Increased Survival and Partly Preserved Cognition in a Patient With ACO2-Related Disease Secondary to a Novel Variant.

J Child Neurol. 2017 Jan 01;:883073817711527

Authors: Srivastava S, Gubbels CS, Dies K, Fulton A, Yu T, Sahin M

Abstract
ACO2 encodes aconitase 2, catalyzing the second step of the tricarboxylic acid. To date, there are only 6 reported families with 5 unique ACO2 mutations. Affected individuals can develop intellectual disability, epilepsy, brain atrophy, hypotonia, ataxia, optic atrophy, and retinal degeneration. Here, we report an 18-year-old boy with a novel ACO2 variant discovered on whole-exome sequencing. He presented with childhood-onset ataxia, impaired self-help skills comparable to severe-profound intellectual disability, intractable epilepsy, cerebellar atrophy, peripheral neuropathy, optic atrophy, and pigmentary retinopathy. His variant is the sixth unique ACO2 mutation. In addition, compared to mild cases (isolated optic atrophy) and severe cases (infantile death), our patient may be moderately affected, evident by increased survival and some preserved cognition (ability to speak full sentences and follow commands), which is a novel presentation. This case expands the disease spectrum to include increased survival with partly spared cognition.

PMID: 28545339 [PubMed - as supplied by publisher]

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HGVA: the Human Genome Variation Archive.

Nucleic Acids Res. 2017 May 23;:

Authors: Lopez J, Coll J, Haimel M, Kandasamy S, Tarraga J, Furio-Tari P, Bari W, Bleda M, Rueda A, Gräf S, Rendon A, Dopazo J, Medina I

Abstract
High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets.

PMID: 28535294 [PubMed - as supplied by publisher]

Human aminoacyl-tRNA synthetases in diseases of the nervous system.

RNA Biol. 2017 May 23;:0

Authors: Ognjenović J, Simonović M

Abstract
Aminoacyl-tRNA synthetases (AaRSs) are ubiquitously expressed enzymes that ensure accurate translation of the genetic information into functional proteins. These enzymes also execute a variety of non-canonical functions that are significant for regulation of diverse cellular processes and that reside outside the realm of protein synthesis. Associations between faults in AaRS-mediated processes and human diseases have been long recognized. Most recent research findings strongly argue that 10 cytosolic and 14 mitochondrial AaRSs are implicated in some form of pathology of the human nervous system. The advent of modern whole-exome sequencing makes it all but certain that similar associations between the remaining 15 ARS genes and neurological illnesses will be defined in future. It is not surprising that an intense scientific debate about the role of translational machinery, in general, and AaRSs, in particular, in the development and maintenance of the healthy human neural cell types and the brain is sparked. Herein, we summarize the current knowledge about causative links between mutations in human AaRSs and diseases of the nervous system and briefly discuss future directions.

PMID: 28534666 [PubMed - as supplied by publisher]

The role of genetics in primary ventricular fibrillation, inherited channelopathies and cardiomyopathies.

Int J Cardiol. 2017 Jun 15;237:45-48

Authors: Crotti L, Kotta MC

Abstract
Sudden cardiac death (SCD) has a strong familial component; however, our understanding of its genetic basis varies significantly according to the underlying causes. When coronary artery disease is involved, the predisposing genetic background is complex and despite some interesting findings it remains largely unknown. Quite different is the case of monogenic structural and non-structural heart diseases, in which a number of disease-causing genes have been established and are being used in clinical practice. As SCD can be the first clinical manifestation of inherited syndromes, in order to ascertain the cause of death, it is extremely important to include molecular autopsy among the standard post-mortem examinations. Indeed, molecular screening of the major disease-causing genes in the deceased person is often the only way to achieve a post-mortem diagnosis in channelopathies, which may prove crucial for the identification and management of at risk family members. Overall, these data, together with the inclusion in current guidelines of molecular screening for diagnosis and/or risk stratification of specific inherited cardiac diseases, exemplify how research on the genetic basis of SCD may be deeply translational, while the transition of genetic testing from the research to the diagnostic setting is already improving every-day clinical practice.

PMID: 28532586 [PubMed - in process]

A pipeline combining multiple strategies for prioritizing heterozygous variants for the identification of candidate genes in exome datasets.

