Next‐generation sequencing identifies novel CACNA1A gene mutations in episodic ataxia type 2
Abstract Episodic Ataxia type 2 (EA2) is a rare autosomal dominantly inherited neurological disorder characterized by recurrent disabling imbalance, vertigo, and episodes of ataxia lasting minutes to hours. EA2 is caused most often by loss of function mutations of the calcium channel gene CACNA1A. In addition to EA2, mutations in CACNA1A are responsible for two other allelic disorders: familial hemiplegic migraine type 1 (FHM1) and spinocerebellar ataxia type 6 (SCA6). Herein, we have utilized next‐generation sequencing (NGS) to screen the coding sequence, exon‐intron boundaries, and Untranslated Regions (UTRs) of five...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Neven Maksemous, Bishakha Roy, Robert A. Smith, Lyn R. Griffiths Tags: Original Article Source Type: research

Sideroblastic anemia: functional study of two novel missense mutations in ALAS2
ConclusionIn view of the results obtained in this study, a clear relationship between genotype and phenotype cannot be established; clinical variability or severity of anemia may be influenced by allelic variants in other genes or transcription factors and environmental conditions. The different types of anemia are distinguished by characteristic hematological parameters and cellular morphology. The genetic study allows a more precise diagnosis. We report four cases with sideroblastic anemia with mutations in the 5‐aminolevulinate synthase (ALAS2) gene. The in silico analysis of mutations and the in vitro study to ...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Manuel Méndez, María‐Isabel Moreno‐Carralero, Marta Morado‐Arias, María‐Cristina Fernández‐Jiménez, Silvia Iglesia Iñigo, María‐José Morán‐Jiménez Tags: Original Article Source Type: research

Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations
ConclusionIn conclusion, we found that our classifications were mostly in accordance with the InSiGHT scheme. In addition to already known MMR mutations, we have also presented 55 novel pathogenic or putative pathogenic mutations. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Wenche Sjursen, Mary McPhillips, Rodney J. Scott, Bente A. Talseth‐Palmer Tags: Original Article Source Type: research

Capture‐based next‐generation sequencing reveals multiple actionable mutations in cancer patients failed in traditional testing
ConclusionOur study has shown that NGS‐based molecular diagnosis is more sensitive and comprehensive to detect genomic alterations in cancer, and supports a direct clinical use for guiding targeted therapy. In this study, we have developed and validated a next‐generation sequencing (NGS)‐based cancer genomic diagnosis targeting hundreds of prognosis and therapeutics relevant genes on multiple types of cancer and specimen. We have assessed analytical sensitivity, specificity, and accuracy of the assay. Also, we developed clinical‐applicable analysis pipelines that are capable of detecting base substitutions, indels...
Source: Molecular Genetics & Genomic Medicine - January 1, 2016 Category: Genetics & Stem Cells Authors: Jing Xie, Xiongxiong Lu, Xue Wu, Xiaoyi Lin, Chao Zhang, Xiaofang Huang, Zhili Chang, Xinjing Wang, Chenlei Wen, Xiaomei Tang, Minmin Shi, Qian Zhan, Hao Chen, Xiaxing Deng, Chenghong Peng, Hongwei Li, Yuan Fang, Yang Shao, Baiyong Shen Tags: Original Article Source Type: research

