functional analysis revealed a severe filament assembly defect in transfected cells and also of the purified recombinant protein. In summary, our functional data suggest that DES‐c.493_520del28insGCGT has to be classified as a likely pathogenic mutation. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Ilona Schirmer, Mareike Dieding, B ärbel Klauke, Andreas Brodehl, Anna Gaertner‐Rommel, Volker Walhorn, Jan Gummert, Uwe Schulz, Lech Paluszkiewicz, Dario Anselmetti, Hendrik Milting Tags: CLINICAL REPORT Source Type: research

A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy
ConclusionWe report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease‐associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations. Targeted resequencing by next‐generation sequencing identified a novel homozygous splice variant in EMC1 gene. Further analysis using RNA sequencing revealed intron retention, which when translated is predicted to result in premature termination and thus an aberrant protein. For the first time we demonstrate the role of aberrant ...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Thenral S. Geetha, Lokesh Lingappa, Abhishek Ravindra Jain, Hridya Govindan, Nitin Mandloi, Sakthivel Murugan, Ravi Gupta, Ramprasad Vedam Tags: CLINICAL REPORT Source Type: research

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications
ConclusionThe yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large‐scale genomic databases used to identify variants that contribute to disease risk. We performed genetic testing including microarray, fragile X testing and targeted gene panel consistently sequencing 161 genes associated with ASD risk in a clinical population of 100 well characterized children with ASD. Copy number variants believed to cont...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Louisa Kalsner, Jennifer Twachtman ‐Bassett, Kristin Tokarski, Christine Stanley, Thyde Dumont‐Mathieu, Justin Cotney, Stormy Chamberlain Tags: ORIGINAL ARTICLE Source Type: research

Short report: Follow ‐up of Bahamian women with a BRCA1 or BRCA2 mutation
ConclusionPreventive surgery is an acceptable option for a significant proportion of Bahamian women with a BRCA1 or BRCA2 mutation. It will be important to identify and reduce barriers to preventive surgery in the Bahamas in order that the benefit of getting testing can be fully realized. We sought to determine to what extent the knowledge of carrying a BRCA1 or BRCA2 mutation influences the uptake of preventive surgeries in Bahamian women. Of the 78 mutation carriers, 19 women had a bilateral salpingo‐oophorectomy (24%). Seven out of 37 patients who had unilateral breast cancer chose to remove the unaffected contralate...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Steven A. Narod, Raleigh Butler, David Bobrowski, Mohammad R. Akbari, DuVaughan Curling, John Lunn, Catherine Ho, Sara Panahi, Marcia Llacuachaqui, Talia Donenberg, Judith Hurley Tags: CLINICAL REPORT Source Type: research

Patients with sporadic and familial amyotrophic lateral sclerosis found value in genetic testing
ConclusionThese data indicate that patients with ALS found value in clinical genetic testing. Patients with ALS have found value in clinical genetic testing. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Karin N. Wagner, Haikady N. Nagaraja, Dawn C. Allain, Adam Quick, Stephen J. Kolb, Jennifer Roggenbuck Tags: ORIGINAL ARTICLE Source Type: research

ENG mutational mosaicism in a family with hereditary hemorrhagic telangiectasia
ConclusionWe provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT. These findings illustrate the importance of considering mutational mosaicism. Almost all cases of HHT have a family history. Very few cases are de novo or mosaicism. However, we provide evidence of ENG mutational mosaicism in an individual presenting with clinical HHT. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Pernille M. T ørring, Anette D. Kjeldsen, Lilian Bomme Ousager, Klaus Brusgaard Tags: CLINICAL REPORT Source Type: research

Deleterious variants in DCHS1 are prevalent in sporadic cases of mitral valve prolapse
ConclusionThis study reveals an important contribution of germline variants in DCHS1 in unrelated patients with mitral valve prolapse and supports genetic testing of this gene to screen individuals at risk. Loss‐of‐function variants in the DCHS1 gene were recently identified to segregate with mitral valve prolapse in three families. In this study, we reported rare and novel mutations predicted as similarly deleterious in 100 sporadic cases of mitral valve prolapse. The enrichment of in silico‐predicted deleterious variants in these cases supports the role of DCHS1 in the disease pathogenesis and highlights the impor...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Alisson Clemenceau, Jean ‐Christophe Bérubé, Paméla Bélanger, Nathalie Gaudreault, Maxime Lamontagne, Oumhani Toubal, Marie‐Annick Clavel, Romain Capoulade, Patrick Mathieu, Philippe Pibarot, Yohan Bosse Tags: CLINICAL REPORT Source Type: research

