EGFR mutations cause a lethal syndrome of epithelial dysfunction with progeroid features
Abstract The epidermal growth factor receptor (EGFR) is part of a large family of receptors required for communicating extracellular signals through internal tyrosine kinases. Epidermal growth factor (EGF) signaling is required for tissue development, whereas constitutive activation of this signaling pathway is associated with oncogenic transformation. We identified homozygous c.1283G>A (p.Gly428Asp) mutations in the extracellular domain of EGFR in two siblings. The children were born prematurely, had abnormalities in skin and hair, suffered multisystem organ failure, and died in the neonatal period from intestinal perf...
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Rebecca Ganetzky, Erin Finn, Atrish Bagchi, Ornella Zollo, Laura Conlin, Matthew Deardorff, Margaret Harr, Michael A. Simpson, John A. McGrath, Elaine Zackai, Mark A. Lemmon, Neal Sondheimer Tags: Original Article Source Type: research

Identification of an Alu‐repeat‐mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype
We report the first regulatory region deletion involving OPTN and caused by Alu‐mediated non‐allelic homologous recombination in a patient with ocular dysgenesis and glaucoma. Optineurin is involved in various cellular functions including protein trafficking, protein secretion, cell division, antiviral/antibacterial signaling and thus its misexpression may have diverse negative effects on normal formation of ocular structures. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Kala F. Schilter, Linda M. Reis, Elena A. Sorokina, Elena V. Semina Tags: Original Article Source Type: research

Mutations in CDK5RAP2 cause Seckel syndrome
This study establishes CDK5RAP2 as a disease‐causing gene for Seckel syndrome and shows that CDK5RAP2 deficiency results in severe defects in mitosis and spindle organization. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Gökhan Yigit, Karen E. Brown, Hülya Kayserili, Esther Pohl, Almuth Caliebe, Diana Zahnleiter, Elisabeth Rosser, Nina Bögershausen, Zehra Oya Uyguner, Umut Altunoglu, Gudrun Nürnberg, Peter Nürnberg, Anita Rauch, Yun Li, Christian Thomas Thiel, Bernd Tags: Original Article Source Type: research

A rigorous approach for selection of optimal variant sets for carrier screening with demonstration of clinical utility
Abstract Carrier screening for certain diseases is recommended by major medical and Ashkenazi Jewish (AJ) societies. Most carrier screening panels test only for common, ethnic‐specific variants. However, with formerly isolated ethnic groups becoming increasingly intermixed, this approach is becoming inadequate. Our objective was to develop a rigorous process to curate all variants, for relevant genes, into a database and then apply stringent clinical validity classification criteria to each in order to retain only those with clear evidence for pathogenicity. The resulting variant set, in conjunction with next‐generatio...
Source: Molecular Genetics & Genomic Medicine - April 23, 2015 Category: Genetics & Stem Cells Authors: Cynthia Perreault‐Micale, Jocelyn Davie, Benjamin Breton, Stephanie Hallam, Valerie Greger Tags: Original Article Source Type: research

Behavioral abnormalities are common and severe in patients with distal 22q11.2 microdeletions and microduplications
We describe six individuals with microdeletions and microduplications in the distal 22q11.2 region detected by microarray. Five of the abnormalities have breakpoints in the low‐copy repeats (LCR) in this region and one patient has an atypical rearrangement. Two of the six patients with abnormalities in the region between LCR22 D–E have hearing loss, which has previously been reported only once in association with these abnormalities. We especially note the behavioral/neuropsychiatric problems, including the severity and early onset, in patients with distal 22q11.2 rearrangements. Our patients add to the genotype&nd...
Source: Molecular Genetics & Genomic Medicine - April 16, 2015 Category: Genetics & Stem Cells Authors: Valerie Lindgren, Anne McRae, Richard Dineen, Alexandria Saulsberry, George Hoganson, Michael Schrift Tags: Original Article Source Type: research

Pseudoexon activation increases phenotype severity in a Becker muscular dystrophy patient
We report a dystrophinopathy patient with an in‐frame deletion of DMD exons 45–47, and therefore a genetic diagnosis of Becker muscular dystrophy, who presented with a more severe than expected phenotype. Analysis of the patient DMD mRNA revealed an 82 bp pseudoexon, derived from intron 44, that disrupts the reading frame and is expected to yield a nonfunctional dystrophin. Since the sequence of the pseudoexon and canonical splice sites does not differ from the reference sequence, we concluded that the genomic rearrangement promoted recognition of the pseudoexon, causing a severe dystrophic phenotype. We chara...
Source: Molecular Genetics & Genomic Medicine - April 15, 2015 Category: Genetics & Stem Cells Authors: Kane Greer, Kayla Mizzi, Emily Rice, Lukas Kuster, Roberto A. Barrero, Matthew I. Bellgard, Bryan J. Lynch, Aileen Reghan Foley, Eoin O Rathallaigh, Steve D. Wilton, Sue Fletcher Tags: Original Article Source Type: research

