A novel single variant in the MEFV gene causing Mediterranean fever and Behçet's disease: a case report.

J Med Case Rep. 2018 Mar 01;12(1):53

Authors: Zerkaoui M, Laarabi FZ, Ajhoun Y, Chkirate B, Sefiani A

Abstract
BACKGROUND: Familial Mediterranean fever is an autoinflammatory disease of unknown etiology, characterized clinically by recurrent attacks of sudden-onset fever with arthralgia and/or thoracoabdominal pain and pathogenetically by autosomal recessive inheritance due to a mutation in the MEFV gene. Behçet's disease is an inflammatory disease characterized by recurrent oral and genital aphthous ulcerations, uveitis, and skin lesions. Preliminarily, our literature review suggested that patients with familial Mediterranean fever who also have Behçet's disease have only a single mutated familial Mediterranean fever gene. The MEFV gene mutation responsible for familial Mediterranean fever is probably a susceptibility factor for Behçet's disease, particularly for patients with vascular involvement, and both disorders can occur concurrently in a patient, as in the present case.
CASE PRESENTATION: A 10-year-old girl of Moroccan origin presented to our institution for genetic consultation for genetic testing of the MEFV gene. She had fever associated with abdominal and diffuse joint pain in addition to headache. These symptoms have oriented pediatricians to familial Mediterranean fever. The evolution was marked by Behçet's syndrome symptoms. Sanger sequencing followed by complete exome sequencing analysis of the MEFV gene for the proband mutation revealed a novel variant. We conclude that the novel single variant c.2078 T > A (p.Met693Lys) could be responsible for the association of familial Mediterranean fever and Behçet's disease.
CONCLUSION: To the best of our knowledge, this is the first report of a new variant in exon 10 of the MEFV gene in a Moroccan family. This novel variant should be listed in the MEFV sequence variant databases.

PMID: 29490685 [PubMed - in process]

[Advances in genetic research of cerebral palsy].

Zhongguo Dang Dai Er Ke Za Zhi. 2017 Sep;19(9):1022-1026

Authors: Wang FF, Luo R, Qu Y, Mu DZ

Abstract
Cerebral palsy is a group of syndromes caused by non-progressive brain injury in the fetus or infant and can cause disabilities in childhood. Etiology of cerebral palsy has always been a hot topic for clinical scientists. More and more studies have shown that genetic factors are closely associated with the development of cerebral palsy. With the development and application of various molecular and biological techniques such as chromosome microarray analysis, genome-wide association study, and whole exome sequencing, new achievements have been made in the genetic research of cerebral palsy. Chromosome abnormalities, copy number variations, susceptibility genes, and single gene mutation associated with the development of cerebral palsy have been identified, which provides new opportunities for the research on the pathogenesis of cerebral palsy. This article reviews the advances in the genetic research on cerebral palsy in recent years.

PMID: 28899476 [PubMed - indexed for MEDLINE]

The Genetics of Usher Syndrome in the Israeli and Palestinian Populations.

Invest Ophthalmol Vis Sci. 2018 Feb 01;59(2):1095-1104

Authors: Khalaileh A, Abu-Diab A, Ben-Yosef T, Raas-Rothschild A, Lerer I, Alswaiti Y, Chowers I, Banin E, Sharon D, Khateb S