Hum Genomics. 2017 May 22;11(1):11

Authors: Requena T, Gallego-Martinez A, Lopez-Escamez JA

Abstract
BACKGROUND: The identification of disease-causing variants in autosomal dominant diseases using exome-sequencing data remains a difficult task in small pedigrees. We combined several strategies to improve filtering and prioritizing of heterozygous variants using exome-sequencing datasets in familial Meniere disease: an in-house Pathogenic Variant (PAVAR) score, the Variant Annotation Analysis and Search Tool (VAAST-Phevor), Exomiser-v2, CADD, and FATHMM. We also validated the method by a benchmarking procedure including causal mutations in synthetic exome datasets.
RESULTS: PAVAR and VAAST were able to select the same sets of candidate variants independently of the studied disease. In contrast, Exomiser V2 and VAAST-Phevor had a variable correlation depending on the phenotypic information available for the disease on each family. Nevertheless, all the selected diseases ranked a limited number of concordant variants in the top 10 ranking, using the three systems or other combined algorithm such as CADD or FATHMM. Benchmarking analyses confirmed that the combination of systems with different approaches improves the prediction of candidate variants compared with the use of a single method. The overall efficiency of combined tools ranges between 68 and 71% in the top 10 ranked variants.
CONCLUSIONS: Our pipeline prioritizes a short list of heterozygous variants in exome datasets based on the top 10 concordant variants combining multiple systems.

PMID: 28532469 [PubMed - in process]

Defects in myosin VB are associated with a spectrum of previously undiagnosed low γ-glutamyltransferase cholestasis.

Hepatology. 2017 May;65(5):1655-1669

Authors: Qiu YL, Gong JY, Feng JY, Wang RX, Han J, Liu T, Lu Y, Li LT, Zhang MH, Sheps JA, Wang NL, Yan YY, Li JQ, Chen L, Borchers CH, Sipos B, Knisely AS, Ling V, Xing QH, Wang JS

Abstract
Hereditary cholestasis in childhood and infancy with normal serum gamma-glutamyltransferase (GGT) activity is linked to several genes. Many patients, however, remain genetically undiagnosed. Defects in myosin VB (MYO5B; encoded by MYO5B) cause microvillus inclusion disease (MVID; MIM251850) with recurrent watery diarrhea. Cholestasis, reported as an atypical presentation in MVID, has been considered a side effect of parenteral alimentation. Here, however, we report on 10 patients who experienced cholestasis associated with biallelic, or suspected biallelic, mutations in MYO5B and who had neither recurrent diarrhea nor received parenteral alimentation. Seven of them are from two study cohorts, together comprising 31 undiagnosed low-GGT cholestasis patients; 3 are sporadic. Cholestasis in 2 patients was progressive, in 3 recurrent, in 2 transient, and in 3 uncategorized because of insufficient follow-up. Liver biopsy specimens revealed giant-cell change of hepatocytes and intralobular cholestasis with abnormal distribution of bile salt export pump (BSEP) at canaliculi, as well as coarse granular dislocation of MYO5B. Mass spectrometry of plasma demonstrated increased total bile acids, primary bile acids, and conjugated bile acids, with decreased free bile acids, similar to changes in BSEP-deficient patients. Literature review revealed that patients with biallelic mutations predicted to eliminate MYO5B expression were more frequent in typical MVID than in isolated-cholestasis patients (11 of 38 vs. 0 of 13).
CONCLUSION: MYO5B deficiency may underlie 20% of previously undiagnosed low-GGT cholestasis. MYO5B deficiency appears to impair targeting of BSEP to the canalicular membrane with hampered bile acid excretion, resulting in a spectrum of cholestasis without diarrhea. (Hepatology 2017;65:1655-1669).

PMID: 28027573 [PubMed - indexed for MEDLINE]

Mutations in PROSC Disrupt Cellular Pyridoxal Phosphate Homeostasis and Cause Vitamin-B6-Dependent Epilepsy.

