SOFT syndrome caused by compound heterozygous mutations of POC1A and its skeletal manifestation.

J Hum Genet. 2016 Jun;61(6):561-4

Authors: Ko JM, Jung S, Seo J, Shin CH, Cheong HI, Choi M, Kim OH, Cho TJ

Abstract
SOFT syndrome (MIM614813) is an extremely rare primordial dwarfism characterized by short stature, onychodysplasia, facial dysmorphism and hypotrichosis, which is caused by biallelic mutations in the POC1A gene. Only 19 patients with mutation-confirmed SOFT syndrome have been reported to date, all of whom carried homozygous variants that were strongly associated with consanguineous marriages. We report an 8.5-year-old boy with SOFT syndrome showing primordial dwarfism, no effect of growth-hormone therapy and skeletal dysplasia. This is the first report of compound heterozygous variants in POC1A, one previously reported and the other novel. A characteristic skeletal manifestation is reported.

PMID: 26791357 [PubMed - indexed for MEDLINE]

Exome-based genome-wide association study and risk assessment using genetic risk score to prostate cancer in the Korean population.

Oncotarget. 2017 Mar 24;:

Authors: Oh JJ, Lee SJ, Hwang JY, Kim D, Lee SE, Hong SK, Ho JN, Yoon S, Sung J, Kim WJ, Byun SS

Abstract
PURPOSE: To investigate exome-wide genetic variants associated with prostate cancer (PCa) in Koreans and evaluate the discriminative ability by the genetic risk score (GRS).
PATIENTS AND METHODS: We prospectively recruited 1,001 PCa cases from a tertiary hospital and conducted a case-control study including 2,641 healthy men (Stage I). Participants were analyzed using HumanExome BeadChip. For the external validation, additionally enrolled 514 PCa cases and 548 controls (independent cohort) were analyzed for the identified single nucleotide polymorphisms (SNPs) of Stage I (Stage II). The GRS was calculated as a non-weighted sum of the risk allele counts and investigated for accuracy of prediction of PCa.
RESULTS: the mean age was 66.3 years, and the median level of prostate specific antigen (PSA) was 9.19 ng/ml in PCa cases. In Stage I, 4 loci containing 5 variants (rs1512268 on 8p21.2; rs1016343 and rs7837688 on 8q24.21; rs7501939 on 17q12, and rs2735839 on 19q13.33) were confirmed to reach exome-wide significance (p<8.3x10-7). In Stage II, the mean GRS was 4.23 ± 1.44 for the controls and 4.78 ± 1.43 for the cases. As a reference to GRS 4, GRS 6, 7 and 8 showed a statistically significant risk of PCa (OR=1.85, 2.11 and 3.34, respectively).
CONCLUSIONS: The five variants were validated to associate with PCa in firstly performed exome-wide study in Koreans. The addition of individualized calculated GRS effectively enhanced the accuracy of prediction. These results need to be validated in future studies.

PMID: 28380453 [PubMed - as supplied by publisher]

Identification of STXBP2 as a novel susceptibility locus for myocardial infarction in Japanese individuals by an exome-wide association study.

Oncotarget. 2017 Mar 23;:

Authors: Yamada Y, Sakuma J, Takeuchi I, Yasukochi Y, Kato K, Oguri M, Fujimaki T, Horibe H, Muramatsu M, Sawabe M, Fujiwara Y, Taniguchi Y, Obuchi S, Kawai H, Shinkai S, Mori S, Arai T, Tanaka M

Abstract
We performed exome-wide association studies to identify genetic variants-in particular, low-frequency variants with a large effect size-that confer susceptibility to coronary artery disease or myocardial infarction in Japanese. The exome-wide association studies were performed with 12,698 individuals (3488 subjects with coronary artery disease including 2438 with myocardial infarction, 9210 controls) and with the use of the Illumina HumanExome-12 DNA Analysis or Infinium Exome-24 BeadChip. The relation of allele frequencies for 41,339 single nucleotide polymorphisms that passed quality control to coronary artery disease or myocardial infarction was examined with Fisher's exact test. The exome-wide association study for coronary artery disease revealed that 126 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of hypertension, diabetes mellitus, and dyslipidemia showed that six of these polymorphisms were related (P < 0.01) to coronary artery disease, but none was significantly (P < 9.92 × 10-5) associated with this condition. The exome-wide association study for myocardial infarction revealed that 114 single nucleotide polymorphisms were significantly (P <1.21 × 10-6) associated with this condition. Multivariable logistic regression analysis with adjustment for covariates revealed that nine of these polymorphisms were related (P < 0.01) to myocardial infarction. Among these nine polymorphisms, rs188212047 [G/T (L212F)] of STXBP2 was significantly (dominant model; P = 4.84 × 10-8; odds ratio, 2.94) associated with myocardial infarction. STXBP2 may thus be a novel susceptibility locus for myocardial infarction in Japanese.