Functional consequences of transferrin receptor‐2 mutations causing hereditary hemochromatosis type 3
We describe three new Spanish families (one pediatric case) and examine the functional consequences of two TFR2 variations (G792R and c.1606‐8A>G) using molecular and computational methods. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a non‐functional TFR2 protein and a defective signalling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in paediatric cases with early‐onset of iron overload. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 6, 2015 Category: Genetics & Stem Cells Authors: Ricky Joshi, Maya Shvartsman, Erica Morán, Sergi Lois, Jessica Aranda, Anna Barqué, Xavier Cruz, Miquel Bruguera, José Manuel Vagace, Guillermo Gervasini, Cristina Sanz, Mayka Sánchez Tags: Original Article Source Type: research

Variability in pathogenicity prediction programs: impact on clinical diagnostics
The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb ‐girdle muscular dystrophy. Performance metrics were compared between the programs to determine the most accurate program for loss of function and gain‐of‐function mechanisms. The best performer was MutPred, which had a weighted accuracy of 82.6% in the full dataset. AbstractCurrent practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the sig...
Source: Molecular Genetics & Genomic Medicine - March 5, 2015 Category: Genetics & Stem Cells Authors: Lauren C. Walters ‐Sen, Sayaka Hashimoto, Devon Lamb Thrush, Shalini Reshmi, Julie M. Gastier‐Foster, Caroline Astbury, Robert E. Pyatt Tags: Method Source Type: research

Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next ‐generation sequencing
In this study, therefore, we performed next ‐generation sequencing (NGS) analysis of the entire coding regions ofBRCA1 andBRCA2 in 135 breast and/or ovarian cancer patients. DeleteriousBRCA1 andBRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation inBRCA1 and two inBRCA2 had not been reported previously. Furthermore, aBRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screeningBRCA1 andBRCA2 mutations by NGS in clinical diagnosis. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 5, 2015 Category: Genetics & Stem Cells Authors: Yosuke Hirotsu, Hiroshi Nakagomi, Ikuko Sakamoto, Kenji Amemiya, Hitoshi Mochizuki, Masao Omata Tags: Original Article Source Type: research

Genetics and Genomic Medicine in Colombia
Genetics and Genomic medicine in Colombia. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 5, 2015 Category: Genetics & Stem Cells Authors: Mauricio De Castro, Carlos Martín Restrepo Tags: Genetics and Genomic Medicine Around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 5, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer
Abstract Approximately 5–10% of all breast and/or ovarian cancer cases are considered as inherited. BRCA1 and BRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial cases without mutations in these genes can also occur. Despite their low penetrance, other hereditary cancer‐related genes are known to be associated with breast and ovarian cancer risk. However, the extent to which these genes prevail in breast and ovarian cancer remains to be elucidated. To estimate the frequency of mutations in these predisposition genes, we analyzed the germline mutations of 25 hereditary cancer...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Yosuke Hirotsu, Hiroshi Nakagomi, Ikuko Sakamoto, Kenji Amemiya, Toshio Oyama, Hitoshi Mochizuki, Masao Omata Tags: Original Article Source Type: research

Inherited CHST11/MIR3922 deletion is associated with a novel recessive syndrome presenting with skeletal malformation and malignant lymphoproliferative disease
Abstract Glycosaminoglycans (GAGs) such as chondroitin are ubiquitous disaccharide carbohydrate chains that contribute to the formation and function of proteoglycans at the cell membrane and in the extracellular matrix. Although GAG‐modifying enzymes are required for diverse cellular functions, the role of these proteins in human development and disease is less well understood. Here, we describe two sisters out of seven siblings affected by congenital limb malformation and malignant lymphoproliferative disease. Using Whole‐Genome Sequencing (WGS), we identified in the proband deletion of a 55 kb region within chro...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Sameer S. Chopra, Ignaty Leshchiner, Hatice Duzkale, Heather McLaughlin, Monica Giovanni, Chengsheng Zhang, Nathan Stitziel, Joyce Fingeroth, Robin M. Joyce, Matthew Lebo, Heidi Rehm, Dana Vuzman, Richard Maas, Shamil R. Sunyaev, Michael Murray, Christoph Tags: Original Article Source Type: research

Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African‐American family
In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.‐153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African‐American family. Functional assays showed that this allele creates an allele‐specific protein‐binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathw...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Nevena Cvjetkovic, Lorena Maili, Katelyn S. Weymouth, S. Shahrukh Hashmi, John B. Mulliken, Jacek Topczewski, Ariadne Letra, Qiuping Yuan, Susan H. Blanton, Eric C. Swindell, Jacqueline T. Hecht Tags: Original Article Source Type: research