Am J Hum Genet. 2016 Dec 01;99(6):1325-1337

Authors: Darin N, Reid E, Prunetti L, Samuelsson L, Husain RA, Wilson M, El Yacoubi B, Footitt E, Chong WK, Wilson LC, Prunty H, Pope S, Heales S, Lascelles K, Champion M, Wassmer E, Veggiotti P, de Crécy-Lagard V, Mills PB, Clayton PT

Abstract
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, functions as a cofactor in humans for more than 140 enzymes, many of which are involved in neurotransmitter synthesis and degradation. A deficiency of PLP can present, therefore, as seizures and other symptoms that are treatable with PLP and/or pyridoxine. Deficiency of PLP in the brain can be caused by inborn errors affecting B6 vitamer metabolism or by inactivation of PLP, which can occur when compounds accumulate as a result of inborn errors of other pathways or when small molecules are ingested. Whole-exome sequencing of two children from a consanguineous family with pyridoxine-dependent epilepsy revealed a homozygous nonsense mutation in proline synthetase co-transcribed homolog (bacterial), PROSC, which encodes a PLP-binding protein of hitherto unknown function. Subsequent sequencing of 29 unrelated indivduals with pyridoxine-responsive epilepsy identified four additional children with biallelic PROSC mutations. Pre-treatment cerebrospinal fluid samples showed low PLP concentrations and evidence of reduced activity of PLP-dependent enzymes. However, cultured fibroblasts showed excessive PLP accumulation. An E.coli mutant lacking the PROSC homolog (ΔYggS) is pyridoxine sensitive; complementation with human PROSC restored growth whereas hPROSC encoding p.Leu175Pro, p.Arg241Gln, and p.Ser78Ter did not. PLP, a highly reactive aldehyde, poses a problem for cells, which is how to supply enough PLP for apoenzymes while maintaining free PLP concentrations low enough to avoid unwanted reactions with other important cellular nucleophiles. Although the mechanism involved is not fully understood, our studies suggest that PROSC is involved in intracellular homeostatic regulation of PLP, supplying this cofactor to apoenzymes while minimizing any toxic side reactions.

PMID: 27912044 [PubMed - indexed for MEDLINE]

Autosomal-Recessive Mutations in AP3B2, Adaptor-Related Protein Complex 3 Beta 2 Subunit, Cause an Early-Onset Epileptic Encephalopathy with Optic Atrophy.

Am J Hum Genet. 2016 Dec 01;99(6):1368-1376

Authors: Assoum M, Philippe C, Isidor B, Perrin L, Makrythanasis P, Sondheimer N, Paris C, Douglas J, Lesca G, Antonarakis S, Hamamy H, Jouan T, Duffourd Y, Auvin S, Saunier A, Begtrup A, Nowak C, Chatron N, Ville D, Mireskandari K, Milani P, Jonveaux P, Lemeur G, Milh M, Amamoto M, Kato M, Nakashima M, Miyake N, Matsumoto N, Masri A, Thauvin-Robinet C, Rivière JB, Faivre L, Thevenon J

Abstract
Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.

PMID: 27889060 [PubMed - indexed for MEDLINE]

Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.

Am J Hum Genet. 2016 Dec 01;99(6):1261-1280

Authors: Swanger SA, Chen W, Wells G, Burger PB, Tankovic A, Bhattacharya S, Strong KL, Hu C, Kusumoto H, Zhang J, Adams DR, Millichap JJ, Petrovski S, Traynelis SF, Yuan H

Abstract
Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function.

PMID: 27839871 [PubMed - indexed for MEDLINE]

The Contribution of Mosaic Variants to Autism Spectrum Disorder.

PLoS Genet. 2016 Sep;12(9):e1006245

Authors: Freed D, Pevsner J

Abstract
De novo mutation is highly implicated in autism spectrum disorder (ASD). However, the contribution of post-zygotic mutation to ASD is poorly characterized. We performed both exome sequencing of paired samples and analysis of de novo variants from whole-exome sequencing of 2,388 families. While we find little evidence for tissue-specific mosaic mutation, multi-tissue post-zygotic mutation (i.e. mosaicism) is frequent, with detectable mosaic variation comprising 5.4% of all de novo mutations. We identify three mosaic missense and likely-gene disrupting mutations in genes previously implicated in ASD (KMT2C, NCKAP1, and MYH10) in probands but none in siblings. We find a strong ascertainment bias for mosaic mutations in probands relative to their unaffected siblings (p = 0.003). We build a model of de novo variation incorporating mosaic variants and errors in classification of mosaic status and from this model we estimate that 33% of mosaic mutations in probands contribute to 5.1% of simplex ASD diagnoses (95% credible interval 1.3% to 8.9%). Our results indicate a contributory role for multi-tissue mosaic mutation in some individuals with an ASD diagnosis.