PMID: 28380445 [PubMed - as supplied by publisher]

Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.

Eur J Hum Genet. 2017 Apr 05;:

Authors: Brien A, Marshall CR, Blaser S, Ray PN, Yoon G

Abstract
Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.European Journal of Human Genetics advance online publication, 5 April 2017; doi:10.1038/ejhg.2017.39.

PMID: 28378817 [PubMed - as supplied by publisher]

A genome-wide linkage and association analysis of imputed insertions and deletions with cardiometabolic phenotypes in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study.

Genet Epidemiol. 2017 Apr 05;:

Authors: Gao C, Hsu FC, Dimitrov LM, Okut H, Chen YI, Taylor KD, Rotter JI, Langefeld CD, Bowden DW, Palmer ND

Abstract
Insertions and deletions (INDELs) represent a significant fraction of interindividual variation in the human genome yet their contribution to phenotypes is poorly understood. To confirm the quality of imputed INDELs and investigate their roles in mediating cardiometabolic phenotypes, genome-wide association and linkage analyses were performed for 15 phenotypes with 1,273,952 imputed INDELs in 1,024 Mexican-origin Americans. Imputation quality was validated using whole exome sequencing with an average kappa of 0.93 in common INDELs (minor allele frequencies [MAFs] ≥ 5%). Association analysis revealed one genome-wide significant association signal for the cholesterylester transfer protein gene (CETP) with high-density lipoprotein levels (rs36229491, P = 3.06 × 10(-12) ); linkage analysis identified two peaks with logarithm of the odds (LOD) > 5 (rs60560566, LOD = 5.36 with insulin sensitivity (SI ) and rs5825825, LOD = 5.11 with adiponectin levels). Suggestive overlapping signals between linkage and association were observed: rs59849892 in the WSC domain containing 2 gene (WSCD2) was associated and nominally linked with SI (P = 1.17 × 10(-7) , LOD = 1.99). This gene has been implicated in glucose metabolism in human islet cell expression studies. In addition, rs201606363 was linked and nominally associated with low-density lipoprotein (P = 4.73 × 10(-4) , LOD = 3.67), apolipoprotein B (P = 1.39 × 10(-3) , LOD = 4.64), and total cholesterol (P = 1.35 × 10(-2) , LOD = 3.80) levels. rs201606363 is an intronic variant of the UBE2F-SCLY (where UBE2F is ubiquitin-conjugating enzyme E2F and SCLY is selenocysteine lyase) fusion gene that may regulate cholesterol through selenium metabolism. In conclusion, these results confirm the feasibility of imputing INDELs from array-based single nucleotide polymorphism (SNP) genotypes. Analysis of these variants using association and linkage replicated previously identified SNP signals and identified multiple novel INDEL signals. These results support the inclusion of INDELs into genetic studies to more fully interrogate the spectrum of genetic variation.

PMID: 28378447 [PubMed - as supplied by publisher]

Detecting PKD1 variants in polycystic kidney disease patients by single-molecule long-read sequencing.

Hum Mutat. 2017 Apr 04;:

Authors: Borràs DM, Vossen R, Liem M, Buermans HP, Dauwerse H, van Heusden D, Gansevoort RT, den Dunnen JT, Janssen B, Peters DJ, Losekoot M, Anvar SY

Abstract
A genetic diagnosis of autosomal dominant polycystic kidney disease (ADPKD) is challenging due to allelic heterogeneity, high GC-content, and homology of the PKD1 gene with six pseudogenes. Short-read next-generation sequencing (NGS) approaches, such as whole genome (WGS) and whole exome sequencing (WES), often fail at reliably characterizing complex regions such as PKD1. However, long-read single-molecule sequencing has been shown to be an alternative strategy that could overcome PKD1 complexities and discriminate between homologous regions of PKD1 and its pseudogenes. In this study, we present the increased power of resolution for complex regions using long-read sequencing to characterize a cohort of 19 patients with ADPKD. Our approach provided high sensitivity in identifying PKD1 pathogenic variants, diagnosing 94.7% of the patients. We show that reliable screening of ADPKD patients in a single test without interference of PKD1 homologous sequences, commonly introduced by residual amplification of PKD1 pseudogenes, by direct long-read sequencing is now possible. This strategy can be implemented in diagnostics and is highly suitable to sequence and resolve complex genomic regions that are of clinical relevance. This article is protected by copyright. All rights reserved.

