Hot off the presses! Sep 11 Am J Hum Genet

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Latest Articles Include:

• This Month in The Journal
  - Am J Hum Genet 85(3):303-304 (2009)
  
• This Month in Genetics
  - Am J Hum Genet 85(3):305-307 (2009)
  
• Genetic Rounds: A Doctor's Encounters in the Field that Revolutionized Medicine
  - Am J Hum Genet 85(3):308 (2009)
  
• Epistasis and Its Implications for Personal Genetics
  - Am J Hum Genet 85(3):309-320 (2009)
  The widespread availability of high-throughput genotyping technology has opened the door to the era of personal genetics, which brings to consumers the promise of using genetic variations to predict individual susceptibility to common diseases. Despite easy access to commercial personal genetics services, our knowledge of the genetic architecture of common diseases is still very limited and has not yet fulfilled the promise of accurately predicting most people at risk. This is partly because of the complexity of the mapping relationship between genotype and phenotype that is a consequence of epistasis (gene-gene interaction) and other phenomena such as gene-environment interaction and locus heterogeneity. Unfortunately, these aspects of genetic architecture have not been addressed in most of the genetic association studies that provide the knowledge base for interpreting large-scale genetic association results. We provide here an introductory review of how epistasis ca! n affect human health and disease and how it can be detected in population-based studies. We provide some thoughts on the implications of epistasis for personal genetics and some recommendations for improving personal genetics in light of this complexity.
• The Editors' Recollections on the Occasion of the 60th Anniversary of The American Journal of Human Genetics
  - Am J Hum Genet 85(3):321-327 (2009)
  Volume 1, Number 1 of The American Journal of Human Genetics was published in September 1949. The first paper was an 18-page preface to the journal by H. J. Muller, president of The American Society of Human Genetics, entitled "Progress and Prospects in Human Genetics." Charles W. Cotterman served as the first editor, and since that time a dozen other human geneticists have shared that distinction. In recognition of the 60th anniversary of AJHG, recollections of five editors are recorded here.
• Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans
  Grillet N Schwander M Hildebrand MS Sczaniecka A Kolatkar A Velasco J Webster JA Kahrizi K Najmabadi H Kimberling WJ Stephan D Bahlo M Wiltshire T Tarantino LM Kuhn P Smith RJ Müller U - Am J Hum Genet 85(3):328-337 (2009)
  Hearing loss is the most common form of sensory impairment in humans and is frequently progressive in nature. Here we link a previously uncharacterized gene to hearing impairment in mice and humans. We show that hearing loss in the ethylnitrosourea (ENU)-induced samba mouse line is caused by a mutation in Loxhd1. LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/α-toxin) domains and is expressed along the membrane of mature hair cell stereocilia. Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate. Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). LOXHD1, MYO3a, and PJVK are the only human genes to date linked to progressive ARNSHL. These three genes are required for hair cell function, suggesting that age-dependent! hair cell failure is a common mechanism for progressive ARNSHL.
• Mutations of the FHL1 Gene Cause Emery-Dreifuss Muscular Dystrophy
  Gueneau L Bertrand AT Jais JP Salih MA Stojkovic T Wehnert M Hoeltzenbein M Spuler S Saitoh S Verschueren A Tranchant C Beuvin M Lacene E Romero NB Heath S Zelenika D Voit T Eymard B Ben Yaou R Bonne G - Am J Hum Genet 85(3):338-353 (2009)
  Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias. So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes. By whole-genome scan, we identified linkage to the Xq26.3 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort. Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions. The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as! joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families. Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy. Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two. Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available. In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy.
• Folate Receptor Alpha Defect Causes Cerebral Folate Transport Deficiency: A Treatable Neurodegenerative Disorder Associated with Disturbed Myelin Metabolism
  Steinfeld R Grapp M Kraetzner R Dreha-Kulaczewski S Helms G Dechent P Wevers R Grosso S Gärtner J - Am J Hum Genet 85(3):354-363 (2009)
