Spontaneous Preterm Birth: Advances Toward the Discovery of Genetic Predisposition.

Am J Obstet Gynecol. 2017 Dec 14;:

Authors: Strauss JF, Romero R, Gomez-Lopez N, Haymond-Thornburg H, Modi BP, Teves ME, Pearson LN, York TP, Schenkein HA

Abstract
Evidence from family and twin-based studies provide strong support for a significant contribution of maternal and fetal genetics to the timing of parturition and spontaneous preterm birth. However, there has only been modest success in the discovery of genes predisposing to preterm birth, despite increasing sophistication of genetic and genomic technology. In contrast, DNA variants associated with other traits/diseases have been identified. For example, there is overwhelming evidence suggests that the nature and intensity of an inflammatory response in adults and children is under genetic control. Since inflammation is often invoked as an etiologic factor in spontaneous preterm birth, the question of whether spontaneous preterm birth has a genetic predisposition in the case of pathologic inflammation has been of long-standing interest to investigators. Here, we review various genetic approaches employed for the discovery of preterm birth genetic variants in the context of inflammation-associated spontaneous preterm birth. Candidate gene studies have sought genetic variants regulating inflammation in the mother and fetus; however, the promising findings have often not been replicated. Genome wide association studies (GWAS), an approach to identifying chromosomal loci responsible for complex traits, have also not yielded compelling evidence for DNA variants predisposing to preterm birth. A recent GWAS including a large number of Caucasian women (>40,000) revealed that maternal loci contribute to preterm birth. Although none of these loci harbored genes directly related to innate immunity, the results were replicated. Another approach to identify DNA variants predisposing to preterm birth is whole exome sequencing (WES), which examines the DNA sequence of protein coding regions of the genome. A recent WES study identified rare mutations in genes encoding for proteins involved in the negative regulation (dampening) of the innate immune response (e.g., CARD6, CARD8, NLRP10, NLRP12, NOD2, TLR10) and anti-microbial peptide/proteins (e.g., DEFB1, MBL2). These findings support the concept that preterm labor, at least in part, has an inflammatory etiology, which can be induced by pathogens (i.e. intra-amniotic infection) or "danger signals" (alarmins) released during cellular stress or necrosis (i.e. sterile intra-amniotic inflammation). These findings support the notion that preterm birth has a polygenic basis involving rare mutations or damaging variants in multiple genes involved in innate immunity and host defense mechanisms against microbes and their noxious products. An overlap among the WES-identified genes and other inflammatory conditions associated with preterm birth such as periodontal disease and inflammatory bowel disease was observed, suggesting a shared genetic substrate for these conditions. We propose that WES, as well as whole genome sequencing, is the most promising approach for the identification of functionally significant genetic variants responsible for spontaneous preterm birth, at least in the context of pathologic inflammation. The identification of genes contributing to preterm birth by WES, or whole genome sequencing, promises to yield valuable population specific biomarkers to identify the risk for spontaneous preterm birth and potential strategies to mitigate such a risk.

PMID: 29248470 [PubMed - as supplied by publisher]

Whole-exome sequencing study reveals common copy number variants in protocadherin genes associated with childhood obesity in Koreans.

Int J Obes (Lond). 2017 Apr;41(4):660-663

Authors: Moon S, Hwang MY, Jang HB, Han S, Kim YJ, Hwang JY, Lee HJ, Park SI, Song J, Kim BJ

Abstract
Recently, the prevalence of childhood obesity has significantly increased in industrialized countries, including Korea, and now controlling obesity is becoming an economic burden. However, knowledge of the risk factors associated with obesity is still limited. In this study, we aimed to discover additional obesity-associated loci in children. To achieve this, we conducted an exome-wide association analysis of copy number variation (CNV) using whole-exome sequencing (WES) data from a total of 102 cases and 86 controls. We newly identified a CNV locus that overlapped two protocadherin genes, PCDHB7 and PCDHB8, which are brain function-related genes (P-value=6.40 × 10-4, odds ratio=2.2189). A subsequent replication analysis using WES data from 203 obese and 291 normal weight children showed that this CNV region satisfied the genome-wide significance standard (Fisher's combined P-value=3.76 × 10-5). Moreover, correlation test using 199 additional samples supported significant association between CNV and increased body mass index. This region also showed a meaningful association with 273 cases and 2596 controls in adult samples. Our findings suggest that differences in the common CNV region at 5q31.3 may have an impact on the pathophysiology of obesity.