Novel recruitment strategy to enrich for LRRK2 mutation carriers
This study was designed to test whether an internet‐based approach could be an effective approach to screen and identify mutation carriers. Individuals with and without PD of AJ ancestry were recruited and consented through an internet‐based study website. An algorithm was applied to a series of screening questions to identify individuals at increased risk to carry the LRRK2 G2019S mutation. About 1000 individuals completed the initial screening. Around 741 qualified for mutation testing and 650 were tested. Seventy‐two individuals carried at least one LRRK2 G2019S mutation; 38 with PD (12.5%) and 34 without (10.1%)....
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Tatiana Foroud, Danielle Smith, Jacqueline Jackson, Jennifer Verbrugge, Cheryl Halter, Leah Wetherill, Katherine Sims, Winnie Xin, Vanessa Arnedo, Shirley Lasch, Kenneth Marek, Tags: Original Article Source Type: research

Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)?
This study supports a genetic etiology for LBWC/ABS, or potentially a new syndrome. We present the first genetic characterization of an individual who has elements of both limb body wall complex (LBWC) and amniotic band sequence (ABS), but may also be a new syndrome. Both LBWC and ABS do not have a known genetic etiology, and there has been much debate on whether these two conditions are the same or separate entities. Using whole exome sequencing, we have found a genetic mutation in the gene IQ motif containing K (IQCK), which has not been previously reported in the medical literature. Using functional studies in the zebr...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Paul Kruszka, Annette Uwineza, Leon Mutesa, Ariel F. Martinez, Yu Abe, Elaine H. Zackai, Rebecca Ganetzky, Brian Chung, Roger E. Stevenson, Robert S. Adelstein, Xuefei Ma, James C. Mullikin, , Sung‐Kook Hong, Maximilian Muenke Tags: Original Article Source Type: research

Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide‐selective sequencing
This study represents the first clinical study with OS‐Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with>15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant‐positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in t...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Sanna Vattulainen, Joonas Aho, Pertteli Salmenperä, Siina Bruce, Jonna Tallila, Massimiliano Gentile, Marja Sankelo, Tarja Laitinen, Juha W. Koskenvuo, Tero‐Pekka Alastalo, Samuel Myllykangas Tags: Original Article Source Type: research

Splicing analysis for exonic and intronic mismatch repair gene variants associated with Lynch syndrome confirms high concordance between minigene assays and patient RNA analyses
Abstract A subset of DNA variants causes genetic disease through aberrant splicing. Experimental splicing assays, either RT‐PCR analyses of patient RNA or functional splicing reporter minigene assays, are required to evaluate the molecular nature of the splice defect. Here, we present minigene assays performed for 17 variants in the consensus splice site regions, 14 exonic variants outside these regions, and two deep intronic variants, all in the DNA mismatch‐repair (MMR) genes MLH1, MSH2, MSH6, and PMS2, associated with Lynch syndrome. We also included two deep intronic variants in APC and PKD2. For one variant (MLH1 ...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Heleen M. Klift, Anne M. L. Jansen, Niki Steenstraten, Elsa C. Bik, Carli M. J. Tops, Peter Devilee, Juul T. Wijnen Tags: Original Article Source Type: research

Validation of a semiconductor next‐generation sequencing assay for the clinical genetic screening of CFTR
Abstract Genetic testing for cystic fibrosis and CFTR‐related disorders mostly relies on laborious molecular tools that use Sanger sequencing to scan for mutations in the CFTR gene. We have explored a more efficient genetic screening strategy based on next‐generation sequencing (NGS) of the CFTR gene. We validated this approach in a cohort of 177 patients with previously known CFTR mutations and polymorphisms. Genomic DNA was amplified using the Ion AmpliSeq™ CFTR panel. The DNA libraries were pooled, barcoded, and sequenced using an Ion Torrent PGM sequencer. The combination of different robust bioinformatics to...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Daniel Trujillano, Maximilian E. R. Weiss, Julia Köster, Efstathios B. Papachristos, Martin Werber, Krishna Kumar Kandaswamy, Anett Marais, Sabrina Eichler, Jenny Creed, Erol Baysal, Iqbal Yousuf Jaber, Dina Ahmed Mehaney, Chantal Farra, Arndt Rolfs Tags: Original Article Source Type: research