PMID: 27632392 [PubMed - indexed for MEDLINE]

Whole Exome Sequencing in Atrial Fibrillation.

PLoS Genet. 2016 Sep;12(9):e1006284

Authors: Lubitz SA, Brody JA, Bihlmeyer NA, Roselli C, Weng LC, Christophersen IE, Alonso A, Boerwinkle E, Gibbs RA, Bis JC, NHLBI GO Exome Sequencing Project, Cupples LA, Mohler PJ, Nickerson DA, Muzny D, Perez MV, Psaty BM, Soliman EZ, Sotoodehnia N, Lunetta KL, Benjamin EJ, Heckbert SR, Arking DE, Ellinor PT, Lin H

Abstract
Atrial fibrillation (AF) is a morbid and heritable arrhythmia. Over 35 genes have been reported to underlie AF, most of which were described in small candidate gene association studies. Replication remains lacking for most, and therefore the contribution of coding variation to AF susceptibility remains poorly understood. We examined whole exome sequencing data in a large community-based sample of 1,734 individuals with and 9,423 without AF from the Framingham Heart Study, Cardiovascular Health Study, Atherosclerosis Risk in Communities Study, and NHLBI-GO Exome Sequencing Project and meta-analyzed the results. We also examined whether genetic variation was enriched in suspected AF genes (N = 37) in AF cases versus controls. The mean age ranged from 59 to 73 years; 8,656 (78%) were of European ancestry. None of the 99,404 common variants evaluated was significantly associated after adjusting for multiple testing. Among the most significantly associated variants was a common (allele frequency = 86%) missense variant in SYNPO2L (rs3812629, p.Pro707Leu, [odds ratio 1.27, 95% confidence interval 1.13-1.43, P = 6.6x10-5]) which lies at a known AF susceptibility locus and is in linkage disequilibrium with a top marker from prior analyses at the locus. We did not observe significant associations between rare variants and AF in gene-based tests. Individuals with AF did not display any statistically significant enrichment for common or rare coding variation in previously implicated AF genes. In conclusion, we did not observe associations between coding genetic variants and AF, suggesting that large-effect coding variation is not the predominant mechanism underlying AF. A coding variant in SYNPO2L requires further evaluation to determine whether it is causally related to AF. Efforts to identify biologically meaningful coding variation underlying AF may require large sample sizes or populations enriched for large genetic effects.

PMID: 27589061 [PubMed - indexed for MEDLINE]

A genetic risk factor for thrombophilia in a Han Chinese family.

Mol Med Rep. 2017 Apr;15(4):1668-1672

Authors: Sun G, Jia Y, Meng J, Ou M, Zhu P, Cong S, Luo Y, Sui W, Dai Y

Abstract
Thrombophilia is a multifactorial disorder involving environmental and genetic factors. Well‑known factors that result in predisposition to congenital disorders associated with thrombophilia include antithrombin deficiency, protein C and S deficiency, Factor V Leiden mutation, abnormal prothrombin and antiphospholipid syndrome. The present study revealed an association between a mutation of the F2 gene, which codes for coagulation factor II, thrombin, and the risk of thrombophilia in a Han Chinese family, of which four members (I‑2, II‑2, II‑3 and III‑1) had a history of deep venous thromboembolism. The disease was measured in this family using laboratory measurements and computed tomography angiography. To identify the abnormality underlying the increased thrombophilia risk, whole‑exome sequencing technology was used to analyze two affected individuals (II‑2 and III‑1). An exonic missense F2 mutation, T165M (NM_000506:c.C494T:p.T165M;rs5896), was identified from a total of 2,222 and 2,203 genetic variations observed in the two affected individuals, respectively, which were subsequently filtered and confirmed using Sanger sequencing. I‑2, II‑3 and III‑1 shared this mutation with the proband (II‑2), and II‑6 had a heterozygous form of the mutation. This deleterious mutation was not identified in normal controls. The present study may improve understanding of the function of the F2 gene.

PMID: 28259966 [PubMed - indexed for MEDLINE]

Developmental dysplasia of the hip: usefulness of next generation genomic tools for characterizing the underlying genes - a mini review.