PMID: 28378423 [PubMed - as supplied by publisher]

[Genetic methods for analysis of autoinflammatory diseases].

Z Rheumatol. 2017 Apr 04;:

Authors: Bienias M, König N, Wolf C, Kretschmer S, Rösen-Wolff A, Berner R, Tüngler V, Lee-Kirsch MA

Abstract
Over the past years the phenotypic and genetic spectrum of autoinflammatory diseases has continuously increased. Moreover, several monogenic autoinflammatory disorders have now been identified where febrile episodes are not among the leading symptoms and which can be accompanied by autoimmune phenomena and susceptibility to infections. Autoinflammatory conditions that are characterized by uncontrolled activity of cytokines, such as interleukin-1 beta (IL1β), tumor necrosis factor alpha (TNF-α) and type 1 interferons (1-IFN), are amenable to specific therapeutic interventions. Thus, identification of the underlying genetic cause is important. During diagnostic work-up, genetic testing of a patient with autoinflammation should be carried out depending on the clinical presentation. If a distinct disorder is suspected, sequencing of the causative gene should be performed. Genetic tests using next generation sequencing (NGS), such as panel sequencing, exome sequencing and array comparative genomic hybridization (CGH) can be carried out if symptoms cannot be assigned to a specific disease entity.

PMID: 28378116 [PubMed - as supplied by publisher]

A novel WDR62 mutation causes primary microcephaly in a large consanguineous Saudi family.

Ann Saudi Med. 2017 Mar-Apr;37(2):148-153

Authors: Naseer MI, Rasool M, Sogaty S, Chaudhary RA, Mansour HM, Chaudhary AG, Abuzenadah AM, Al-Qahtani MH

Abstract
BACKGROUND: Primary microcephaly (MCPH) is a rare developmental defect characterized by impaired cognitive functions, retarded neurodevelopment and reduced brain size. It is genetically heterogeneous and more than 17 genes so far have been identified that are associated with this disease.
OBJECTIVE: To study the genetic defect in a consanguineous Saudi family with primary microcephaly.
DESIGN: Cross-sectional clinical genetics study of a Saudi family.
SETTING: Medical genomics research center.
PATIENTS AND METHODS: Blood samples collected from six members of a family of healthy consanguineous parents were analyzed by whole exome sequencing to identify the underlying pathogenic mutations in two members of the family (23-year-old female and 7-year-old male) who presented with primary microcephaly, intellectual disability, delayed psychomotor development and walking difficulty, speech impedi-ments and seizures.
MAIN OUTCOME MEASURE(S): Detection of mutation in the WD repeat domain 62 (WDR62) gene in a family segregating autosomal recessive primary microcephaly.
RESULTS: The exome variant analysis identified a novel missense mutation (c.3878C > A) in WDR62 gene in exon 30 resulting in amino acid change from alanine to aspartate (p.Ala1293Asp). Further validation in the affected patients and healthy members of family and 100 unrelated healthy persons as controls confirmed it to be pathogenic.
CONCLUSIONS: Functional impairment of the WDR62 gene can lead to severe neurodevelopmental de-fects, brain malformations and reduced head size. A missense mutation of exon 30 changed alanine to aspartate in the WDR62 protein leading to the typical MCPH phenotype.
LIMITATIONS: Mutation was identified in a single family.

PMID: 28377545 [PubMed - in process]

Caution in interpretation of disease causality for heterozygous loss-of-function variants in the MYH8 gene associated with autosomal dominant disorder.