A review of structural brain abnormalities in Pallister ‐Killian syndrome
ConclusionOur study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder. We report two cases of Pallister‐Killian Syndrome, and conducted a literature review to describe a diverse neuropathological basis for impaired brain function in children diagnosed with this rare disorder. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Cathryn Poulton, Gareth Baynam, Clarissa Yates, Hamid Alinejad ‐Rokny, Simon Williams, Helen Wright, Karen J. Woodward, Soruba Sivamoorthy, Joanne Peverall, Peter Shipman, David Ravine, John Beilby, Julian Ik‐Tsen Heng Tags: ORIGINAL ARTICLE Source Type: research

Human perforin gene variation is geographically distributed
ConclusionsThis study concludes with a novel hypothesis that nondeleterious mutation in PRF1, which decreases perforin expression and/or activity, may be an example of selective advantage in the context of environmental stressors prevalent near the equator. Our studies illustrate how perforin deficiency can be protective from injuries resulting in blood–brain barrier (BBB) disruption. Perforin gene variation in humans has been an understudied aspect of human immunology. In this analysis, we have determined the number of perforin variants in the human populations is more extensive than previously known and increases ...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Robin C. Willenbring, Yasuhiro Ikeda, Larry R. Pease, Aaron J. Johnson Tags: ORIGINAL ARTICLE Source Type: research

Association of MGMT promoter methylation with tumorigenesis features in patients with ovarian cancer: A systematic meta ‐analysis
Abstract BackgroundThe MGMT is a key tumor suppressor gene and aberrant promoter methylation has been reported in many cancers. However, the relationship between MGMT promoter methylation and ovarian cancer remains controversial. This meta‐analysis was first conducted to estimate the clinical significance of MGMT promoter methylation in ovarian carcinoma. MethodsLiterature search was performed in the PubMed, Embase, EBSCO and Cochrane Library databases. The pooled odds ratio (OR) and their corresponding 95% confidence interval (95% CI) were summarized. ResultsFinal 10 studies with 910 ovarian tissue samples were included...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Baoli Qiao, Zhenyu Zhang, Yanfang Li Tags: ORIGINAL ARTICLE Source Type: research

Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype
ConclusionUnlike sequence point variants, intragenic duplications are difficult to precisely define, accurately quantify, and may be very unstable, challenging the proper diagnosis. The reversion of genomic duplication to the WT allele results in somatic mosaicism and may explain the relatively milder phenotype displayed by the FA‐B patient described here. Fanconi anemia patients harboring X‐linked FANCB pathogenic variants usually present with severe congenital malformations. We report a patient exhibiting a milder phenotype with an intragenic duplication of exon 3, and its flanking regions, in FANCB. Somatic mosaici...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Rajalakshmi S. Asur, Danielle C. Kimble, Francis P. Lach, Moonjung Jung, Frank X. Donovan, Aparna Kamat, Raymond J. Noonan, James W. Thomas, Morgan Park, Peter Chines, Adrianna Vlachos, Arleen D. Auerbach, Agata Smogorzewska, Settara C. Chandrasekharappa Tags: ORIGINAL ARTICLE Source Type: research

SYNJ1 gene associated with neonatal onset of neurodegenerative disorder and intractable seizure
ConclusionA clinical pattern of neonatal‐onset intractable seizure, profound developmental delay, muscular hypotonia, hypsarrhythmia, and no focal abnormality of brain MRI should prompt initiation of molecular genetic analysis of SYNJ1. Establishment of the diagnosis permits genetic counseling, prevents patients undergoing unhelpful diagnostic procedures and allows for accurate prognosis. A clinical pattern of neonatal‐onset intractable seizure, profound developmental delay, muscular hypotonia, hypsarrhythmia, and no focal abnormality of brain MRI should prompt initiation of molecular genetic analysis of SYNJ1. Establ...
Source: Molecular Genetics & Genomic Medicine - November 1, 2017 Category: Genetics & Stem Cells Authors: Nuha Al Zaabi, Noora Al Menhali, Fatma Al ‐Jasmi Tags: CLINICAL REPORT Source Type: research