Clin Genet. 2016 Jul;90(1):16-20

Authors: Basit S, Hannan MA, Khoshhal KI

Abstract
Developmental dysplasia of the hip (DDH) is one of the most common skeletal anomalies. DDH encompasses a spectrum of the disorder ranging from minor acetabular dysplasia to irreducible dislocation, which may lead to premature arthritis in later life. Involvement of genetic factors underlying DDH became evident when several studies reported chromosomal loci linked to DDH in families with multiple affected individuals. Moreover, using association studies, variants in genes involved in chondrogenesis and joint formation have been shown to be associated with DDH. At least, one study identified a pathogenic variant in the chemokine receptor gene in DDH. No genetic analysis has been reported or carried out in DDH patients from the Middle East. Here, we review the literature related to genetics of DDH and emphasized the usefulness of new generation technologies in identifying genetic variants underlying DDH in consanguineous families.

PMID: 26842108 [PubMed - indexed for MEDLINE]

Unfolding the pathogenesis of scleroderma through genomics and epigenomics.

J Autoimmun. 2017 May 16;:

Authors: Tsou PS, Sawalha AH

Abstract
With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc.

PMID: 28526340 [PubMed - as supplied by publisher]

Next-generation sequencing for D47N mutation in Cx50 analysis associated with autosomal dominant congenital cataract in a six-generation Chinese family.

BMC Ophthalmol. 2017 May 19;17(1):73

Authors: Shen C, Wang J, Wu X, Wang F, Liu Y, Guo X, Zhang L, Cao Y, Cao X, Ma H

Abstract
BACKGROUND: Congenital cataract is the most frequent cause of blindness during infancy or early childhood. To date, more than 40 loci associated with congenital cataract have been identified, including at least 26 genes on different chromosomes associated with inherited cataract. This present study aimed to identify the genetic mutation in a six-generation Chinese family affected with congenital cataract.
METHODS: A detailed six-generation Chinese cataract family history and clinical data of the family members were recorded. A total of 27 family members, including 14 affected and 13 unaffected individuals were recruited. Whole exome sequencing was performed to determine the disease-causing mutation. Sanger sequencing was used to confirm the results.
RESULTS: A known missense mutation, c. 139G > A (p. D47N), in Cx50 was identified. This mutation co-segregated with all affected individuals and was not observed in the unaffected family members or in 100 unrelated controls. The homology modeling showed that the structure of the mutant protein was different with that wild-type Cx50.
CONCLUSIONS: The missense mutation c.139G > A in GJA8 gene is associated with autosomal dominant congenital cataract in a six-generation Chinese family. The result of this present study provides further evidence that the p. D47N mutation in CX50 is a hot-spot mutation.

PMID: 28526010 [PubMed - in process]

Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant.

Am J Hum Genet. 2016 Nov 03;99(5):1117-1129

Authors: Di Donato N, Jean YY, Maga AM, Krewson BD, Shupp AB, Avrutsky MI, Roy A, Collins S, Olds C, Willert RA, Czaja AM, Johnson R, Stover JA, Gottlieb S, Bartholdi D, Rauch A, Goldstein A, Boyd-Kyle V, Aldinger KA, Mirzaa GM, Nissen A, Brigatti KW, Puffenberger EG, Millen KJ, Strauss KA, Dobyns WB, Troy CM, Jinks RN

Abstract
Lissencephaly is a malformation of cortical development typically caused by deficient neuronal migration resulting in cortical thickening and reduced gyration. Here we describe a "thin" lissencephaly (TLIS) variant characterized by megalencephaly, frontal predominant pachygyria, intellectual disability, and seizures. Trio-based whole-exome sequencing and targeted re-sequencing identified recessive mutations of CRADD in six individuals with TLIS from four unrelated families of diverse ethnic backgrounds. CRADD (also known as RAIDD) is a death-domain-containing adaptor protein that oligomerizes with PIDD and caspase-2 to initiate apoptosis. TLIS variants cluster in the CRADD death domain, a platform for interaction with other death-domain-containing proteins including PIDD. Although caspase-2 is expressed in the developing mammalian brain, little is known about its role in cortical development. CRADD/caspase-2 signaling is implicated in neurotrophic factor withdrawal- and amyloid-β-induced dendritic spine collapse and neuronal apoptosis, suggesting a role in cortical sculpting and plasticity. TLIS-associated CRADD variants do not disrupt interactions with caspase-2 or PIDD in co-immunoprecipitation assays, but still abolish CRADD's ability to activate caspase-2, resulting in reduced neuronal apoptosis in vitro. Homozygous Cradd knockout mice display megalencephaly and seizures without obvious defects in cortical lamination, supporting a role for CRADD/caspase-2 signaling in mammalian brain development. Megalencephaly and lissencephaly associated with defective programmed cell death from loss of CRADD function in humans implicate reduced apoptosis as an important pathophysiological mechanism of cortical malformation. Our data suggest that CRADD/caspase-2 signaling is critical for normal gyration of the developing human neocortex and for normal cognitive ability.