Eur J Med Genet. 2017 Apr 01;:

Authors: Dai Z, Whitt Z, Mighion LC, Pontoglio A, Bean LJ, Colombo R, Hegde M

Abstract
To date, the NM_002472.2(MYH8):c.2021G>A (p.Arg674Gln) missense variant in the MYH8 gene is the only known genetic change in individuals with autosomal dominant trismus-pseudocamptodactyly syndrome with unknown molecular mechanism. Next-generation sequencing (NGS), including targeted gene panels and whole-exome sequencing, is routinely performed in many clinical diagnostic laboratories as standard-of-care testing aimed at identifying disease-causing genomic variants. Whole-exome sequencing has revealed loss-of-function variants in the MYH8 gene. To properly classify the MYH8 loss-of-function variants, we either retrieved them from public databases or retrospectively collected them from individuals genetically tested by custom NGS panels or by whole-exome sequencing and confirmed using Sanger sequencing. We further evaluated the respective clinical presentations of these individuals with the MYH8 loss-of-function variants. Heterozygous loss-of-function variants in the MYH8 gene were detected in 16 individuals without trismus-pseudocamptodactyly syndrome. Four of these 16 individuals had a pathogenic or likely pathogenic variant detected in another gene that could explain their clinical presentation. Moreover, there are ∼100 MYH8 heterozygous protein-truncating and splice site variants in the ExAC database in different populations. Our results, combined with the population data, indicate that loss-of-function variants in the MYH8 gene do not cause autosomal dominant trismus-pseudocamptodactyly syndrome, and the clinical significance of these variants remains unknown at present. This result highlights the importance of considering the molecular mechanism of disease, variants published in the medical literature, and population genomic data for the correct interpretation of loss-of-function variants in genes associated with autosomal dominant diseases.

PMID: 28377322 [PubMed - as supplied by publisher]

Novel Presentation of Rosai-Dorfman Histiocytosis With a Prolonged Course of Cranial and Peripheral Neuropathies.

Pediatr Neurol. 2017 Mar 08;:

Authors: Tripathi R, Serajee F, Jiang H, Huq AH

Abstract
BACKGROUND: Rosai-Dorfman disease is a form of histiocytosis affecting the systemic lymph nodes. Intracranial Rosai-Dorfman disease is rare and presents with extra-parenchymal or intraparenchymal proliferative mass lesions. Cranial neuropathy has not been reported in Rosai-Dorfman disease except when caused by mass effect by an adjacent lesion.
PATIENT DESCRIPTION: We describe a girl with Rosai-Dorfman disease who presented with peripheral and multiple cranial neuropathies. Detailed clinical, immunologic, neurophysiology, imaging, and genetic studies were performed. She had a prolonged course but recovered fully after immune therapies. She had increased titers of striated muscle and smooth muscle antibodies. Imaging studies revealed contrast enhancement of cranial nerves and striated muscles. Demyelination was evident in the nerve twigs from muscle biopsy. Exome sequencing did not reveal a genetic mutation.
CONCLUSIONS: Most patients with Rosai-Dorfman disease have a benign course, but severe neurological dysfunction due to bulbar involvement and cranial and peripheral neuropathies may occur. Treatment with immunoglobulin and steroids may be of benefit.

PMID: 28377039 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

(exome OR "exome sequencing") AND disease

These pubmed results were generated on 2017/04/05

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Cousins not twins: intra and inter-tumoral heterogeneity in syndromic neuroendocrine tumours.

J Pathol. 2017 Mar 31;:

Authors: Flynn A, Dwight T, Benn D, Deb S, Colebatch AJ, Fox S, Harris J, Duncan EL, Robinson B, Hogg A, Ellul J, To H, Duong C, Miller JA, Yates C, James P, Trainer A, Gill AJ, Clifton-Bligh R, Hicks RJ, Tothill RW

Abstract
Hereditary endocrine neoplasias, including phaeochromocytoma/paraganglioma and medullary thyroid cancer, are caused by autosomal dominant mutations in several familial cancer genes. A common feature of these diseases is the presentation of multiple primary tumours, or multifocal disease representing independent tumour clones that have arisen from the same initiating genetic lesion, but have undergone independent clonal evolution. Such tumours provide an opportunity to discover common co-operative changes required for tumorigenesis, while controlling for the genetic background of the individual. We performed genomic analysis of synchronous and metachronous tumours from five patients bearing germline mutations in the genes SDHB, RET and MAX. Using whole exome sequencing and high-density SNP arrays, we analyzed two to four primary tumours from each patient. We also applied multi-regional sampling, to assess intra-tumoral heterogeneity and clonal evolution, in two cases involving phaeochromocytoma/paraganglioma and medullary thyroid cancer, respectively. Heterogeneous patterns of genomic change existed between synchronous or metachronous tumours, with evidence of branching evolution. We observed striking examples of evolutionary convergence involving the same rare somatic copy-number events in synchronous primary phaeochromocytoma/paraganglioma. Convergent events also occurred during clonal evolution of metastatic medullary thyroid cancer. These observations suggest that genetic or epigenetic changes acquired early within precursor cells, or pre-existing within the genetic background of the individual, create contingencies that determine the evolutionary trajectory of the tumour.