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits
Abstract Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to acc...
Source: Molecular Genetics & Genomic Medicine - September 20, 2017 Category: Genetics & Stem Cells Authors: Megan Stringer, Charles R. Goodlett, Randall J. Roper Tags: Review Article Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 20, 2017 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Military genomics: a perspective on the successes and challenges of genomic medicine in the Armed Services
We describe the impact genomics has on the health and readiness of the military service member, highlight several examples of the current and future plans for genomic medicine within the military, discuss challenges to implementation and provide recommendations to address some of those challenges. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 14, 2017 Category: Genetics & Stem Cells Authors: Mauricio J. De Castro, Clesson E. Turner Tags: Invited Commentary Source Type: research

Newborn genetic screening for spinal muscular atrophy in the UK: The views of the general population
ConclusionsPublic acceptability is a key component in the evaluation of any potential screening program in the UK. This study demonstrates that newborn screening for SMA is viewed largely positively by people unfamiliar with the condition. The importance of early identification overrode all other social and ethical concerns about screening for the majority of participants. Very little is known about the views of the general population toward newborn screening for spinal muscular atrophy, even though this is currently the focus of intense policy debates. Using an online survey (n = 232), this study demonstrates t...
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Felicity K. Boardman, Chloe Sadler, Philip J. Young Tags: ORIGINAL ARTICLE Source Type: research

Breakpoint mapping and haplotype analysis of translocation t(1;12)(q43;q21.1) in two apparently independent families with vascular phenotypes
ConclusionsThis study demonstrates a balanced t(1;12)(q43;q21.1) with conserved haplotypes on the derived chromosomes. The translocation seems to result in vascular phenotype, with or without neurological symptoms, in at least two families. We suggest that the translocation influences the positional expression of CHRM3, RYR2, TRHDE, KCNC2, and/or ATXN7L3B. We identified two apparently independent families with a balanced t(1;12)(q43;q21.1) as an outcome of a “Systematic Survey of Balanced Chromosomal Rearrangements in Finns.” The translocation seems to result in vascular phenotype, with or without neurological...
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Tiia Maria Luukkonen, Mana M. Mehrjouy, Minna P öyhönen, Anna‐Kaisa Anttonen, Päivi Lahermo, Pekka Ellonen, Lars Paulin, Niels Tommerup, Aarno Palotie, Teppo Varilo Tags: ORIGINAL ARTICLE Source Type: research

Genetic analysis of osteogenesis imperfecta in the Palestinian population: molecular screening of 49 affected families
ConclusionThis is the first genetic screening of an OI cohort from the Palestinian population. Our data are important for genetic counseling of OI patients and families in highly consanguineous populations. In 41 Palestinian families with osteogensis imperfecta (OI), we identified 28 different mutations in nine OI genes, of which 11 mutations were novel. In eight remaining probands no mutation was found suggesting further genetic heterogeneity in OI. In contrast to the high frequency of the AD forms caused by defects in the structure or quantity of type I collagen in nonconsanguineous populations, AR forms of OI are expec...
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Osama Essawi, Sofie Symoens, Maha Fannana, Mohammad Darwish, Mohammad Farraj, Andy Willaert, Tamer Essawi, Bert Callewaert, Anne De Paepe, Fransiska Malfait, Paul J. Coucke Tags: Original Article Source Type: research

Consumer use and response to online third ‐party raw DNA interpretation services
ConclusionConsumers face challenges in understanding the results and may seek out clinical assistance in interpreting their raw DNA results. With the availability of raw DNA generated from direct‐to‐consumer (DTC) testing companies, there has been a proliferation of third‐party online services that are available to interpret the raw data for both genealogy and/or health purposes. This study examines the current landscape and downstream clinical implications of consumer use of third‐party services. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Catharine Wang, Tiernan J. Cahill, Andrew Parlato, Blake Wertz, Qiankun Zhong, Tricia Norkunas Cunningham, James J. Cummings Tags: ORIGINAL ARTICLE Source Type: research

Improvement of life quality measured by Lansky Score after enzymatic replacement therapy in children with Gaucher disease type 1
ConclusionThe use of ERT with imiglucerase 60 mg/kg every two weeks has substantial benefits and significantly improves QoL, assessed with Lansky Score, of the five children with GD1 studied. The quality of life of children with Gaucher disease type 1 measured with Lansky Score improved because hepatoesplenomegaly, biological markers and growth rate recovers their normal range after ERT. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Magdalena Cer ón‐Rodríguez, Edgar Barajas‐Colón, Lyuva Ramírez‐Devars, Claudia Gutiérrez‐Camacho, Juan L. Salgado‐Loza Tags: Original Article Source Type: research

Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation
ConclusionThe panel of mutations suggested as an initial screening for the Ecuadorian population with cystic fibrosis should contain the mutations: p.F508del, p.G85E, p.G330E, p.A455E, p.G970S, W1098X, R1162X, and N1303K. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Sof ía C. Ortiz, Santiago J. Aguirre, Sofía Flores, Claudio Maldonado, Juan Mejía, Lilian Salinas Tags: Original Article Source Type: research

Comprehensive analysis of mutations in the MEFV gene reveal that the location and not the substitution type determines symptom severity in FMF
ConclusionWe found presumptive FMF‐causing mutations that did not cluster with DCMs based on their allele frequencies. We also observed that the type of mutation is less likely to determine the severity of the FMF symptoms; rather it was the location of the mutations that was the determining factor. The mutations in the MEFV gene responsible for FMF symptoms were extensively analyzed through statistical clustering and identification of nucleotide and amino acid substitution patterns. This study showed that about 8% of the reported nonsynonymous substitutions may not be of pathogenic nature due to significance difference...
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Mike M. Moradian, Davit Babikyan, Dion Banoian, Hasmik Hayrapetyan, Hakob Manvelyan, Nareh Avanesian, Tamara Sarkisian Tags: Original Article Source Type: research

RYR1 causing distal myopathy
ConclusionWe expand the spectrum of RYR1‐related myopathy with the description of a novel phenotype in an adult patient presenting with hand weakness and suggest considering RYR1 analysis in the diagnosis of distal myopathies. We describe a patient with distal myopathy and jaw contractures due to RYR1 variants. Our findings suggest that RYR1 gene analysis should be included in the list of genes causative of distal myopathies. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Ruple S. Laughlin, Zhiyv Niu, Eric Wieben, Margherita Milone Tags: Clinical Report Source Type: research

The maternal uniparental disomy of chromosome 6  (upd(6)mat) “phenotype”: result of placental trisomy 6 mosaicism?
ConclusionA common upd(6)mat phenotype is not obvious, but placental dysfunction due to trisomy 6 mosaicism probably contributes to IUGR and preterm delivery. In fact, other clinical features observed in upd(6)mat patients might be caused by homozygosity of recessive mutations or by an undetected trisomy 6 cell line. Upd(6)mat itself is not associated with clinical features, and can rather be regarded as a biomarker. In case upd(6)mat is detected, the cause for the phenotype is identified indirectly, but the UPD is not the basic cause. Maternal uniparental disomy of chromosome 6 (upd(6)mat) is a rare finding, and its clin...
Source: Molecular Genetics & Genomic Medicine - September 1, 2017 Category: Genetics & Stem Cells Authors: Thomas Eggermann, Barbara Oehl ‐Jaschkowitz, Severin Dicks, Wolfgang Thomas, Deniz Kanber, Beate Albrecht, Matthias Begemann, Ingo Kurth, Jasmin Beygo, Karin Buiting Tags: Original Article Source Type: research

Sickle cell trait knowledge and health literacy in caregivers who receive in ‐person sickle cell trait education
ConclusionOur results suggest that caregivers’ baseline SCT knowledge is low, improves with in‐person education but may decline with time. Caregivers who do not achieve high SCT knowledge after education had lower health literacy and baseline knowledge. Future studies should determine if adapting in‐person education to caregivers’ health literacy and knowledge levels results in high and sustained SCT knowledge among all caregivers and more individuals who know their SCT status. Only 16% of individuals with sickle cell trait know their status. This prospective study of caregivers of infants with sickle cell...
Source: Molecular Genetics & Genomic Medicine - August 23, 2017 Category: Genetics & Stem Cells Authors: Susan Creary, Ismahan Adan, Joseph Stanek, Sarah H. O'Brien, Deena J. Chisolm, Tanica Jeffries, Kristin Zajo, Elizabeth Varga Tags: Original Article Source Type: research

Clinical verification of genetic results returned to research participants: findings from a Colon Cancer Family Registry
ConclusionThese findings suggest researchers will need to address barriers to seeking clinical verification in order to ensure that the intended benefits of returning genetic research results are realized. The extent to which participants act to clinically verify research results is largely unknown. This study examined whether participants who received Lynch syndrome‐related findings pursued researchers’ recommendation to verify results with testing performed by a CLIA‐certified clinical laboratory. Our study findings suggest researchers will need to address barriers to seeking clinical verification in order to ...
Source: Molecular Genetics & Genomic Medicine - August 23, 2017 Category: Genetics & Stem Cells Authors: Mercy Y. Laurino, Anjali R. Truitt, Lederle Tenney, Douglass Fisher, Noralane M. Lindor, David Veenstra, Gail P. Jarvik, Polly A. Newcomb, Stephanie M. Fullerton Tags: Original Article Source Type: research