PMID: 27773430 [PubMed - indexed for MEDLINE]

Mutations in CIT, encoding citron rho-interacting serine/threonine kinase, cause severe primary microcephaly in humans.

Hum Genet. 2016 Oct;135(10):1191-7

Authors: Shaheen R, Hashem A, Abdel-Salam GM, Al-Fadhli F, Ewida N, Alkuraya FS

Abstract
Primary microcephaly is a clinical phenotype in which the head circumference is significantly reduced at birth due to abnormal brain development, primarily at the cortical level. Despite the marked genetic heterogeneity, most primary microcephaly-linked genes converge on mitosis regulation. Two consanguineous families segregating the phenotype of severe primary microcephaly, spasticity and failure to thrive had overlapping autozygomes in which exome sequencing identified homozygous splicing variants in CIT that segregate with the phenotype within each family. CIT encodes citron, an effector of the Rho signaling that is required for cytokinesis specifically in proliferating neuroprogenitors, as well as for postnatal brain development. In agreement with the critical role assigned to the kinase domain in effecting these biological roles, we show that both splicing variants predict variable disruption of this domain. The striking phenotypic overlap between CIT-mutated individuals and the knockout mice and rats that are specifically deficient in the kinase domain supports the proposed causal link between CIT mutation and primary microcephaly in humans.

PMID: 27503289 [PubMed - indexed for MEDLINE]

Whole-Exome Sequencing Suggests LAMB3 as a Susceptibility Gene for Morbid Obesity.

Diabetes. 2016 Oct;65(10):2980-9

Authors: Jiao H, Kulyté A, Näslund E, Thorell A, Gerdhem P, Kere J, Arner P, Dahlman I

Abstract
Identification of rare sequencing variants with a larger functional impact has the potential to highlight new pathways contributing to obesity. Using whole-exome sequencing followed by genotyping, we have identified a low-frequency coding variant rs2076349 (V527M) in the laminin subunit β3 (LAMB3) gene showing strong association with morbid obesity and thereby risk of type 2 diabetes. We exome-sequenced 200 morbidly obese subjects and 100 control subjects with pooled DNA samples. After several filtering steps, we retained 439 obesity-enriched low-frequency coding variants. Associations between genetic variants and obesity were validated sequentially in two case-control cohorts. In the final analysis of 1,911 morbidly obese and 1,274 control subjects, rs2076349 showed strong association with obesity (P = 9.67 × 10(-5); odds ratio 1.84). This variant was also associated with BMI and fasting serum leptin. Moreover, LAMB3 expression in adipose tissue was positively correlated with BMI and adipose morphology (few but large fat cells). LAMB3 knockdown by small interfering RNA in human adipocytes cultured in vitro inhibited adipogenesis. In conclusion, we identified a previously not reported low-frequency coding variant that was associated with morbid obesity in the LAMB3 gene. This gene may be involved in the development of excess body fat.

PMID: 27431458 [PubMed - indexed for MEDLINE]

Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis.

Am J Hum Genet. 2016 Jul 07;99(1):125-38

Authors: Fenwick AL, Kliszczak M, Cooper F, Murray J, Sanchez-Pulido L, Twigg SR, Goriely A, McGowan SJ, Miller KA, Taylor IB, Logan C, WGS500 Consortium, Bozdogan S, Danda S, Dixon J, Elsayed SM, Elsobky E, Gardham A, Hoffer MJ, Koopmans M, McDonald-McGinn DM, Santen GW, Savarirayan R, de Silva D, Vanakker O, Wall SA, Wilson LC, Yuregir OO, Zackai EH, Ponting CP, Jackson AP, Wilkie AO, Niedzwiedz W, Bicknell LS

Abstract
DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.

PMID: 27374770 [PubMed - indexed for MEDLINE]