PMID: 28100915 [PubMed - indexed for MEDLINE]

Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.

Psychiatr Genet. 2016 Dec;26(6):297-301

Authors: Hnoonual A, Sripo T, Limprasert P

Abstract
To identify the underlying genetic cause of autism spectrum disorder (ASD), we performed whole-exome sequencing in 10 unrelated Thai patients with ASD. We identified a novel heterozygous missense variant (c.425C>G, p.Pro142Arg) in the Engrailed 2 (EN2) gene in two patients. The G variant has never been reported in public databases and was absent in 100 Thai patients with ASD and 435 Thai controls. A case-control study showed that the G allele of c.425C>G was significantly associated with ASD (Fisher's exact test, P=0.0359). In addition, the new variant was predicted to be possibly damaging to the EN2 protein by the PolyPhen-2 and FATHMM bioinformatic programs. Our findings suggest that the arginine variant of the EN2 protein may play an important role in the pathology of ASD. Therefore, EN2 protein functional studies should be carried out to determine whether the novel variant has an effect on protein expression.

PMID: 27755371 [PubMed - indexed for MEDLINE]

Identification of rare variants in KCTD13 at the schizophrenia risk locus 16p11.2.

Psychiatr Genet. 2016 Dec;26(6):293-296

Authors: Degenhardt F, Heinemann B, Strohmaier J, Pfohl MA, Giegling I, Hofmann A, Ludwig KU, Witt SH, Ludwig M, Forstner AJ, Albus M, Schwab SG, Borrmann-Hassenbach M, Lennertz L, Wagner M, Hoffmann P, Rujescu D, Maier W, Cichon S, Rietschel M, Nöthen MM

Abstract
Duplications in 16p11.2 are a risk factor for schizophrenia (SCZ). Using genetically modified zebrafish, Golzio and colleagues identified KCTD13 within 16p11.2 as a major driver of the neuropsychiatric phenotype observed in humans. The aims of the present study were to explore the role of KCTD13 in the development of SCZ and to provide a more complete picture of the allelic architecture at this risk locus. The exons of KCTD13 were sequenced in 576 patients. The mutations c.6G>T and c.598G>A were identified in one patient each. Both mutations were predicted to be functionally relevant and were absent from the 1000 Genomes Project data and the Exome Variant Server. The mutation c.6G>T was predicted to abolish a potential transcription factor-binding site for specifity protein 1. Altered specifity protein 1 expression has been reported in SCZ patients compared with controls. Further studies in large cohorts are warranted to determine the relevance of the two identified mutations.

PMID: 27668412 [PubMed - indexed for MEDLINE]

SLC6A1 Mutation and Ketogenic Diet in Epilepsy With Myoclonic-Atonic Seizures.

Pediatr Neurol. 2016 Nov;64:77-79

Authors: Palmer S, Towne MC, Pearl PL, Pelletier RC, Genetti CA, Shi J, Beggs AH, Agrawal PB, Brownstein CA