Structural and functional influences of coagulation factor XIII subunit B heterozygous missense mutants
Abstract The coagulation factor XIII(FXIII) is a plasma circulating heterotetrameric protransglutaminase that acts at the end of the coagulation cascade by covalently cross‐linking preformed fibrin clots (to themselves and to fibrinolytic inhibitors) in order to stabilize them against fibrinolysis. It circulates in the plasma as a heterotetramer composed of two homomeric catalytic Factor XIIIA2 (FXIIIA2) and two homomeric protective/carrier Factor XIIIB2 subunit (FXIIIB2). Congenital deficiency of FXIII is of two types: severe homozygous/compound heterozygous FXIII deficiency which results in severe bleeding symptoms and...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Anne Thomas, Arijit Biswas, Vytautas Ivaskevicius, Johannes Oldenburg Tags: Original Article Source Type: research

Novel pathogenic variants and genes for myopathies identified by whole exome sequencing
We present four unique childhood myopathy cases characterized by relatively mild muscle weakness, slowly progressing course, mildly elevated creatine phosphokinase (CPK), and contractures. We also present two additional cases characterized by severe prenatal/neonatal myopathy. Prior extensive genetic testing and histology of these cases did not reveal the genetic etiology of disease. Here, we applied whole exome sequencing (WES) and bioinformatics to identify likely causal pathogenic variants in each pedigree. In two cases, we identified novel pathogenic variants in COL6A3. In a third case, we identified novel likely patho...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Jesse M. Hunter, Mary Ellen Ahearn, Christopher D. Balak, Winnie S. Liang, Ahmet Kurdoglu, Jason J. Corneveaux, Megan Russell, Matthew J. Huentelman, David W. Craig, John Carpten, Stephen W. Coons, Daphne E. DeMello, Judith G. Hall, Saunder M. Bernes, Lis Tags: Original Article Source Type: research

It's complicated: criteria for policy decisions for the clinical integration of genome‐scale sequencing for reproductive decision making
The integration of genome scale sequencing into clinical practice for reproductive decision making raises similar policy issues for carrier testing for cystic fibrosis and sickle cell anemia. In all cases, the importance of the information is based on personal values, rather than medical benefit. Policy decisions to fund such testing will depend on clinical research that demonstrates how to efectively and safely deliver that information in the context of a health system's resources. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Benjamin S. Wilfond, Katrina A.B. Goddard Tags: Invited Commentary Source Type: research

Global epidemiology of Familial Mediterranean fever mutations using population exome sequences
Abstract Familial Mediterranean fever (FMF) is an inherited disorder characterized by recurrent episodes of fever accompanied by sterile peritonitis, arthritis, and pleuritis. Many mutations in the MEFV gene have been identified as causing FMF. However, accompanying epidemiological information remains quite scarce except in some Mediterranean countries, and the degree of penetrance has been a subject of controversy. Here, I established a genetic epidemiology of full FMF mutations using two population exome studies. Of 57 mutations associated with FMF, 22 were detected in a total of 9007 individuals from two exome sequences...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Kohei Fujikura Tags: Original Article Source Type: research

Critical roles for WDR72 in calcium transport and matrix protein removal during enamel maturation
Abstract Defects in WDR72 (WD repeat‐containing protein 72) cause autosomal recessive hypomaturation amelogenesis imperfecta. We generated and characterized Wdr72‐knockout/lacZ‐knockin mice to investigate the role of WDR72 in enamel formation. In all analyses, enamel formed by Wdr72 heterozygous mice was indistinguishable from wild‐type enamel. Without WDR72, enamel mineral density increased early during the maturation stage but soon arrested. The null enamel layer was only a tenth as hard as wild‐type enamel and underwent rapid attrition following eruption. Despite the failure to further mineralize enamel deposi...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Shih‐Kai Wang, Yuanyuan Hu, Jie Yang, Charles E. Smith, Stephanie M. Nunez, Amelia S Richardson, Soumya Pal, Andrew C. Samann, Jan C.‐C. Hu, James P. Simmer Tags: Original Article Source Type: research

SMN1 and SMN2 copy numbers in cell lines derived from patients with spinal muscular atrophy as measured by array digital PCR
In this study, we describe the development of an assay to assess SMN1 and SMN2 copy numbers in DNA samples using an array‐based digital PCR (dPCR) system. This dPCR assay can accurately and reliably measure the number of SMN1 and SMN2 copies in DNA samples. In a cohort of SMA patient‐derived cell lines, the assay confirmed a strong inverse correlation between SMN2 copy number and disease severity. Array dPCR is a practical technique to determine, accurately and reliably, SMN1 and SMN2 copy numbers from SMA samples. We describe here a new method to reliably and accurately measure SMN1 and SMN2 copy number variations in...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Deborah L. Stabley, Ashlee W. Harris, Jennifer Holbrook, Nicholas J. Chubbs, Kevin W. Lozo, Thomas O. Crawford, Kathryn J. Swoboda, Vicky L. Funanage, Wenlan Wang, William Mackenzie, Mena Scavina, Katia Sol‐Church, Matthew E. R. Butchbach Tags: Method Source Type: research