MMP20, KLK4, and MMP20/KLK4 double null mice define roles for matrix proteases during dental enamel formation
Abstract Matrix metalloproteinase 20 (MMP20) and kallikrein‐related peptidase 4 (KLK4) are secreted proteinases that are essential for proper dental enamel formation. We characterized and compared enamel formed in wild‐type, Mmp20−/−, Klk4−/−, Mmp20+/−Klk4+/−, and Mmp20−/−Klk4−/− mice using dissecting and light microscopy, backscattered scanning electron microscopy (bSEM), SEM, microcomputed tomography (μCT), and energy‐dispersive X‐ray analysis (EDX). Following eruption, fractures were observed on Mmp20−/−, Klk4−/−, Mmp20+/...
Source: Molecular Genetics & Genomic Medicine - December 20, 2015 Category: Genetics & Stem Cells Authors: Yuanyuan Hu, Charles E. Smith, Amelia S Richardson, John D. Bartlett, Jan C.C. Hu, James P. Simmer 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 including GATA5 as a potential gene to be screened in patients with this phenotype. GATA proteins have been shown to play a major role in organ development and function by controlling different aspects of cell proliferation and differentiation. Mouse models with targeted genes inactivation recapitulate human congenital diseases phenotypes and genotypes with subtle variations in genetic backgrounds. We screened for mutations in the GATA5 gene that could be linked to congenital heart defects, and found novel variants and previously reported var...
Source: Molecular Genetics & Genomic Medicine - December 20, 2015 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

Foreword to volume 3, issue 6
As 2015 draws to a close so too do the many celebrations of the 150th anniversary of Mendel's presentation of his work entitled “Experiments in Plant Hybridization” to the Natural History Society of Brno. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 11, 2015 Category: Genetics & Stem Cells Authors: P. Suzanne Hart, Maximilian Muenke Tags: Editorial Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 11, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Genetics and genomic medicine in Ecuador
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: César Paz‐y‐Miño, María J. Guillen Sacoto, Paola E. Leone Tags: Genetics and Genomic Medicine around the World Source Type: research

The pathogenicity of genetic variants previously associated with left ventricular non‐compaction
ConclusionsIn this article, we identified 9 ESP‐positive and 18 ExAC‐positive variants of 60 previously reported LVNC‐associated variants, suggesting that these variants are not necessarily the monogenic cause of LVNC. We report the results of the first study on the left ventricular non‐compaction associated gene and variants. We performed prediction analysis to estimate the pathogenicity of LVNC‐associated variants. Exome sequencing database was systematically searched for the LVNC‐ associated variants. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Yeganeh Abbasi, Javad Jabbari, Reza Jabbari, Ren‐Qiang Yang, Bjarke Risgaard, Lars Køber, Stig Haunsø, Jacob Tfelt‐Hansen Tags: Original Article Source Type: research

Next generation sequencing‐based copy number analysis reveals low prevalence of deletions and duplications in 46 genes associated with genetic cardiomyopathies
ConclusionClinically significant deletions and duplications were identified in only 9 of 1425 (0.63%) individuals. The majority of those (6/9) represented intragenic events. We conclude that the added benefit of exon level deletion/duplication analysis is low for currently known cardiomyopathy genes and may not outweigh the increased cost and complexity of incorporating it into routine diagnostic testing for these disorders. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Ozge Ceyhan‐Birsoy, Trevor J. Pugh, Mark J. Bowser, Elizabeth Hynes, Ashley L. Frisella, Lisa M. Mahanta, Matt S. Lebo, Sami S. Amr, Birgit H. Funke Tags: Original Article Source Type: research

A recurrent F8 mutation (c.6046C>T) causing hemophilia A in 8% of northern Italian patients: evidence for a founder effect
Abstract Hemophilia A is a heterogeneous hemorrhagic disorder caused by a large number of mutations. Recurrent mutations are rare, except intron 22 and intron 1 inversions. The substitution of a cytosine to a thymine at nucleotide 6046 in F8 gene was identified in a group of Italian patients affected by hemophilia A from a specific region of Northern Italy with a prevalence of 7.6%. This F8 variant was the second most frequent mutation in our cohort, after the intron 22 inversion. The identification of the same mutation in a restricted population gets to suppose the existence of a founder effect. Intragenic and extragenic ...
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Isabella Garagiola, Sabrina Seregni, Mimosa Mortarino, Maria Elisa Mancuso, Maria Rosaria Fasulo, Lucia Dora Notarangelo, Flora Peyvandi Tags: Original Article Source Type: research