Abstract
BACKGROUND: Epilepsy with myoclonic-atonic seizures, also known as myoclonic-astatic epilepsy or Doose syndrome, has been recently linked to variants in the SLC6A1 gene. Epilepsy with myoclonic-atonic seizures is often refractory to antiepileptic drugs, and the ketogenic diet is known for treating medically intractable seizures, although the mechanism of action is largely unknown. We report a novel SLC6A1 variant in a patient with epilepsy with myoclonic-atonic seizures, analyze its effects, and suggest a mechanism of action for the ketogenic diet.
METHODS: We describe a ten-year-old girl with epilepsy with myoclonic-atonic seizures and a de novo SLC6A1 mutation who responded well to the ketogenic diet. She carried a c.491G>A mutation predicted to cause p.Cys164Tyr amino acid change, which was identified using whole exome sequencing and confirmed by Sanger sequencing. High-resolution structural modeling was used to analyze the likely effects of the mutation.
RESULTS: The SLC6A1 gene encodes a transporter that removes gamma-aminobutyric acid from the synaptic cleft. Mutations in SLC6A1 are known to disrupt the gamma-aminobutyric acid transporter protein 1, affecting gamma-aminobutyric acid levels and causing seizures. The p.Cys164Tyr variant found in our study has not been previously reported, expanding on the variants linked to epilepsy with myoclonic-atonic seizures.
CONCLUSION: A 10-year-old girl with a novel SLC6A1 mutation and epilepsy with myoclonic-atonic seizures had an excellent clinical response to the ketogenic diet. An effect of the diet on gamma-aminobutyric acid reuptake mediated by gamma-aminobutyric acid transporter protein 1 is suggested. A personalized approach to epilepsy with myoclonic-atonic seizures patients carrying SLC6A1 mutation and a relationship between epilepsy with myoclonic-atonic seizures due to SLC6A1 mutations, GABAergic drugs, and the ketogenic diet warrants further exploration.

PMID: 27600546 [PubMed - indexed for MEDLINE]

Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes.

Heart Rhythm. 2016 Oct;13(10):2012-9

Authors: Pipilas DC, Johnson CN, Webster G, Schlaepfer J, Fellmann F, Sekarski N, Wren LM, Ogorodnik KV, Chazin DM, Chazin WJ, Crotti L, Bhuiyan ZA, George AL

Abstract
BACKGROUND: Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
OBJECTIVE: The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
METHODS: The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
RESULTS: A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.
CONCLUSION: Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.

PMID: 27374306 [PubMed - indexed for MEDLINE]

Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum.

J Bone Miner Res. 2016 Aug;31(8):1577-85

Authors: Taylan F, Costantini A, Coles N, Pekkinen M, Héon E, Şıklar Z, Berberoğlu M, Kämpe A, Kıykım E, Grigelioniene G, Tüysüz B, Mäkitie O

Abstract
Spondyloocular syndrome is an autosomal-recessive disorder with spinal compression fractures, osteoporosis, and cataract. Mutations in XYLT2, encoding isoform of xylosyltransferase, were recently identified as the cause of the syndrome. We report on 4 patients, 2 unrelated patients and 2 siblings, with spondyloocular syndrome and novel mutations in XYLT2. Exome sequencing revealed a homozygous nonsense mutation, NM_022167.3(XYLT2): c.2188C>T, resulting in a premature stop codon (p.Arg730*) in a female patient. The patient presents visual impairment, generalized osteoporosis, short stature with short trunk, spinal compression fractures, and increased intervertebral disc space and hearing loss. We extended our XYLT2 analysis to a cohort of 22 patients with generalized osteoporosis, mostly from consanguineous families. In this cohort, we found by Sanger sequencing 2 siblings and 1 single patient who were homozygous for missense mutations in the XYLT2 gene (p.Arg563Gly and p.Leu605Pro). The patients had osteoporosis, compression fractures, cataracts, and hearing loss. Bisphosphonate treatment in 1 patient resulted in almost complete normalization of vertebral structures by adolescence, whereas treatment response in the others was variable. This report together with a previous study shows that mutations in the XYLT2 gene result in a variable phenotype dominated by spinal osteoporosis, cataract, and hearing loss. © 2016 American Society for Bone and Mineral Research.

PMID: 26987875 [PubMed - indexed for MEDLINE]

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A novel missense mutation in HSF4 causes autosomal-dominant congenital lamellar cataract in a British family.