Contiguous mutation syndrome in the era of high‐throughput sequencing
We report on two siblings presenting the association of typical AP4‐deficiency neurological presentation and severe obesity with early onset. Using whole‐exome sequencing, we demonstrated that the siblings' phenotype results from the combined effects of two homozygous substitutions in AP4M1 and AZGP1 that account for the neurological signs and the morbid obesity of early onset, respectively. These two genes are located 170 kb apart on 7q22.1. We propose to broaden the concept of contiguous gene syndromes to phenotypes resulting from independent mutations in two genetically linked genes causing a contiguous mutatio...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Maéva Langouët, Karine Siquier‐Pernet, Sylvia Sanquer, Christine Bole‐Feysot, Patrick Nitschke, Nathalie Boddaert, Arnold Munnich, Grazia M. S. Mancini, Robert Barouki, Jeanne Amiel, Laurence Colleaux Tags: Original Article Source Type: research

Copy number variation in the ATP‐binding cassette transporter ABCC6 gene and ABCC6 pseudogenes in patients with pseudoxanthoma elasticum
In conclusion, by pyrosequencing and quantitative PCR, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused the PXE phenotype. Pyrosequencing may be used in PXE patients who have obtained incomplete genotype from conventional techniques. The frequency of ABCC6P2 pseudogene duplication was more common in PXE patients than healthy individuals and may affect the PXE phenotype. In this study, principally by pyrosequencing, we were able to detect known and possibly new deletions in the ABCC6 gene that may have caused pseudoxanthoma elasticum (PXE). Also, duplication of the ABCC6P2 pseu...
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Marianne K. Kringen, Camilla Stormo, Jens Petter Berg, Sharon F. Terry, Christine M. Vocke, Samar Rizvi, Doris Hendig, Armin P. Piehler Tags: Original Article Source Type: research

Perspectives on what is needed to implement genomic medicine
This commentary briefly explores some of the additional factors needed to incorporate genomics into clinical care including the role of electronic health records, measuring the value of interventions and implementation science. Distinctions between genomic, personalized and precision medicine will be examined. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - March 1, 2015 Category: Genetics & Stem Cells Authors: Marc S. Williams Tags: Invited Commentary Source Type: research

Improved inherited peripheral neuropathy genetic diagnosis by whole‐exome sequencing
This study highlights the advantage of using WES for genetic diagnosis in highly heterogeneous diseases such as IPNs and has been particularly powerful in this cohort where genetic diagnosis could not be achieved due to phenotype and mode of inheritance not being previously obvious. However, first tier testing for common genes in clinically well‐defined cases remains important and will account for most positive results. We performed WES for 110 index patients with IPN where the genetic cause was undetermined after previous screening for mutations in common genes selected by phenotype and mode of inheritance. We identifi...
Source: Molecular Genetics & Genomic Medicine - January 14, 2015 Category: Genetics & Stem Cells Authors: Alexander P. Drew, Danqing Zhu, Aditi Kidambi, Carolyn Ly, Shelisa Tey, Megan H. Brewer, Azlina Ahmad‐Annuar, Garth A. Nicholson, Marina L. Kennerson Tags: Original Article Source Type: research

Taurodontism, variations in tooth number, and misshapened crowns in Wnt10a null mice and human kindreds
We characterized the dentitions ofWnt10a null mice and observed mandibular fourth molars, abnormal molar cusp patterning, molar root taurodontism, and distinctive basal –lingual wedge‐shaped defects in mandibular incisors. We characterized the dentitions six families with WNT10A mutations in the absence ofEDA, EDAR, orEDARADD defects and observed, in heterozygotes, molar root taurodontism and mild tooth agenesis, and in homozygotes, severe tooth agenesis and molars with fewer cusps. This expands the known clinical phenotype in WNT10A families and demonstrates differences in the roles of Wnt signaling in early tooth...
Source: Molecular Genetics & Genomic Medicine - January 8, 2015 Category: Genetics & Stem Cells Authors: Jie Yang, Shih ‐Kai Wang, Murim Choi, Bryan M. Reid, Yuanyuan Hu, Yuan‐Ling Lee, Curtis R. Herzog, Hera Kim‐Berman, Moses Lee, Paul J. Benke, K. C. Kent Lloyd, James P. Simmer, Jan C.‐C. Hu Tags: Original Article Source Type: research

Whole exome sequencing reveals mutations in NARS2 and PARS2, encoding the mitochondrial asparaginyl ‐tRNA synthetase and prolyl‐tRNA synthetase, in patients with Alpers syndrome
This report links for the first time mutations in these genes to human disease in general and to Alpers syndrome in particular. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2015 Category: Genetics & Stem Cells Authors: Kalliopi Sofou, Gittan Kollberg, Maria Holmstr öm, Marcela Dávila, Niklas Darin, Claes M. Gustafsson, Elisabeth Holme, Anders Oldfors, Már Tulinius, Jorge Asin‐Cayuela Tags: Original Article Source Type: research