Mid1/Mid2 expression in craniofacial development and a literature review of X‐linked opitz syndrome
ConclusionsOur results support the hypothesis of functional redundancy of Mid1/Mid2 and their potential roles in regulating tissue remodelling in early development. MID1 is the causative gene of X‐linked Opitz syndrome and MID2 is its homolog. We conducted expression studies on Mid1/Mid2 in mouse embryos. Our results suggested a tendency of a mutually repressive expression pattern between Mid1 and Mid2 during early development. Further investigations revealed strong expressions of Mid1 and Mid2 in the epithelium of approaching facial prominences and downregulated expressions after fusion. This study supports the hypothe...
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Bijun Li, Tianhong Zhou, Yi Zou Tags: Original Article Source Type: research

Effect of lifestyle and reproductive factors on the onset of breast cancer in female BRCA 1 and 2 mutation carriers
Abstract BackgroundThe birth year‐dependent onset of breast cancer (BC) in BRCA1/2 mutation carriers suggests a risk‐modifying role for reproductive and life style factors. We therefore examined possible associations between these factors and age at diagnosis. MethodsCox regression analysis and log‐Rank testing were used to estimate the effect of potential life style factors on the onset of BC in 197 BRCA mutation carriers. ResultsNulliparous BRCA mutation carriers developed BC earlier than those who had delivered (36.4 vs. 40.9; P = 0.001). Similarly, smokers and women who had used oral contraceptives expe...
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Viktoria Rieder, Mohamed Salama, Lena Glöckner, Daniela Muhr, Andreas Berger, Muy‐Kheng Tea, Georg Pfeiler, Christine Rappaport‐Fuerhauser, Daphne Gschwantler‐Kaulich, Sigrid Weingartshofer, Christian F Singer Tags: Original Article Source Type: research

Cellular defects caused by hypomorphic variants of the Bloom syndrome helicase gene BLM
ConclusionAllele frequency and cellular defects suggest candidates for new Bloom syndrome causing mutations, and intermediate BLM variants that are hypomorphic which, instead of causing Bloom syndrome, may increase a person's risk for cancer or possibly other Bloom‐syndrome‐associated disorders, such as type‐2 diabetes. In this study, we have determined the ability of eight new BLM variants (P690L, R717L, R791C, W803R, Y811C, P868L, G972V, G1120R) to complement defects of Bloom syndrome patient‐derived cells in DNA recombination and the DNA damage response. The study focuses on the first three hypomorphic BLM vari...
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Vivek M. Shastri, Kristina H. Schmidt Tags: Original Article Source Type: research

Hutterite‐type cataract maps to chromosome 6p21.32‐p21.31, cosegregates with a homozygous mutation in LEMD2, and is associated with sudden cardiac death
ConclusionWe performed a genetic and genomic study of Hutterite‐type cataract and found evidence for an association of this phenotype with sudden cardiac death. Using combined genetic and genomic approaches, we mapped cataracts to a small portion of chromosome 6 and propose that they result from a homozygous missense mutation in LEMD2. We mapped autosomal recessive Hutterite‐type cataracts to chromosome 6p21.32‐p21.31. We identified a predicted damaging mutation in LEMD2 (c.T38G) that segregates with the phenotype in extended Hutterite kindreds (LOD = 9.62), suggesting that LEMD2 is the disease gene for th...
Source: Molecular Genetics & Genomic Medicine - November 1, 2015 Category: Genetics & Stem Cells Authors: Philip M. Boone, Bo Yuan, Shen Gu, Zhiwei Ma, Tomasz Gambin, Claudia Gonzaga‐Jauregui, Mahim Jain, Todd J. Murdock, Janson J. White, Shalini N. Jhangiani, Kimberly Walker, Qiaoyan Wang, Donna M. Muzny, Richard A. Gibbs, J. Fielding Hejtmancik, James R. 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. AbstractSeckel syndrome is a heterogeneous, autosomal recessive disorder marked by prenatal proportionate short stature, severe microcephaly, intellectual disability, and characteristic facial features. Here, we describe the novel homozygous splice ‐site mutations c.383+1G>C and c.4005 ‐9A>G inCDK5RAP2 in two consanguineous families with Seckel syndrome.CDK5RAP2 (CEP215) encodes a centrosomal protein which is known to be essential for cen...
Source: Molecular Genetics & Genomic Medicine - September 15, 2015 Category: Genetics & Stem Cells Authors: G ökhan 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 Thoma Tags: Original Article Source Type: research