PMID: 28369925 [PubMed - as supplied by publisher]

Genome-wide linkage and sequence analysis challenge CCDC66 as a human retinal dystrophy candidate gene and support a distinct NMNAT1-related fundus phenotype.

Clin Genet. 2017 Mar 30;:

Authors: Khan AO, Budde BS, Nürnberg P, Kawalia A, Lenzner S, Bolz HJ

Abstract
To uncover the genotype underlying early-onset cone-rod dystrophy and central nummular macular atrophic lesion in two siblings from an endogamous Arab family, we performed targeted next-generation sequencing (NGS) of 44 retinal dystrophy genes, whole-exome sequencing (WES) and genome-wide linkage analysis. Targeted NGS and WES in the index patient highlighted two homozygous variants, a CCDC66 frameshift deletion and a novel missense NMNAT1 variant, c.500G>A (p.Asn167Ser). Linkage and segregation analysis excluded the CCDC66 variant and confirmed the NMNAT1 mutation. Biallelic NMNAT1 mutations cause Leber congenital amaurosis with a central nummular macular atrophic lesion (LCA9). The NMNAT1 mutation reported here underlied cone-rod dystrophy rather than LCA but the fundus lesion was compatible with that of LCA9 patients, highlighting that such a fundus appearance should raise suspicion for biallelic mutations in NMNAT1 when in the context of any retinal dystrophy. Although Ccdc66 mutations have been proposed to cause retinal disease in dogs, our results and public databases challenge CCDC66 as a candidate gene for human retinal dystrophy.

PMID: 28369829 [PubMed - as supplied by publisher]

Whole Exome Sequencing Identified a Novel Frameshift Mutation in SDR9C7 underlying Autosomal Recessive Congenital Ichthyosis in a Pakistani Family.

Br J Dermatol. 2017 Mar 31;:

Authors: Karim N, Murtaza G, Naeem M

Abstract
Autosomal Recessive Congenital Ichthyosis (ARCI) is a group of cornification disorders (prevalence 1:200,000) broadly divided into three classes namely Harlequin Ichthyosis (HI; OMIM#242500), Lamellar Ichthyosis (LI; OMIM#242304) and Congenital Ichthyosiform Erythroderma (CIE; OMIM#242100). ARCI clinical features include generalized scaling, hypohidrosis and palmo-plantar hyperlinearity although presentation and severity may vary significantly. A large number of affected individuals present with collodion membrane at birth. HI is the most severe and fatal form of the disease and the neonates are born covered with thick, hard, armor-like plates of cornified skin. The classic form of LI present with dark brown, plate-like scales with no erythroderma and CIE with fine and white scales adjoining generalized erythema. Affected individuals with severe involvement can have ectropion, eclabium, scarring alopecia and palmoplantar keratoderma. Currently, ten genes are reported in association with different ARCI phenotypes: TGM1, ALOX12B, ALOXE3, ABCA12, CYP4F22, NIPAL4, LIPN, CERS3, PNPLA1 and SDR9C7(1,2,3) . Here we report a novel frameshift mutation in SDR9C7 (short-chain dehydrogenase/reductase family 9C member 7) underlying ARCI in a consanguineous Pakistani family. This article is protected by copyright. All rights reserved.

PMID: 28369735 [PubMed - as supplied by publisher]

Estimating the selective effects of heterozygous protein-truncating variants from human exome data.