Genetics and genomic medicine in Slovakia
Provision of medical genetics services in the Slovak Republic has a well established organisational structure, network of providers, personnel and methodical conditions which ensure high‐level services. The main limiting factor is finance allocated to these services by insurance companies; far below eligible demand. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2015 Category: Genetics & Stem Cells Authors: Ludevít Kádaši, František Cisárik Tags: Invited Commentary Genetics and Genomic Medicine Around the World Source Type: research

MENDEL: Morphologist and Mathematician Founder of Genetics – To Begin a Celebration of the 2015 Sesquicentennial of Mendel's Presentation in 1865 of his Versuche über Pflanzenhybriden
On the eve of the Mendel sesquicentennial (1865) it seems relevant to revisit his eudaimonia, which made him, along with his contemporary Darwin, the most respected thinker in Western Biology since Aristotle. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2015 Category: Genetics & Stem Cells Authors: John M. Opitz, Diana W. Bianchi Tags: Invited Commentary Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 8, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach
We report variants in the ARX gene detected in 19 patients belonging to 17 families. Seven pathogenic variants, being expansion mutations in both polyalanine tract 1 and tract 2, were identifyed, including a novel mutation in polyalanine tract 1 that expands the first tract to 20 alanines. This precise number of alanines is sufficient to cause pathogenicity when expanded in polyalanine tract 2. Five cases presented a probably non‐pathogenic variant, including the novel HGVS: c.441_455del, classified as unlikely disease causing, consistent with reports that suggest that in frame deletions in polyalanine stretches of ARX r...
Source: Molecular Genetics & Genomic Medicine - January 1, 2015 Category: Genetics & Stem Cells Authors: Isabel Marques, Maria João Sá, Gabriela Soares, Maria do Céu Mota, Carla Pinheiro, Lisa Aguiar, Marta Amado, Christina Soares, Angelina Calado, Patrícia Dias, Ana Berta Sousa, Ana Maria Fortuna, Rosário Santos, Katherine B. Howell, Monique M. Ryan, R Tags: Original Article Source Type: research

Identification of novel mutations in Mexican patients with Aarskog–Scott syndrome
This study represents the first molecular analysis of the faciogenital dysplasia (FGD1) gene in Mexican patients with characteristic Aarskog–Scott syndrome (AAS). We present the clinical and molecular analysis of four unrelated families. This analysis identified two stop mutations not previously reported in the literature, broadening the spectrum of reported mutations. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 1, 2015 Category: Genetics & Stem Cells Authors: Mariana Pérez‐Coria, José J. Lugo‐Trampe, Michell Zamudio‐Osuna, Iram P. Rodríguez‐Sánchez, Angel Lugo‐Trampe, Beatriz Fuente‐Cortez, Luis D. Campos‐Acevedo, Laura E. Martínez‐de‐Villarreal Tags: Original Article Source Type: research

Diversity of the causal genes in hearing impaired Algerian individuals identified by whole exome sequencing
Abstract The genetic heterogeneity of congenital hearing disorders makes molecular diagnosis expensive and time‐consuming using conventional techniques such as Sanger sequencing of DNA. In order to design an appropriate strategy of molecular diagnosis in the Algerian population, we explored the diversity of the involved mutations by studying 65 families affected by autosomal recessive forms of nonsyndromic hearing impairment (DFNB forms), which are the most prevalent early onset forms. We first carried out a systematic screening for mutations in GJB2 and the recurrent p.(Arg34*) mutation in TMC1, which were found in 31 (...
Source: Molecular Genetics & Genomic Medicine - January 1, 2015 Category: Genetics & Stem Cells Authors: Fatima Ammar‐Khodja, Crystel Bonnet, Malika Dahmani, Sofiane Ouhab, Gaelle M. Lefèvre, Hassina Ibrahim, Jean‐Pierre Hardelin, Dominique Weil, Malek Louha, Christine Petit Tags: Original Article Source Type: research

Quantifying the cumulative effect of low‐penetrance genetic variants on breast cancer risk
Abstract Many common diseases have a complex genetic basis in which large numbers of genetic variations combine with environmental factors to determine risk. However, quantifying such polygenic effects has been challenging. In order to address these difficulties we developed a global measure of the information content of an individual's genome relative to a reference population, which may be used to assess differences in global genome structure between cases and appropriate controls. Informally this measure, which we call relative genome information (RGI), quantifies the relative “disorder” of an individual's g...
Source: Molecular Genetics & Genomic Medicine - January 1, 2015 Category: Genetics & Stem Cells Authors: Conor Smyth, Iva Špakulová, Owen Cotton‐Barratt, Sajjad Rafiq, William Tapper, Rosanna Upstill‐Goddard, John L. Hopper, Enes Makalic, Daniel F. Schmidt, Miroslav Kapuscinski, Jörg Fliege, Andrew Collins, Jacek Brodzki, Diana M. Eccles, Ben D. MacAr Tags: Original Article Source Type: research