Multigene panel analysis identified germline mutations of DNA repair genes in breast and ovarian cancer
We analyzed the germline mutations of 25 hereditary cancer ‐related genes in 155 patients using targeted next‐generation sequencing. Of these, three patients (1.9%) had pathogenic mutations inATM, MRE11A, orMSH6, all of which have a central role in DNA repair and the mismatch repair pathway. These results suggested deficiencies in cellular DNA repair functions result in the development of breast and ovarian cancer. AbstractApproximately 5 –10% of all breast and/or ovarian cancer cases are considered as inherited.BRCA1 andBRCA2 tumor suppressor genes account for a high penetrance of hereditary cases, but familial ...
Source: Molecular Genetics & Genomic Medicine - September 15, 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

Medical genetics and genomic medicine in Greece: achievements and challenges
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 15, 2015 Category: Genetics & Stem Cells Authors: Irini Manoli, Helen Fryssira Tags: Genetics and Genomic Medicine around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 15, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Remembering Johann Gregor Mendel: a human, a Catholic priest, an Augustinian monk, and abbot
Johann Mendel (Gregor was the name given to him only later by his Augustinian order, Fig. ) was born on July 20, 1822 to an ethnic German family, Anton and Rosina Mendel (Fig. ), in Heinzendorf in the Austrian Empire at the Moravian‐Silesian border (now Hynčice, Czech Republic). (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Father Clemens Richter Tags: Invited Commentary Source Type: research

Medical genetics and genomic medicine in Rwanda
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Annette Uwineza, Leon Mutesa Tags: Genetics and Genomic Medicine Around the World Source Type: research

Allelic variants of the Melanocortin 4 receptor (MC4R) gene in a South African study group
Abstract Obesity is a global epidemic that results in significant morbidity and mortality. Mutations in the melanocortin 4 receptor (MC4R) gene, which codes for a G‐protein‐coupled receptor responsible for postprandial satiety signaling, have been associated with monogenic obesity. The prevalence of obesity is on the increase in South Africa, and it is hypothesized that mutations in MC4R are a contributing factor. The aim of this study was to perform a retrospective assessment of the relationship between allelic variants of MC4R and BMI in a South African study cohort. DNA was isolated from a demographically representa...
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Murray Logan, Maria‐Teresa Van der Merwe, Tyren M. Dodgen, Renier Myburgh, Arinda Eloff, Marco Alessandrini, Michael S. Pepper Tags: Original Article Source Type: research

A distinctive oral phenotype points to FAM20A mutations not identified by Sanger sequencing
This study confirms the link between biallelic FAM20A mutations and the characteristic oral phenotype. It highlights for the first time examples of FAM20A mutations missed by the most commonly used mutation screening techniques. This information informed renal assessment and ongoing clinical care. We identified two recessive Amelogenesis Imperfecta families in whom monoallelic FAM20A mutations were identified by Sanger sequencing of genomic DNA. Further screening by reverse‐transcriptase PCR and CNV detection by whole genome sequencing (CNVseq) was required in order to identify the second mutation in each case. Our stud...
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: James A. Poulter, Claire E. L. Smith, Gina Murrillo, Sandra Silva, Sally Feather, Marianella Howell, Laura Crinnion, David T. Bonthron, Ian M. Carr, Christopher M. Watson, Chris F. Inglehearn, Alan J. Mighell Tags: Original Article Source Type: research