Eye (Lond). 2017 Dec 15;:

Authors: Berry V, Pontikos N, Moore A, Ionides ACW, Plagnol V, Cheetham ME, Michaelides M

Abstract
PurposeInherited cataract, opacification of the lens, is the most common worldwide cause of blindness in children. We aimed to identify the genetic cause of isolated autosomal-dominant lamellar cataract in a five-generation British family.MethodsWhole exome sequencing (WES) was performed on two affected individuals of the family and further validated by direct sequencing in family members.ResultsA novel missense mutation NM_001040667.2:c.190A>G;p.K64E was identified in the DNA-binding-domain of heat-shock transcription factor 4 (HSF4) and found to co-segregate with disease.ConclusionWe have identified a novel mutation in HSF4 in a large British pedigree causing dominant congenital lamellar cataract. This is the second mutation in this gene found in the British population. This mutation is likely to be dominant negative and affect the DNA-binding affinity of HSF4.Eye advance online publication, 15 December 2017; doi:10.1038/eye.2017.268.

PMID: 29243736 [PubMed - as supplied by publisher]

A non-coding variant in GANAB explains isolated polycystic liver disease (PCLD) in a large family.

Hum Mutat. 2017 Dec 15;:

Authors: Besse W, Choi J, Ahram D, Mane S, Sanna-Cherchi S, Torres V, Somlo S

Abstract
Expanded mutation detection and novel gene discovery for isolated polycystic liver disease (PCLD) are necessary as 50% of cases do not have identified mutations in the seven published disease genes. We investigated a family with 5 affected siblings for which no loss of function variants were identified by whole exome sequencing analysis. SNP genotyping and linkage analysis narrowed the candidate regions to ∼8% of the genome, which included two published PCLD genes in close proximity to each other, GANAB and LRP5. Based on these findings, we re-evaluated the exome sequencing data and identified a novel intronic nine base pair deletion in the vicinity of the GANAB exon 24 splice donor that had initially been discarded by the sequence analysis pipelines. We used a minigene assay to show that this deletion leads to skipping of exon 24 in cell lines and primary human cholangiocytes. These findings prompt genomic evaluation beyond the coding region to enhance mutation detection in PCLD and to avoid premature implication of other genes in linkage disequilibrium. This article is protected by copyright. All rights reserved.

PMID: 29243290 [PubMed - as supplied by publisher]

The landscape of human mutually exclusive splicing.

Mol Syst Biol. 2017 Dec 14;13(12):959

Authors: Hatje K, Rahman RU, Vidal RO, Simm D, Hammesfahr B, Bansal V, Rajput A, Mickael ME, Sun T, Bonn S, Kollmar M

Abstract
Mutually exclusive splicing of exons is a mechanism of functional gene and protein diversification with pivotal roles in organismal development and diseases such as Timothy syndrome, cardiomyopathy and cancer in humans. In order to obtain a first genomewide estimate of the extent and biological role of mutually exclusive splicing in humans, we predicted and subsequently validated mutually exclusive exons (MXEs) using 515 publically available RNA-Seq datasets. Here, we provide evidence for the expression of over 855 MXEs, 42% of which represent novel exons, increasing the annotated human mutually exclusive exome more than fivefold. The data provide strong evidence for the existence of large and multi-cluster MXEs in higher vertebrates and offer new insights into MXE evolution. More than 82% of the MXE clusters are conserved in mammals, and five clusters have homologous clusters in Drosophila Finally, MXEs are significantly enriched in pathogenic mutations and their spatio-temporal expression might predict human disease pathology.

PMID: 29242366 [PubMed - in process]

Identification of Intellectual Disability Genes in Female Patients with a Skewed X-Inactivation Pattern.