A slowly progressive form of limb‐girdle muscular dystrophy type 2C associated with founder mutation in the SGCG gene in Puerto Rican Hispanics
In this report, we describe four unrelated LGMD2C patients of Hispanic descent from the island of Puerto Rico that share a E263K (G787A) mutation within exon 8 of the SGCG gene. A slowly progressive phenotype with prolonged preservation of ambulation is illustrated in two of our patients. We also confirmed the founder effect of this mutation among Puerto Rican Hispanics using linkage analysis and determined that this mutation in affected individuals segregates with alleles inherited from each parent. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 1, 2015 Category: Genetics & Stem Cells Authors: Samiah A. Al‐Zaidy, Vinod Malik, Kelley Kneile, Xiomara Q. Rosales, Ana Maria Gomez, Sarah Lewis, Sayaka Hashimoto, Julie Gastier‐Foster, Peter Kang, Basil Darras, Louis Kunkel, Jose Carlo, Zarife Sahenk, Steven A. Moore, Robert Pyatt, Jerry R. Mendel Tags: Original Article Source Type: research

A positive genotype–phenotype correlation in a large cohort of patients with Pseudohypoparathyroidism Type Ia and Pseudo‐pseudohypoparathyroidism and 33 newly identified mutations in the GNAS gene
In this study, we sequenced exon 1–13 of GNAS in a large cohort of PHPIa‐ and PPHP patients and identified 58 different mutations in 88 patients and 27 relatives. Thirty‐three mutations including 15 missense mutations were newly discovered. Furthermore, we found three hot spots: a known hotspot (p.D190MfsX14), a second at codon 166 (p.R166C), and a third at the exon 5 acceptor splice site (c.435 + 1G>A), found in 15, 5, and 4 unrelated patients, respectively. Comparing the clinical features to the molecular genetic data, a significantly higher occurrence of subcutaneous calcifications in patients har...
Source: Molecular Genetics & Genomic Medicine - December 4, 2014 Category: Genetics & Stem Cells Authors: Susanne Thiele, Ralf Werner, Joachim Grötzinger, Bettina Brix, Pia Staedt, Dagmar Struve, Benedikt Reiz, Jennane Farida, Olaf Hiort Tags: Original Article Source Type: research

Variability in pathogenicity prediction programs: impact on clinical diagnostics
Abstract Current practice by clinical diagnostic laboratories is to utilize online prediction programs to help determine the significance of novel variants in a given gene sequence. However, these programs vary widely in their methods and ability to correctly predict the pathogenicity of a given sequence change. The performance of 17 publicly available pathogenicity prediction programs was assayed using a dataset consisting of 122 credibly pathogenic and benign variants in genes associated with the RASopathy family of disorders and limb‐girdle muscular dystrophy. Performance metrics were compared between the programs to ...
Source: Molecular Genetics & Genomic Medicine - December 3, 2014 Category: Genetics & Stem Cells Authors: Lauren C. Walters‐Sen, Sayaka Hashimoto, Devon Lamb Thrush, Shalini Reshmi, Julie M. Gastier‐Foster, Caroline Astbury, Robert E. Pyatt Tags: Original Article Source Type: research

Familial adenomatous polyposis in an adolescent with coexisting schizophrenia: treatment strategies and implications
Abstract Schizophrenia is associated with high mortality and morbidity. The etiology of schizophrenia remains unclear, studies implicate a multifactorial origin with genetic and environmental factors. The adenomatous polyposis coli (APC) gene has been associated with FAP (familial adenomatous polyposis), and studies have linked it to schizophrenia. However, there are few studies which examine the association between FAP and schizophrenia. Limited data exist regarding recommendations for genetic counseling of adolescents with comorbid psychiatric illness. A case of an adolescent with FAP who developed psychotic symptoms is ...
Source: Molecular Genetics & Genomic Medicine - December 3, 2014 Category: Genetics & Stem Cells Authors: Luisa Gonzalez, Jose Alvarez, Erica Weinstein, Panagiota Korenis Tags: Clinical Report Source Type: research