Nat Genet. 2017 Apr 03;:

Authors: Cassa CA, Weghorn D, Balick DJ, Jordan DM, Nusinow D, Samocha KE, O'Donnell-Luria A, MacArthur DG, Daly MJ, Beier DR, Sunyaev SR

Abstract
The evolutionary cost of gene loss is a central question in genetics and has been investigated in model organisms and human cell lines. In humans, tolerance of the loss of one or both functional copies of a gene is related to the gene's causal role in disease. However, estimates of the selection and dominance coefficients in humans have been elusive. Here we analyze exome sequence data from 60,706 individuals to make genome-wide estimates of selection against heterozygous loss of gene function. Using this distribution of selection coefficients for heterozygous protein-truncating variants (PTVs), we provide corresponding Bayesian estimates for individual genes. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, Mendelian disease-associated genes, and regulators of transcription. Screening by essentiality, we find a large set of genes under strong selection that are likely to have crucial functions but have not yet been thoroughly characterized.

PMID: 28369035 [PubMed - as supplied by publisher]

Genetic disorders of nuclear receptors.

J Clin Invest. 2017 Apr 03;127(4):1181-1192

Authors: Achermann JC, Schwabe J, Fairall L, Chatterjee K

Abstract
Following the first isolation of nuclear receptor (NR) genes, genetic disorders caused by NR gene mutations were initially discovered by a candidate gene approach based on their known roles in endocrine pathways and physiologic processes. Subsequently, the identification of disorders has been informed by phenotypes associated with gene disruption in animal models or by genetic linkage studies. More recently, whole exome sequencing has associated pathogenic genetic variants with unexpected, often multisystem, human phenotypes. To date, defects in 20 of 48 human NR genes have been associated with human disorders, with different mutations mediating phenotypes of varying severity or several distinct conditions being associated with different changes in the same gene. Studies of individuals with deleterious genetic variants can elucidate novel roles of human NRs, validating them as targets for drug development or providing new insights into structure-function relationships. Importantly, human genetic discoveries enable definitive disease diagnosis and can provide opportunities to therapeutically manage affected individuals. Here we review germline changes in human NR genes associated with "monogenic" conditions, including a discussion of the structural basis of mutations that cause distinctive changes in NR function and the molecular mechanisms mediating pathogenesis.

PMID: 28368288 [PubMed - in process]

Genetic Variation in the Exome: Associations With Alcohol and Tobacco Co-Use.

Psychol Addict Behav. 2017 Apr 03;:

Authors: Otto JM, Gizer IR, Ellingson JM, Wilhelmsen KC

Abstract
Shared genetic factors represent one underlying mechanism thought to contribute to high rates of alcohol and tobacco co-use and dependence. Common variants identified by molecular genetic studies tend to confer only small disease risk, and rare protein-coding variants are posited to contribute to disease risk, as well. However, given that genotyping technologies allowing for their inclusion in association studies have only recently become available, the magnitude of their contribution is poorly understood. The current study examined genetic variation in protein-coding regions (i.e., the exome) for associations with measures of lifetime alcohol and tobacco co-use. Participants from the UCSF Family Alcoholism Study (N = 1,862) were genotyped using an exome-focused genotyping array, and assessed for DSM-IV diagnoses of alcohol and tobacco dependence and quantitative consumption measures using a modified version of the Semi-Structured Assessment for the Genetics of Alcoholism. Analyses included single variant, gene-based, and pathway-based tests of association. One EMR3 variant and a pathway related to genes upregulated in mesenchymal stem cells during the late phase of adipogenesis met criteria for statistical significance. Suggestive associations were consistent with previous findings from studies of substance use and dependence, including variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster with cigarettes smoked per day. Further, several variants and genes demonstrated suggestive association across phenotypes, suggesting that shared genetic factors may underlie risk for increased levels of alcohol and tobacco use, as well as psychopathology more broadly, providing insight into our understanding of the genetic architecture underlying these traits. (PsycINFO Database Record

PMID: 28368157 [PubMed - as supplied by publisher]

The Phe932Ile mutation in KCNT1 channels associated with severe epilepsy, delayed myelination and leukoencephalopathy produces a loss-of-function channel phenotype.