Hum Mutat. 2016 Aug;37(8):804-11

Authors: Fieremans N, Van Esch H, Holvoet M, Van Goethem G, Devriendt K, Rosello M, Mayo S, Martinez F, Jhangiani S, Muzny DM, Gibbs RA, Lupski JR, Vermeesch JR, Marynen P, Froyen G

Abstract
Intellectual disability (ID) is a heterogeneous disorder with an unknown molecular etiology in many cases. Previously, X-linked ID (XLID) studies focused on males because of the hemizygous state of their X chromosome. Carrier females are generally unaffected because of the presence of a second normal allele, or inactivation of the mutant X chromosome in most of their cells (skewing). However, in female ID patients, we hypothesized that the presence of skewing of X-inactivation would be an indicator for an X chromosomal ID cause. We analyzed the X-inactivation patterns of 288 females with ID, and found that 22 (7.6%) had extreme skewing (>90%), which is significantly higher than observed in the general population (3.6%; P = 0.029). Whole-exome sequencing of 19 females with extreme skewing revealed causal variants in six females in the XLID genes DDX3X, NHS, WDR45, MECP2, and SMC1A. Interestingly, variants in genes escaping X-inactivation presumably cause both XLID and skewing of X-inactivation in three of these patients. Moreover, variants likely accounting for skewing only were detected in MED12, HDAC8, and TAF9B. All tested candidate causative variants were de novo events. Hence, extreme skewing is a good indicator for the presence of X-linked variants in female patients.

PMID: 27159028 [PubMed - indexed for MEDLINE]

DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System.

Hum Mutat. 2016 Aug;37(8):812-9

Authors: Sommen M, Schrauwen I, Vandeweyer G, Boeckx N, Corneveaux JJ, van den Ende J, Boudewyns A, De Leenheer E, Janssens S, Claes K, Verstreken M, Strenzke N, Predöhl F, Wuyts W, Mortier G, Bitner-Glindzicz M, Moser T, Coucke P, Huentelman MJ, Van Camp G

Abstract
Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss. One-hundred thirty one presumed autosomal-recessive NSHL (arNSHL) patients of Western-European ethnicity were analyzed for SNVs, Indels, and CNVs. In addition, we established a straightforward variant classification system to deal with the large number of variants encountered. We estimate that combining prescreening of GJB2 with our panel leads to a diagnosis in 25%-30% of patients. Our data show that after GJB2, the most commonly mutated genes in a Western-European population are TMC1, MYO15A, and MYO7A (3.1%). CNV analysis resulted in the identification of causative variants in two patients in OTOA and STRC. One of the major challenges for diagnostic gene panels is assigning pathogenicity for variants. A collaborative database collecting all identified variants from multiple centers could be a valuable resource for hearing loss diagnostics.

PMID: 27068579 [PubMed - indexed for MEDLINE]

Clinical Course of Six Children With GNAO1 Mutations Causing a Severe and Distinctive Movement Disorder.

Pediatr Neurol. 2016 Jun;59:81-4

Authors: Ananth AL, Robichaux-Viehoever A, Kim YM, Hanson-Kahn A, Cox R, Enns GM, Strober J, Willing M, Schlaggar BL, Wu YW, Bernstein JA

Abstract
OBJECTIVES: Mutations in GNAO1 have been described in 11 patients to date. Although most of these individuals had epileptic encephalopathy, four patients had a severe movement disorder as the prominent feature. We describe the largest series of patients with de novoGNAO1 mutations who have severe chorea, developmental delay, and hypotonia in the absence of epilepsy.
METHODS: Six patients with recurrent missense mutations in GNAO1 as detected by whole exome sequencing were identified at three institutions. We describe the presentation, clinical course, and response to treatment of these patients.
RESULTS: All six patients exhibited global developmental delay and hypotonia from infancy. Chorea developed by age four years in all but one patient, who developed chorea at 14 years. Treatments with neuroleptics and tetrabenazine were most effective in the baseline management of chorea. The chorea became gradually progressive and marked by episodes of severe, refractory ballismus requiring intensive care unit admissions in four of six patients. Exacerbations indirectly led to the death of two patients.
CONCLUSIONS: Patients with GNAO1 mutations can present with a severe, progressive movement disorder in the absence of epilepsy. Exacerbations may be refractory to treatment and can result in life-threatening secondary complications. Early and aggressive treatment of these exacerbations with direct admission to intensive care units for treatment with anesthetic drips may prevent some secondary complications. However the chorea and ballismus can be refractory to maximum medical therapy.