Compound heterozygous CASQ2 mutations and long ‐term course of catecholaminergic polymorphic ventricular tachycardia
ConclusionThis study describes a novel CPVT genotype and further characterizes the effect of a previously reported CASQ2 splice site mutation. The long‐term follow‐up of 23 years since first symptom provides additional insight into the natural history of CASQ2‐associated CPVT. We report a case of CPVT caused by compound homozygous loss‐of‐function mutations in CASQ2, a missense early stop codon and splice site mutation with documented disruption of mRNA processing. Details of a greater than 23‐year follow‐up provides new insights on natural history of this potentially lethal disease. (Source: Molecular ...
Source: Molecular Genetics & Genomic Medicine - August 22, 2017 Category: Genetics & Stem Cells Authors: Katherine Josephs, Kunjan Patel, Christopher M. Janson, Cristina Montagna, Thomas V. McDonald Tags: Clinical Report Source Type: research

Panel ‐based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns
ConclusionThis study highlights that panel‐based WES is a reliable and effective strategy for the genetic diagnosis of MA. Furthermore, using this technique, the mutational spectrum of these diseases was broadened, with novel variants identified in each of the OTX2, PAX6, and RBP4 genes. Moreover, we report new cases of reduced penetrance, mosaicism, and variable phenotypic expressivity associated with MA, further demonstrating the heterogeneity of such disorders. We evaluated the implementation of whole exome sequencing (WES) for the genetic analysis of a panel in which all dominant, recessive, and X‐linked MA candid...
Source: Molecular Genetics & Genomic Medicine - August 21, 2017 Category: Genetics & Stem Cells Authors: Marina Riera, Ana Wert, Isabel Nieto, Esther Pomares Tags: Original Article Source Type: research

Living with a rare disorder: a systematic review of the qualitative literature
ConclusionThe findings highlight the need for more research on the shared psychological and social impact of living with a rare diagnosis across conditions, in order to identify risk factors and inform clinical practice. Individuals with rare diseases may face challenges that are different from those experienced in more common medical conditions. We performed a systematic review, including qualitative studies on adults, published between 2000 and 2016. The findings highlight the need for more research on the shared psychological and social impact of living with a rare diagnosis across conditions, in order to identify risk...
Source: Molecular Genetics & Genomic Medicine - July 23, 2017 Category: Genetics & Stem Cells Authors: Charlotte Lippe, Plata S. Diesen, Kristin B. Feragen Tags: Review Article Source Type: research

Clinical management of pheochromocytoma and paraganglioma in Singapore: missed opportunities for genetic testing
Abstract BackgroundPheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors of the adrenal glands and paraganglia, occurring sporadically or as a range of hereditary tumor syndromes. About 30% of PPGLs are attributed to germline mutations. Clinical presentation, including localization, malignant potential, and age of onset, varies depending on the genetic background. Genetic testing for PPGLs is not well studied in Southeast Asia. We reviewed clinical management of PPGLs in Singapore, highlighting current gaps in clinical practice. MethodsMedical records of patients with PPGLs between 2005 and 2016 were revie...
Source: Molecular Genetics & Genomic Medicine - July 20, 2017 Category: Genetics & Stem Cells Authors: Winston Hong Wern Chew, Eliza Courtney, Kok Hing Lim, Shao Tzu Li, Yanni Chen, Min Han Tan, Alexander Chung, Joan Khoo, Amos Loh, Shui Yen Soh, Prasad Iyer, Lih Ming Loh, Joanne Ngeow Tags: Clinical Report Source Type: research