CREBBP and EP300 mutational spectrum and clinical presentations in a cohort of Swedish patients with Rubinstein–Taybi syndrome
In this study, 17 patients with a clinical diagnosis of RTS were investigated with direct sequencing, MLPA, and array‐CGH in search for mutations in these two genes. Eleven patients (64.7%) had disease‐causing point mutations or a deletion in CREBBP and in one patient (5.9%) a causal de novo frameshift mutation in EP300 was identified. This patient had broad thumbs, mild intellectual disability, and autism. In addition, an inherited missense mutation of uncertain clinical significance was identified in EP300 in one patient and his healthy father, and three patients had intronic nucleotide changes of uncertain clinical ...
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Josephine Wincent, Aron Luthman, Martine Belzen, Christian Lans, Johanna Albert, Ann Nordgren, Britt‐Marie Anderlid Tags: Original Article Source Type: research

Fam83h null mice support a neomorphic mechanism for human ADHCAI
Abstract Truncation mutations in FAM83H (family with sequence similarity 83, member H) cause autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI), but little is known about FAM83H function and the pathogenesis of ADHCAI. We recruited three ADHCAI families and identified two novel (p.Gln457*; p.Lys639*) and one previously documented (p.Q452*) disease‐causing FAM83H mutations. We generated and characterized Fam83h‐knockout/lacZ‐knockin mice. Surprisingly, enamel thickness, density, Knoop hardness, morphology, and prism patterns were similar in Fam83h+/+, Fam83h+/−, and Fam83h−/− mice. The...
Source: Molecular Genetics & Genomic Medicine - September 1, 2015 Category: Genetics & Stem Cells Authors: Shih‐Kai Wang, Yuanyuan Hu, Jie Yang, Charles E. Smith, Amelia S Richardson, Yasuo Yamakoshi, Yuan‐Ling Lee, Figen Seymen, Mine Koruyucu, Koray Gencay, Moses Lee, Murim Choi, Jung‐Wook Kim, Jan C‐C. Hu, James P. Simmer 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 - July 14, 2015 Category: Genetics & Stem Cells Authors: Benjamin S. Wilfond, Katrina A.B. Goddard Tags: Invited Commentary Source Type: research

Medical genetics and genomic medicine in Chile: opportunities for improvement
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 14, 2015 Category: Genetics & Stem Cells Authors: Silvia Castillo Taucher Tags: Genetics and Genomic Medicine around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 14, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

The rs3737964 single‐nucleotide polymorphism of the chloride channel‐6 gene as a risk factor for coronary heart disease
Abstract The present study investigates the association of single‐nucleotide polymorphisms (SNPs) on the chloride channel‐6 (CLC‐6) gene with coronary heart disease (CHD) in China. We carried out a large case–control study among 1193 CHD patients and 1200 unrelated healthy control subjects. Information on the participants' health status was collected through the modified Inter‐heart questionnaire. Genomic DNA from peripheral blood samples was analyzed for the genotypes of rs3737964 and rs3737965 SNPs on the CLC‐6 gene using Taqman probe‐based quantitative real‐time PCR (qPCR). We compared the collected ...
Source: Molecular Genetics & Genomic Medicine - July 14, 2015 Category: Genetics & Stem Cells Authors: Li Zhang, Tao Zhang, Zhengkai Xiang, Shengqiang Lu Tags: Original Article Source Type: research