PMID: 27068059 [PubMed - indexed for MEDLINE]

Fibrinogen as a Pleiotropic Protein Causing Human Diseases: The Mutational Burden of Aα, Bβ, and γ Chains.

Int J Mol Sci. 2017 Dec 14;18(12):

Authors: Paraboschi EM, Duga S, Asselta R

Abstract
Fibrinogen is a highly pleiotropic protein that is involved in the final step of the coagulation cascade, wound healing, inflammation, and angiogenesis. Heterozygous mutations in Aα, Bβ, or γ fibrinogen-chain genes (FGA, FGB, FGG) have been described as being responsible for fibrinogen deficiencies (hypofibrinogenemia, hypo-dysfibrinogenemia, dysfibrinogenemia) and for more rare conditions, such as fibrinogen storage disease and hereditary renal amyloidosis. Instead, biallelic mutations have been associated with afibrinogenemia/severe hypofibrinogenemia, i.e., the severest forms of fibrinogen deficiency, affecting approximately 1-2 cases per million people. However, the "true" prevalence for these conditions on a global scale is currently not available. Here, we defined the mutational burden of the FGA, FGB, and FGG genes, and estimated the prevalence of inherited fibrinogen disorders through a systematic analysis of exome/genome data from ~140,000 individuals belonging to the genome Aggregation Database. Our analysis showed that the world-wide prevalence for recessively-inherited fibrinogen deficiencies could be 10-fold higher than that reported so far (prevalence rates vary from 1 in 10⁶ in East Asians to 24.5 in 10⁶ in non-Finnish Europeans). The global prevalence for autosomal-dominant fibrinogen disorders was estimated to be ~11 in 1000 individuals, with heterozygous carriers present at a frequency varying from 3 every 1000 individuals in Finns, to 1-2 every 100 individuals among non-Finnish Europeans and Africans/African Americans. Our analysis also allowed for the identification of recurrent (i.e., FGG-p.Ala108Gly, FGG-Thr47Ile) or ethnic-specific mutations (e.g., FGB-p.Gly103Arg in Admixed Americans, FGG-p.Ser245Phe in Africans/African Americans).

PMID: 29240685 [PubMed - in process]

Analysis of 60 706 Exomes Questions the Role of De Novo Variants Previously Implicated in Cardiac Disease.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Paludan-Müller C, Ahlberg G, Ghouse J, Svendsen JH, Haunsø S, Olesen MS

Abstract
BACKGROUND: De novo variants in the exome occur at a rate of 1 per individual per generation, and because of the low reproductive fitness for de novo variants causing severe disease, the likelihood of finding these as standing variations in the general population is low. Therefore, this study sought to evaluate the pathogenicity of de novo variants previously associated with cardiac disease based on a large population-representative exome database.
METHODS AND RESULTS: We performed a literature search for previous publications on de novo variants associated with severe arrhythmias and structural heart diseases and investigated whether these variants were present in the Exome Aggregation Consortium (ExAC) database (n=60 706). We identified monogenic variants in single case reports and smaller studies (≤200 subjects) and variants considered to increase susceptibility of disease in 3 larger trio studies (>1000 subjects). Of the monogenic variants, 11% (23/211) were present in ExAC, whereas 26% (802/3050) variants believed to increase susceptibility of disease were identified in ExAC. Monogenic de novo variants in ExAC had a total allele count of 109 and with ≈844 expected cases in ExAC, these variants would account for 13% of all cases in the studied diseases if truly monogenetic.
CONCLUSIONS: We observed numerous de novo variants associated with cardiac disease as standing variation in ExAC, thus these variants are less likely monogenetic causes or major risk contributors for cardiac disease. This highlights the importance of investigating the pathogenicity of de novo variants because they are not as exclusive and pathogenically evident as presumed previously.