Medical genetics and genomic medicine in the United States of America. Part 1: history, demographics, legislation, and burden of disease
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 16, 2017 Category: Genetics & Stem Cells Authors: Carlos R. Ferreira, Debra S. Regier, Donald W. Hadley, P. Suzanne Hart, Maximilian Muenke Tags: Genetics and Genomic Medicine around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 16, 2017 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Assessing risk for Mendelian disorders in a Bronx population
ConclusionScreening for a broader range of disorders could offer the benefits of early or presymptomatic diagnosis and reproductive choice. A panel of 75 variants displaying autosomal dominant, autosomal recessive, autosomal recessive/digenic recessive, X‐linked recessive, and X‐linked dominant inheritance patterns representing 39 Mendelian disorders were identified among Dominicans, Puerto Ricans and African Americans, representative of 85% of the population of the Bronx. Screening for a broader range of disorders could offer the benefits of early or presymptomatic diagnosis and reproductive choice. (Source: Molecula...
Source: Molecular Genetics & Genomic Medicine - July 6, 2017 Category: Genetics & Stem Cells Authors: Guy diSibio, Kinnari Upadhyay, Philip Meyer, Carole Oddoux, Harry Ostrer Tags: Original Article Source Type: research

The NextGen Study: patient motivation for participation in genome sequencing for carrier status
ConclusionGenomic carrier testing may need to be offered to women prior to active pregnancy efforts to be useful for reproductive planning. Most preconception women reported that obtaining general health information from genome sequencing was their primary motivator for being in the study, even though they were recruited to join a study to learn more about carrier status. Forty‐two percent of enrolled women became pregnant prior to obtaining sequencing results. Genomic carrier testing may need to be offered to women prior to active pregnancy efforts to be useful for reproductive planning. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 2, 2017 Category: Genetics & Stem Cells Authors: Tia L. Kauffman, Stephanie A. Irving, Michael C. Leo, Marian J. Gilmore, Patricia Himes, Carmit K. McMullen, Elissa Morris, Jennifer Schneider, Benjamin S. Wilfond, Katrina A. B. Goddard Tags: Original Article Source Type: research

Role of WNT10A in failure of tooth development in humans and zebrafish
ConclusionsOur results reveal a novel compound heterozygous variant in WNT10A as pathogenic for oligodontia, and demonstrate that perturbations of wnt10a expression in zebrafish may directly and/or indirectly affect tooth development recapitulating the agenesis phenotype observed in humans. Our results reveal a novel compound heterozygous variant in WNT10A as pathogenic for oligodontia, and demonstrate that perturbations of wnt10a expression in zebrafish may directly and/or indirectly affect tooth development recapitulating the agenesis phenotype observed in humans. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Qiuping Yuan, Min Zhao, Bhavna Tandon, Lorena Maili, Xiaoming Liu, Anqi Zhang, Evan H. Baugh, Tam Tran, Renato M. Silva, Jacqueline T. Hecht, Eric C. Swindell, Daniel S. Wagner, Ariadne Letra Tags: Original Article Source Type: research

Allelic spectrum of formiminotransferase ‐cyclodeaminase gene variants in individuals with formiminoglutamic aciduria
ConclusionWe observed additional FTCD alleles leading to urinary FIGLU elevations, and thus, providing molecular evidence of FTCD deficiency in cases identified by newborn screening or clinical biochemical genetic laboratory testing. Our study of 20 individuals with formiminoglutamic aciduria identified new variants in the FTCD gene that contributed to this genetic condition. This study expands the number of FTCD variants that leads to increased excretion of formiminoglutamic aciduria. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Ramanath Majumdar, Andrew Yori, Peggy W. Rush, Kimiyo Raymond, Dimitar Gavrilov, Silvia Tortorelli, Dietrich Matern, Piero Rinaldo, Gerald L. Feldman, Devin Oglesbee Tags: Clinical Report Source Type: research

Medical genetics and genomic medicine in Turkey: a bright future at a new era in life sciences
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Tayfun Özçelik Tags: Genetics and Genomic Medicine around the World Source Type: research

Mutations in fetal genes involved in innate immunity and host defense against microbes increase risk of preterm premature rupture of membranes (PPROM)
ConclusionsWe conclude that rare damaging mutations in innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies complicated by PPROM. These findings suggest that the risk of preterm birth in African‐Americans may be conferred by mutations in multiple genes encoding proteins involved in dampening the innate immune response or protecting the host against microbial infection and microbial products. Rare damaging mutations in fetal innate immunity and host defense genes, the majority being heterozygous, are more frequent in neonates born of pregnancies compli...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Bhavi P. Modi, Maria E. Teves, Laurel N. Pearson, Hardik I. Parikh, Hannah Haymond ‐Thornburg, John L. Tucker, Piya Chaemsaithong, Nardhy Gomez‐Lopez, Timothy P. York, Roberto Romero, Jerome F. Strauss Tags: Original Article Source Type: research