Neuroscience. 2017 Mar 30;:

Authors: Evely KM, Pryce KD, Bhattacharjee A

Abstract
Sodium-activated potassium (KNa) channels contribute to firing frequency adaptation and slow afterhyperpolarization. The KCNT1 gene (also known as SLACK) encodes a KNa subunit that is expressed throughout the central and peripheral nervous systems. Missense mutations of the SLACK C-terminus have been reported in several patients with rare forms of early onset epilepsy and in some cases severely delayed myelination. To date, such mutations identified in patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), epilepsy of infancy with migrating focal seizures (EIMFS) and Otahara syndrome (OS) have been reported to be gain-of-function mutations (Villa and Combi, 2016). An exome sequencing study identified a p.Phe932Ile KCNT1 mutation as the disease-causing change in a child with severe early infantile epileptic encephalopathy and abnormal myelination (Vanderver et al., 2014). We characterized an analogous mutation in the rat Slack channel and unexpectedly found this mutation to produce a loss-of-function phenotype. In an effort to restore current, we tested the known Slack channel opener loxapine. Loxapine exhibited no effect, indicating that this mutation either caused the channel to be insensitive to this established opener or proper translation and trafficking to the membrane was disrupted. Protein analysis confirmed that while total mutant protein did not differ from wild type, membrane expression of the mutant channel was substantially reduced. Although gain-of-function mutations to the Slack channel are linked to epileptic phenotypes, this is the first reported loss-of-function mutation linked to severe epilepsy and delayed myelination.

PMID: 28366665 [PubMed - as supplied by publisher]

Deleterious variants in TRAK1 disrupt mitochondrial movement and cause fatal encephalopathy.

Brain. 2017 Mar 01;140(3):568-581

Authors: Barel O, Christine V Malicdan M, Ben-Zeev B, Kandel J, Pri-Chen H, Stephen J, Castro IG, Metz J, Atawa O, Moshkovitz S, Ganelin E, Barshack I, Polak-Charcon S, Nass D, Marek-Yagel D, Amariglio N, Shalva N, Vilboux T, Ferreira C, Pode-Shakked B, Heimer G, Hoffmann C, Yardeni T, Nissenkorn A, Avivi C, Eyal E, Kol N, Glick Saar E, Wallace DC, Gahl WA, Rechavi G, Schrader M, Eckmann DM, Anikster Y

Abstract
Cellular distribution and dynamics of mitochondria are regulated by several motor proteins and a microtubule network. In neurons, mitochondrial trafficking is crucial because of high energy needs and calcium ion buffering along axons to synapses during neurotransmission. The trafficking kinesin proteins (TRAKs) are well characterized for their role in lysosomal and mitochondrial trafficking in cells, especially neurons. Using whole exome sequencing, we identified homozygous truncating variants in TRAK1 (NM_001042646:c.287-2A > C), in six lethal encephalopathic patients from three unrelated families. The pathogenic variant results in aberrant splicing and significantly reduced gene expression at the RNA and protein levels. In comparison with normal cells, TRAK1-deficient fibroblasts showed irregular mitochondrial distribution, altered mitochondrial motility, reduced mitochondrial membrane potential, and diminished mitochondrial respiration. This study confirms the role of TRAK1 in mitochondrial dynamics and constitutes the first report of this gene in association with a severe neurodevelopmental disorder.

PMID: 28364549 [PubMed - in process]

Development and Validation of Clinical Whole-Exome and Whole-Genome Sequencing for Detection of Germline Variants in Inherited Disease.

Arch Pathol Lab Med. 2017 Mar 31;:

Authors: Hegde M, Santani A, Mao R, Ferreira-Gonzalez A, Weck K, Voelkerding K

Abstract
CONTEXT: - With the decrease in the cost of sequencing, the clinical testing paradigm has shifted from single gene to gene panel and now whole-exome and whole-genome sequencing. Clinical laboratories are rapidly implementing next-generation sequencing-based whole-exome and whole-genome sequencing. Because a large number of targets are covered by whole-exome and whole-genome sequencing, it is critical that a laboratory perform appropriate validation studies, develop a quality assurance and quality control program, and participate in proficiency testing.
OBJECTIVE: - To provide recommendations for whole-exome and whole-genome sequencing assay design, validation, and implementation for the detection of germline variants associated in inherited disorders.
DATA SOURCES: - An example of trio sequencing, filtration and annotation of variants, and phenotypic consideration to arrive at clinical diagnosis is discussed.
CONCLUSIONS: - It is critical that clinical laboratories planning to implement whole-exome and whole-genome sequencing design and validate the assay to specifications and ensure adequate performance prior to implementation. Test design specifications, including variant filtering and annotation, phenotypic consideration, guidance on consenting options, and reporting of incidental findings, are provided. These are important steps a laboratory must take to validate and implement whole-exome and whole-genome sequencing in a clinical setting for germline variants in inherited disorders.

PMID: 28362156 [PubMed - as supplied by publisher]