PMID: 29237690 [PubMed - in process]

Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Kinnamon DD, Morales A, Bowen DJ, Burke W, Hershberger RE, DCM Consortium*

Abstract
BACKGROUND: The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality.
METHODS: On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity-ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives.
CONCLUSIONS: We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives.
CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

PMID: 29237686 [PubMed - in process]

Pathogenicity of De Novo Rare Variants: Challenges and Opportunities.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Mani A

PMID: 29237683 [PubMed - in process]

Familial Ebstein Anomaly: Whole Exome Sequencing Identifies Novel Phenotype Associated With FLNA.

Circ Cardiovasc Genet. 2017 Dec;10(6):

Authors: Mercer CL, Andreoletti G, Carroll A, Salmon AP, Temple IK, Ennis S

Abstract
BACKGROUND: Familial Ebstein anomaly is a rare form of congenital heart disease. We report 7 individuals among 2 generations of 1 family with Ebstein anomaly. This family was first reported in 1991 by Balaji et al in which family members were also reported to have a mild skeletal phenotype. The most likely mechanism of inheritance was concluded to be autosomal dominant. We sought to identify the genetic pathogenesis in this family using a next generation sequencing approach.
METHODS AND RESULTS: Whole exome sequencing was performed in 2 cousins in this family using the Agilent SureSelect Human all Exon 51 Mb version 5 capture kit. Data were processed through an analytic in-house pipeline. Whole exome sequencing identified a missense mutation in FLNA (Filamin A), an actin-binding protein located at Xq28, mutations in which are associated with the skeletal phenotypes Frontometaphyseal dysplasia, Otopalatodigital, and Melnick-Needles syndrome, with X-linked periventricular nodular heterotopia and FG syndrome (Omim, 305450). Review of the phenotypes of those with the mutation in this family shows increased severity of the cardiac phenotype and associated skeletal features in affected males, consistent with X-linked inheritance.
CONCLUSIONS: Although congenital heart disease is reported in families with mutations in FLNA, this is the first report of individuals being affected by Ebstein anomaly because of a mutation in this gene and details the concurrent skeletal phenotype observed in this family.

PMID: 29237676 [PubMed - in process]

Lung tumor exome files with T-cell receptor recombinations: a mouse model of T-cell infiltrates reflecting mutation burdens.

Lab Invest. 2017 Dec;97(12):1516-1520

Authors: Tu YN, Tong WL, Fawcett TJ, Blanck G

Abstract
Tumor exomes and RNASeq data were originally intended for obtaining tumor mutations and gene expression profiles, respectively. However, recent work has determined that tumor exome and RNAseq read files contain reads representing T-cell and B-cell receptor (TcR and BcR) recombinations, presumably due to infiltrating lymphocytes. Furthermore, the recovery of immune receptor recombination reads has demonstrated correlations with specific, previously appreciated aspects of tumor immunology. To further understand the usefulness of recovering TcR and BcR recombinations from tumor exome files, we developed a scripted algorithm for recovery of reads representing these recombinations from a previously described mouse model of lung tumorigenesis. Results indicated that exomes representing lung adenomas reveal significantly more TcR recombinations than do exomes from lung adenocarcinomas; and that exome files representing high mutation adenomas, arising from chemical mutagens, have more TcR recombinations than do exome files from low mutation adenomas arising from an activating Kras mutation. The latter results were also consistent with a similar analysis performed on human lung adenocarcinoma exomes. The mouse and human results for obtaining TcR recombination reads from tumor specimen exomes are consistent with human tumor biology results indicating that adenomas and high mutation cancers are sites of high immune activity. The results indicate hitherto unappreciated opportunities for the use of tumor specimen exome files, particularly from experimental animal models, to study the connection between the adenoma stage of tumorigenesis, or high cancer mutation rates, and high level lymphocyte infiltrates.

PMID: 28805806 [PubMed - indexed for MEDLINE]