The genetic profile of Leber congenital amaurosis in an Australian cohort
ConclusionThe high resolution rate achieved, equivalent to recent findings using whole exome/genome sequencing, reflects the progression from hypothesis (LCA Panel) to non‐hypothesis (RD Panel) testing and, coupled with Array CGH analysis, is a highly effective first‐tier test for LCA. Leber congenital amaurosis (LCA) is a severe visual impairment responsible for infantile blindness, representing ~5% of all inherited retinal dystrophies. We present the molecular findings for an Australian LCA cohort, sourced from the Australian Inherited Retinal Disease Registry & DNA Bank, which utilized next‐generation sequenc...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Jennifer A. Thompson, John N. De Roach, Terri L. McLaren, Hannah E. Montgomery, Ling H. Hoffmann, Isabella R. Campbell, Fred K. Chen, David A. Mackey, Tina M. Lamey Tags: Original Article Source Type: research

Novel autosomal dominant TNNT1 mutation causing nemaline myopathy
ConclusionThis novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism. Novel heterozygous missense TNNT1 mutation with a mild phenotype of nemaline myopathy. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Chamindra G. Konersman, Fernande Freyermuth, Thomas L. Winder, Michael W. Lawlor, Clotilde Lagier ‐Tourenne, Shailendra B. Patel Tags: Original Article Source Type: research

Inherited SHQ1 mutations impair interaction with NAP57/dyskerin, a major target in dyskeratosis congenita
ConclusionIntrauterine growth retardation and the neurological phenotype of the patient are reminiscent of the severe clinical variant of DC, the Hoyeraal‐Hreidarsson syndrome (HH). Hence, SHQ1 screening may be warranted in patients with inherited bone marrow failure syndromes. We describe the first inherited patient mutations in SHQ1 and their impact on SHQ1 interaction with NAP57/dyskerin, the major target in the bone marrow failure syndrome dyskeratosis congenita. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Jonathan Bizarro, U. Thomas Meier Tags: Case Report Source Type: research

Unique genetic background and outcome of non ‐Caucasian Japanese probands with arrhythmogenic right ventricular dysplasia/cardiomyopathy
Abstract BackgroundArrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is an inherited cardiomyopathy mainly caused by desmosomal gene mutation. More than half of Caucasian probands have desmosomal mutations, which lead to earlier onset of ventricular arrhythmias. Among non‐Caucasians, the genetic background of ARVD/C probands and its prognostic impact remain unclear. Methods and ResultsWe genotyped 99 unrelated Japanese ARVD/C probands for plakophilin 2 (PKP2), desmoglein 2 (DSG2), desmoplakin (DSP), and desmocollin 2 (DSC2) between 2005 and 2014. Seventy‐five probands who fulfilled “definite&rdqu...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Yuko Wada, Seiko Ohno, Takeshi Aiba, Minoru Horie Tags: Original Article Source Type: research

Pediatric healthcare costs for patients with 22q11.2 deletion syndrome
ConclusionThis study demonstrates that there are significant medical costs associated with 22q11.2 deletion syndrome. The 22q11.2 deletion syndrome is a variably expressed disorder that can include cardiac, palate, and other physical abnormalities, immunodeficiency, and hypocalcemia. Because of the extreme variability in phenotype, there has been no available estimate of the total medical expenditure associated with the average case. From a data set of 624 patients with 22q11.2 deletion syndrome we calculated that the average cost per patient was $727,178. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Peter Benn, Sushma Iyengar, Terrence Blaine Crowley, Elaine H. Zackai, Evanette K. Burrows, Solomon Moshkevich, Donna M. McDonald ‐McGinn, Kathleen E. Sullivan, Zachary Demko Tags: Original Article Source Type: research

Analysis of sequence data to identify potential risk variants for oral clefts in multiplex families
ConclusionNeither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts. Nonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. In this study, we analyze whole exome and whole genome sequence data to identify enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4. (Source: Mol...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Emily R. Holzinger, Qing Li, Margaret M. Parker, Jacqueline B. Hetmanski, Mary L. Marazita, Elisabeth Mangold, Kerstin U. Ludwig, Margaret A. Taub, Ferdouse Begum, Jeffrey C. Murray, Hasan Albacha ‐Hejazi, Khalid Alqosayer, Giath Al‐Souki, Abdullatiff Tags: Original Article Source Type: research