Medical Genetics in Paraguay
Medical genetics in Paraguay is still in its infancy, with many tests being sent out of the country given the lack of local availability, no genetic counselors, no accredited post‐doctoral residency training program in genetics, and only one clinical geneticist serving a country of almost 7 million people. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 3, 2014 Category: Genetics & Stem Cells Authors: Carlos Raúl Ferreira, María Beatriz Herreros Tags: Invited Commentary: Genetics and Genomic Medicine Around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 3, 2014 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Distribution of fragile X mental retardation 1 CGG repeat and flanking haplotypes in a large Chinese population
This study provides important information for future large‐scale screening and genetic counseling for FXS in China. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Wen Huang, Qiuping Xia, Shiyu Luo, Hua He, Ting Zhu, Qian Du, Ranhui Duan Tags: Original Article Source Type: research

Genetic counselors and Genomic Counseling in the United Kingdom
Is genomic counselling an extension of genetic counselling? We explore the different ways that genomic data might be delivered to patients; and discuss the skills that genetic counsellors and clinical geneticists are already using to deliver results from sequencing technologies. As genomics is introduced into mainstream health services, genetic counsellors need to be part of the conversation about the familial implications of genomic data as well as Œhow¹ to actually communicate this appropriately. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Anna Middleton, Georgina Hall, Christine Patch Tags: Invited Commentary Source Type: research

Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population
In this report, the carrier frequencies for eleven mutations in eight PCD‐associated genes (DNAI1, DNAI2, DNAH5, DNAH11, CCDC114, CCDC40, CCDC65, and C21orf59) that had been found in individuals of Ashkenazi Jewish descent were investigated in order to advise on including them in existing clinical mutation panels for this population. Results showed relatively high carrier frequencies for the DNAH5 c.7502G>C mutation (0.58%), the DNAI2 c.1304G>A mutation (0.50%), and the C21orf59 c.735C>G mutation (0.48%), as well as lower frequencies for mutations in DNAI1, CCDC65, CCDC114, and DNAH11 (0.10–0.29%). These r...
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Anastasia M. Fedick, Chaim Jalas, Nathan R. Treff, Michael R. Knowles, Maimoona A. Zariwala Tags: Original Article Source Type: research

Detection of BRCA1 and BRCA2 germline mutations in Japanese population using next‐generation sequencing
In this study, therefore, we performed next‐generation sequencing (NGS) analysis of the entire coding regions of BRCA1 and BRCA2 in 135 breast and/or ovarian cancer patients. Deleterious BRCA1 and BRCA2 mutations were detected in 10 patients (7.4%) by NGS analysis. Of these, one mutation in BRCA1 and two in BRCA2 had not been reported previously. Furthermore, a BRCA2 mutation found in a proband was also identified in two unaffected relatives. These data suggest the utility of screening BRCA1 and BRCA2 mutations by NGS in clinical diagnosis. BRCA1 and BRCA2 are tumor suppressor genes associated with the hereditary risk o...
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Yosuke Hirotsu, Hiroshi Nakagomi, Ikuko Sakamoto, Kenji Amemiya, Hitoshi Mochizuki, Masao Omata Tags: Original Article Source Type: research

Personalized treatment of Sézary syndrome by targeting a novel CTLA4:CD28 fusion
Abstract Matching molecularly targeted therapies with cancer subtype‐specific gene mutations is revolutionizing oncology care. However, for rare cancers this approach is problematic due to the often poor understanding of the disease's natural history and phenotypic heterogeneity, making treatment of these cancers a particularly unmet medical need in clinical oncology. Advanced Sézary syndrome (SS), an aggressive, exceedingly rare variant of cutaneous T‐cell lymphoma (CTCL) is a prototypical example of a rare cancer. Through whole genome and RNA sequencing (RNA‐seq) of a SS patient's tumor we discovered a highl...
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Aleksandar Sekulic, Winnie S. Liang, Waibhav Tembe, Tyler Izatt, Semyon Kruglyak, Jeffrey A. Kiefer, Lori Cuyugan, Victoria Zismann, Christophe Legendre, Mark R. Pittelkow, John J. Gohmann, Fernando R. De Castro, Jeffrey Trent, John Carpten, David W. Crai Tags: Original Article Source Type: research

Performance evaluation of Sanger sequencing for the diagnosis of primary hyperoxaluria and comparison with targeted next generation sequencing
In this study, Sanger sequencing results for 200 referred patients were reviewed, identifying that 25% of patients were potentially undiagnosed as full gene sequencing was not requested. To overcome this diagnostic gap, a targeted Next Generation Sequencing assay for the simultaneous analysis of all three genes was evaluated in 90 affected patients. Results showed 98% agreement with Sanger sequencing and diagnostic sensitivity was 97%. Use of NGS would prevent undue diagnostic delay which is associated with poorer patient outcome. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2014 Category: Genetics & Stem Cells Authors: Emma L. Williams, Eleanor A. L. Bagg, Michael Mueller, Jana Vandrovcova, Timothy J. Aitman, Gill Rumsby Tags: Original Article Source Type: research