  Sufficient folate supplementation is essential for a multitude of biological processes and diverse organ systems. At least five distinct inherited disorders of folate transport and metabolism are presently known, all of which cause systemic folate deficiency. We identified an inherited brain-specific folate transport defect that is caused by mutations in the folate receptor 1 (FOLR1) gene coding for folate receptor alpha (FRα). Three patients carrying FOLR1 mutations developed progressive movement disturbance, psychomotor decline, and epilepsy and showed severely reduced folate concentrations in the cerebrospinal fluid (CSF). Brain magnetic resonance imaging (MRI) demonstrated profound hypomyelination, and MR-based in vivo metabolite analysis indicated a combined depletion of white-matter choline and inositol. Retroviral transfection of patient cells with either FRα or FRβ could rescue folate binding. Furthermore, CSF folate concentrations, as well as glial choline ! and inositol depletion, were restored by folinic acid therapy and preceded clinical improvements. Our studies not only characterize a previously unknown and treatable disorder of early childhood, but also provide new insights into the folate metabolic pathways involved in postnatal myelination and brain development.
• A Generalized Family-Based Association Test for Dichotomous Traits
  Chen WM Manichaikul A Rich SS - Am J Hum Genet 85(3):364-376 (2009)
  Recent advances in genotyping technology make it possible to utilize large-scale association analysis for disease-gene mapping. Powerful and robust family-based association methods are crucial for successful gene mapping. We propose a family-based association method, the generalized disequilibrium test (GDT), in which the genotype differences of all discordant relative pairs are utilized in assessing association within a family. The improvement of the GDT over existing methods is threefold: (1) information beyond first-degree relatives is incorporated efficiently, yielding substantial gains in power in comparison to existing tests; (2) the GDT statistic is implemented via a robust technique that does not rely on large sample theory, resulting in further power gains, especially at high levels of significance; and (3) covariates and weights based on family size are incorporated. Advantages of the GDT over existing methods are demonstrated by extensive computer simulation! s and by application to recently published large-scale genome-wide linkage data from the Type 1 Diabetes Genetics Consortium (T1DGC). In our simulations, the GDT consistently outperforms other tests for a common disease and frequently outperforms other tests for a rare disease; the power improvement is > 13% in 6 out of 8 extended pedigree scenarios. All of the six strongest associations identified by the GDT have been reported by other studies, whereas only three or four of these associations can be identified by existing methods. For the T1D association at gene UBASH3A, the GDT resulted in a genome-wide significance (p = 4.3 × 10−6), much stronger than the published significance (p = 10−4).
• Allele-Specific Chromatin Remodeling in the ZPBP2/GSDMB/ORMDL3 Locus Associated with the Risk of Asthma and Autoimmune Disease
  Verlaan DJ Berlivet S Hunninghake GM Madore AM Larivière M Moussette S Grundberg E Kwan T Ouimet M Ge B Hoberman R Swiatek M Dias J Lam KC Koka V Harmsen E Soto-Quiros M Avila L Celedón JC Weiss ST Dewar K Sinnett D Laprise C Raby BA Pastinen T Naumova AK - Am J Hum Genet 85(3):377-393 (2009)
  Common SNPs in the chromosome 17q12-q21 region alter the risk for asthma, type 1 diabetes, primary biliary cirrhosis, and Crohn disease. Previous reports by us and others have linked the disease-associated genetic variants with changes in expression of GSDMB and ORMDL3 transcripts in human lymphoblastoid cell lines (LCLs). The variants also alter regulation of other transcripts, and this domain-wide cis-regulatory effect suggests a mechanism involving long-range chromatin interactions. Here, we further dissect the disease-linked haplotype and identify putative causal DNA variants via a combination of genetic and functional analyses. First, high-throughput resequencing of the region and genotyping of potential candidate variants were performed. Next, additional mapping of allelic expression differences in Yoruba HapMap LCLs allowed us to fine-map the basis of the cis-regulatory differences to a handful of candidate functional variants. Functional assays identified allel! e-specific differences in nucleosome distribution, an allele-specific association with the insulator protein CTCF, as well as a weak promoter activity for rs12936231. Overall, this study shows a common disease allele linked to changes in CTCF binding and nucleosome occupancy leading to altered domain-wide cis-regulation. Finally, a strong association between asthma and cis-regulatory haplotypes was observed in three independent family-based cohorts (p = 1.78 × 10−8). This study demonstrates the requirement of multiple parallel allele-specific tools for the investigation of noncoding disease variants and functional fine-mapping of human disease-associated haplotypes.
• Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females
  Giorda R Bonaglia MC Beri S Fichera M Novara F Magini P Urquhart J Sharkey FH Zucca C Grasso R Marelli S Castiglia L Di Benedetto D Musumeci SA Vitello GA Failla P Reitano S Avola E Bisulli F Tinuper P Mastrangelo M Fiocchi I Spaccini L Torniero C Fontana E Lynch SA Clayton-Smith J Black G Jonveaux P Leheup B Seri M Romano C Bernardina BD Zuffardi O - Am J Hum Genet 85(3):394-400 (2009)
  Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8–9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical fea! tures, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
• Acute Infantile Liver Failure Due to Mutations in the TRMU Gene
  Zeharia A Shaag A Pappo O Mager-Heckel AM Saada A Beinat M Karicheva O Mandel H Ofek N Segel R Marom D Rötig A Tarassov I Elpeleg O - Am J Hum Genet 85(3):401-407 (2009)
  Acute liver failure in infancy accompanied by lactic acidemia was previously shown to result from mtDNA depletion. We report on 13 unrelated infants who presented with acute liver failure and lactic acidemia with normal mtDNA content. Four died during the acute episodes, and the survivors never had a recurrence. The longest follow-up period was 14 years. Using homozygosity mapping, we identified mutations in the TRMU gene, which encodes a mitochondria-specific tRNA-modifying enzyme, tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase. Accordingly, the 2-thiouridylation levels of the mitochondrial tRNAs were markedly reduced. Given that sulfur is a TRMU substrate and its availability is limited during the neonatal period, we propose that there is a window of time whereby patients with TRMU mutations are at increased risk of developing liver failure.
• A Positive Modifier of Spinal Muscular Atrophy in the SMN2 Gene
  Prior TW Krainer AR Hua Y Swoboda KJ Snyder PC Bridgeman SJ Burghes AH Kissel JT - Am J Hum Genet 85(3):408-413 (2009)
  Spinal muscular atrophy (SMA) is a common autosomal-recessive motor neuron disease caused by the homozygous loss of the SMN1 gene. A nearly identical gene, SMN2, has been shown to decrease the severity of SMA in a dose-dependent manner. However SMN2 is not the sole phenotypic modifier, because there are discrepant SMA cases in which the SMN2 copy number does not explain the clinical phenotype. This report describes three unrelated SMA patients who possessed SMN2 copy numbers that did not correlate with the observed mild clinical phenotypes. A single base substitution in SMN2, c.859G>C,, was identified in exon 7 in the patients' DNA. We now show that the change creates a new exonic splicing enhancer element and increases the amount of full-length transcripts, thus resulting in the less severe phenotypes. This demonstrates that the c.859G>C substitution is a positive modifier of the SMA phenotype and that not all SMN2 genes are equivalent. We have shown not only that the! SMA phenotype is modified by the number of SMN2 genes but that SMN2 sequence variations can also affect the disease severity.
• FREM1 Mutations Cause Bifid Nose, Renal Agenesis, and Anorectal Malformations Syndrome
  Alazami AM Shaheen R Alzahrani F Snape K Saggar A Brinkmann B Bavi P Al-Gazali LI Alkuraya FS - Am J Hum Genet 85(3):414-418 (2009)
  An autosomal-recessive syndrome of bifid nose and anorectal and renal anomalies (BNAR) was previously reported in a consanguineous Egyptian sibship. Here, we report the results of linkage analysis, on this family and on two other families with a similar phenotype, which identified a shared region of homozygosity on chromosome 9p22.2-p23. Candidate-gene analysis revealed homozygous frameshift and missense mutations in FREM1, which encodes an extracellular matrix component of basement membranes. In situ hybridization experiments demonstrated gene expression of Frem1 in the midline of E11.5 mouse embryos, in agreement with the observed cleft nose phenotype of our patients. FREM1 is part of a ternary complex that includes FRAS1 and FREM2, and mutations of the latter two genes have been reported to cause Fraser syndrome in mice and humans. The phenotypic variability previously reported for different Frem1 mouse mutants suggests that the apparently distinct phenotype of BNAR! in humans may represent a previously unrecognized variant of Fraser syndrome.
• Complex Segmental Duplications Mediate a Recurrent dup(X)(p11.22-p11.23) Associated with Mental Retardation, Speech Delay, and EEG Anomalies in Males and Females
  - Am J Hum Genet 85(3):419 (2009)
  
• Mutations in MMP9 and MMP13 Determine the Mode of Inheritance and the Clinical Spectrum of Metaphyseal Anadysplasia
  - Am J Hum Genet 85(3):420 (2009)