Inherited 2q23.1 microdeletions involving the MBD5 locus
ConclusionsInherited forms of MBD5 deletions are rare, but do occur, especially in a mosaic form. The phenotypic spectrum of MAND may be wider than previously thought. This report describes three families with inherited 2q23.1 microdeletions including a parent who has the deletion in an apparently nonmosaic form and has mental health issues in the absence of developmental delay or dysmorphic features. We also report two instances of parental mosaicism, which could be significant for counseling parents of an affected child with an apparent de novo deletion. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Shereen Tadros, Rubin Wang, Jonathan J. Waters, Christine Waterman, Amanda L. Collins, Morag N. Collinson, Joo W. Ahn, Dragana Josifova, Ravi Chetan, Ajith Kumar Tags: Clinical Report Source Type: research

Expanding the mutational spectrum in Johanson ‐Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation‐dependent probe amplification analysis
ConclusionWe conclude that single or multi‐exon deletions or duplications account for a substantial proportion of JBS‐associated UBR1 mutations. Johanson‐Blizzard syndrome is a very rare autosomal recessive disorder caused by mutations of the UBR1 gene. Sanger sequencing could detect mutations in 93.1% of 130 disease‐associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this multiplex ligation‐dependent probe amplification (MLPA) study, raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles). (Source: Molecular ...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Maja Sukalo, Eva Sch äflein, Ina Schanze, David B. Everman, Nima Rezaei, Jesús Argente, Isabel Lorda‐Sanchez, Charu Deshpande, Tsutomu Takahashi, Alexander Kleger, Martin Zenker Tags: Clinical Report Source Type: research

Novel compound heterozygous mutations in TELO2 in a patient with severe expression of You ‐Hoover‐Fong syndrome
ConclusionThis report of Danish siblings with YHFS serves to expand the presentation of this new syndrome to include features in keeping with a form of microcephalic primordial dwarfism on the severe end of the clinical spectrum, and adds two novel mutations to the TELO2 mutational spectrum. Recently, compound heterozygous loss‐of‐function mutations in TELO2 were shown to underlie You‐Hoover‐Fong syndrome. Patients with mutations in TELO2 present with microcephaly and associated intellectual disability, postnatal growth retardation and dysmorphic features. Here, we describe Danish siblings with two novel mutations...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Shahida Moosa, Janine Altm üller, Troels Lyngbye, Rikke Christensen, Yun Li, Peter Nürnberg, Gökhan Yigit, Ida Vogel, Bernd Wollnik Tags: Clinical Report Source Type: research

Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes
Abstract BackgroundMutations in several genes predispose to colorectal cancer. Genetic testing for hereditary colorectal cancer syndromes was previously limited to single gene tests; thus, only a very limited number of genes were tested, and rarely those infrequently mutated in colorectal cancer. Next‐generation sequencing technologies have made it possible to sequencing panels of genes known and suspected to influence colorectal cancer susceptibility. MethodsTargeted sequencing of 36 known or putative CRC susceptibility genes was conducted for 1231 CRC cases from five subsets: (1) Familial Colorectal Cancer Type X (n&nb...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Melissa S. DeRycke, Shanaka Gunawardena, Jessica R. Balcom, Angela M. Pickart, Lindsey A. Waltman, Amy J. French, Shannon McDonnell, Shaun M. Riska, Zachary C. Fogarty, Melissa C. Larson, Sumit Middha, Bruce W. Eckloff, Yan W. Asmann, Matthew J. Ferber, R Tags: Original Article Source Type: research

A novel splice site variant in CYP11A1 in trans with the p.E314K variant in a male patient with congenital adrenal insufficiency
ConclusionCongenital adrenal insufficiency with 46XY sex reversal is a rare disorder that is characterized by dysregulation of steroid hormone synthesis, leading to adrenal and gonadal dysfunction. In this report, we describe a patient with adrenal insufficiency, hypospadias, and skin hyperpigmentation who was found to have a novel c.425+1G>A variant in trans with the p.E314K variant in CYP11A1. We performed structural analyses to examine the effect of the p.E314K variant on protein function and show that it falls in the core of the protein may disrupt cholesterol binding in the active site. In this report, we describe...
Source: Molecular Genetics & Genomic Medicine - July 1, 2017 Category: Genetics & Stem Cells Authors: Montserrat Lara ‐Velazquez, Alexander Perdomo‐Pantoja, Patrick R. Blackburn, Jennifer M. Gass, Thomas R. Caulfield, Paldeep S. Atwal Tags: Clinical Report Source Type: research