The dentin phosphoprotein repeat region and inherited defects of dentin
Abstract Nonsyndromic dentin defects classified as type II dentin dysplasia and types II and III dentinogenesis imperfecta are caused by mutations in DSPP (dentin sialophosphoprotein). Most reported disease‐causing DSPP mutations occur within the repetitive DPP (dentin phosphoprotein) coding sequence. We characterized the DPP sequences of five probands with inherited dentin defects using single molecule real‐time (SMRT) DNA sequencing. Eight of the 10 sequences matched previously reported DPP length haplotypes and two were novel. Alignment with known DPP sequences showed 32 indels arranged in 36 different patterns. Six...
Source: Molecular Genetics & Genomic Medicine - July 1, 2015 Category: Genetics & Stem Cells Authors: Jie Yang, Kazuhiko Kawasaki, Moses Lee, Bryan M. Reid, Stephanie M. Nunez, Murim Choi, Figen Seymen, Mine Koruyucu, Yelda Kasimoglu, Ninna Estrella‐Yuson, Brent P. J. Lin, James P. Simmer, Jan C.‐C. Hu Tags: Original Article Source Type: research

Genetic analysis of nonalcoholic fatty liver disease within a Caribbean–Hispanic population
In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean–Hispanic population is warranted. We performed the first genetic investigation of Nonalcoholic fatty liver disease (NAFLD) in Hispanic patients of majority Caribbean descent. Genotype analysis was performed to determine allelic frequencies of 74 known single‐nucleotide polymorphisms (SNPs) associated with NAFLD risk. Results suggest that variations in PNPLA3 and SAMM50 may be correlated with NAFLD, and SNPs in CHUK and E...
Source: Molecular Genetics & Genomic Medicine - July 1, 2015 Category: Genetics & Stem Cells Authors: Deborah Edelman, Harmit Kalia, Maria Delio, Mustafa Alani, Karthik Krishnamurthy, Mortadha Abd, Adam Auton, Tao Wang, Allan W. Wolkoff, Bernice E. Morrow Tags: Original Article Source Type: research

Evaluation of genetic association of neurodevelopment and neuroimmunological genes with antipsychotic treatment response in schizophrenia in Indian populations
We report genetic associations of antipsychotic response in 742 schizophrenia patients from Indian populations of Indo‐European and Dravidian ancestry, segregated by disease severity. Meta‐analysis comparing the two populations identified CCL2 [rs4795893: OR (95% CI) = 1.79 (1.27–2.52), P = 7.62 × 10−4; rs4586: OR (95% CI) = 1.74 (1.24–2.43), P = 1.13 × 10−3] and GRIA4 [rs2513265: OR (95% CI) = 0.53 (0.36–0.78), P = 1.44 × 10−3] in low severity group; and, ADCY2 [rs1544938: OR ...
Source: Molecular Genetics & Genomic Medicine - July 1, 2015 Category: Genetics & Stem Cells Authors: Ajay Jajodia, Harpreet Kaur, Kalpana Kumari, Neha Kanojia, Meenal Gupta, Ruchi Baghel, Mamta Sood, Sanjeev Jain, Rakesh K. Chadda, Ritushree Kukreti Tags: Original Article Source Type: research

Utility and limitations of animal models for the functional validation of human sequence variants
This article highlights the often difficult decisions we must face when confronted by a list of variants from genome‐scale sequencing data and some key points to consider when deciding how to best test and validate, using animal models, any given variant as pathogenic. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2015 Category: Genetics & Stem Cells Authors: Timothy C. Cox Tags: Invited Commentary Source Type: research

Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9
We report three patients with hitherto unreported SOX9 abnormalities. Our data broaden pathogenic SOX9 abnormalities to include C‐terminal missense substitutions which lead to target‐gene specific protein dysfunction, and enhancer‐containing upstream microdeletions. Notably, the patients manifested testicular dysgenesis and regression without skeletal dysplasia. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - July 1, 2015 Category: Genetics & Stem Cells Authors: Yuko Katoh‐Fukui, Maki Igarashi, Keisuke Nagasaki, Reiko Horikawa, Toshiro Nagai, Takayoshi Tsuchiya, Erina Suzuki, Mami Miyado, Kenichiro Hata, Kazuhiko Nakabayashi, Keiko Hayashi, Yoichi Matsubara, Takashi Baba, Ken‐ichirou Morohashi, Arisa Igarashi Tags: Original Article Source Type: research

Medical genetics and genomic medicine in India: current status and opportunities ahead
. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 14, 2015 Category: Genetics & Stem Cells Authors: Shagun Aggarwal, Shubha R Phadke Tags: Genetics and Genomic Medicine Around the World Source Type: research

Issue Information
(Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 14, 2015 Category: Genetics & Stem Cells Tags: Issue Information Source Type: research

Actionable clinical decisions based on comprehensive genomic evaluation in asymptomatic adults
Abstract Whole‐exome sequencing (WES) arises as a new approach in diagnosing individuals affected by multigenic and complex phenotypes. Herein, we aim to examine whether WES is useful in screening asymptomatic individuals for actionable interventions, which has not yet been established. Twenty‐five healthy adults underwent WES, bioinformatics, and manual curation of their exomes. Six participants (24%) harbored significant, management‐changing variants in cancer predisposition genes, American College of Medical Genetics, and genomics reportable cardiac diseases and pharmacogenomic biomarkers that have led to clinical...
Source: Molecular Genetics & Genomic Medicine - May 6, 2015 Category: Genetics & Stem Cells Authors: Nir Pillar, Ofer Isakov, Daphna Weissglas‐Volkov, Shay Botchan, Eitan Friedman, Nadir Arber, Noam Shomron Tags: Original Article Source Type: research

126 novel mutations in Italian patients with neurofibromatosis type 1
We present an overview of our Neurofibromatosis type 1 (NF1) diagnostic research with a focus on the description of 126 novel mutations. These data support the use of RNA‐based methods for genetic analysis and provide novel information for improving the management of symptoms in oligosymptomatic patients. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Donatella Bianchessi, Sara Morosini, Veronica Saletti, Maria Cristina Ibba, Federica Natacci, Silvia Esposito, Claudia Cesaretti, Daria Riva, Gaetano Finocchiaro, Marica Eoli Tags: Original Article Source Type: research

Identification of point mutations and large intragenic deletions in Fanconi anemia using next‐generation sequencing technology
Abstract Fanconi anemia (FA) is a rare bone marrow failure disorder characterized by clinical and genetic heterogeneity with at least 17 genes involved, which make molecular diagnosis complex and time‐consuming. Since next‐generation sequencing technologies could greatly improve the genetic testing in FA, we sequenced DNA samples with known and unknown mutant alleles using the Ion PGM™ system (IPGM). The molecular target of 74.2 kb in size covered 96% of the FA‐coding exons and their flanking regions. Quality control testing revealed high coverage. Comparing the IPGM and Sanger sequencing output of FANCA, ...
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Elena Nicchia, Chiara Greco, Daniela De Rocco, Vanna Pecile, Angela D'Eustacchio, Enrico Cappelli, Paola Corti, Nicoletta Marra, Ugo Ramenghi, Marta Pillon, Piero Farruggia, Carlo Dufour, Alberto Pallavicini, Lucio Torelli, Anna Savoia Tags: Method Source Type: research

Uncovering the molecular pathogenesis of congenital hyperinsulinism by panel gene sequencing in 32 Chinese patients
This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families. This study describes novel and previously identified mutations in patients with CHI. The spectrum of mutations in CHI patients represents an important tool for the diagnosis and prognosis of CHI patients in the Chinese population as well as for the genetic counseling of CHI families. (Source: Molecular Genetics & Genomic Medicine)
Source: Molecular Genetics & Genomic Medicine - May 1, 2015 Category: Genetics & Stem Cells Authors: Zi‐chuan Fan, Jin‐wen Ni, Lin Yang, Li‐yuan Hu, Si‐min Ma, Mei Mei, Bi‐jun Sun, Hui‐jun Wang, Wen‐hao Zhou Tags: Original Article Source Type: research

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