Abstract
Purpose: Usher syndrome (USH) is the most common cause for deaf-blindness. It is genetically and clinically heterogeneous and prevalent in populations with high consanguinity rate. We aim to characterize the set of genes and mutations that cause USH in the Israeli and Palestinian populations.
Methods: Seventy-four families with USH were recruited (23 with USH type 1 [USH1], 33 with USH2, seven with USH3, four with atypical USH, and seven families with an undetermined USH type). All affected subjects underwent a full ocular evaluation. A comprehensive genetic analysis, including Sanger sequencing for the detection of founder mutations, homozygosity mapping, and whole exome sequencing in large families was performed.
Results: In 79% of the families (59 out of 74), an autosomal recessive inheritance pattern could be determined. Mutation detection analysis led to the identification of biallelic causative mutations in 51 (69%) of the families, including 21 families with mutations in USH2A, 17 in MYO7A, and seven in CLRN1. Our analysis revealed 28 mutations, 11 of which are novel (including c.802G>A, c.8558+1G>T, c.10211del, and c.14023A>T in USH2A; c.285+2T>G, c.2187+1G>T, c.3892G>A, c.5069_5070insC, c.5101C>T, and c.6196C>T in MYO7A; and c.15494del in GPR98).
Conclusions: We report here novel homozygous mutations in various genes causing USH, extending the spectrum of causative mutations. We also prove combined sequencing techniques as useful tools to identify novel disease-causing mutations. To the best of our knowledge, this is the largest report of a genetic analysis of Israeli and Palestinian families (n = 74) with different USH subtypes.

PMID: 29490346 [PubMed - in process]

Managing Bardet-Biedl Syndrome-Now and in the Future.

Front Pediatr. 2018;6:23

Authors: Forsythe E, Kenny J, Bacchelli C, Beales PL

Abstract
Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localize to the primary cilium/basal body complex. Twenty-one disease-causing genes have been identified to date. It is one of the most well-studied conditions in the family of diseases caused by defective cilia collectively known as ciliopathies. In this review, we provide an update on diagnostic developments, clinical features, and progress in the management of Bardet-Biedl syndrome. Advances in diagnostic technologies including exome and whole genome sequencing are expanding the spectrum of patients who are diagnosed with Bardet-Biedl syndrome and increasing the number of cases with diagnostic uncertainty. As a result of the diagnostic developments, a small number of patients with only one or two clinical features of Bardet-Biedl syndrome are being diagnosed. Our understanding of the syndrome-associated renal disease has evolved and is reviewed here. Novel interventions are developing at a rapid pace and are explored in this review including genetic therapeutics such as gene therapy, exon skipping therapy, nonsense suppression therapy, and gene editing. Other non-genetic therapies such as gene repurposing, targeted therapies, and non-pharmacological interventions are also discussed.

PMID: 29487844 [PubMed]

Exome sequencing reveals a novel PLP1 mutation in a Moroccan family with connatal Pelizaeus-Merzbacher disease: a case report.

BMC Pediatr. 2018 Feb 27;18(1):90

Authors: Lyahyai J, Oulad Amar Bencheikh B, Elalaoui SC, Mansouri M, Boualla L, DIonne-Laporte A, Spiegelman D, Dion PA, Cossette P, Rouleau GA, Sefiani A

Abstract
BACKGROUND: Epilepsy regroups a common and diverse set of chronic neurological disorders that are characterized by spontaneous, unprovoked, and recurrent epileptic seizures. Epilepsies have a highly heterogeneous background with a strong genetic contribution and various mode of inheritance. X-linked epilepsy usually manifests as part of a syndrome or epileptic encephalopathy. The variability of clinical manifestations of X-linked epilepsy may be attributed to several factors including the causal genetic mutation, making diagnosis, genetic counseling and treatment decisions difficult. We report the description of a Moroccan family referred to our genetic department with X-linked epileptic seizures as the only initial diagnosis.
CASE PRESENTATION: Knowing the new contribution of Next-Generation Sequencing (NGS) for clinical investigation, and given the heterogeneity of this group of disorders we performed a Whole-Exome Sequencing (WES) analysis and co-segregation study in several members of this large family. We detected a novel pathogenic PLP1 missense mutation c.251C > A (p.Ala84Asp) allowing us to make a diagnosis of Pelizaeus-Merzbacher Disease for this family.
CONCLUSION: This report extends the spectrum of PLP1 mutations and highlights the diagnostic utility of NGS to investigate this group of heterogeneous disorders.

PMID: 29486744 [PubMed - in process]

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

Cephalalgia. 2018 Jan 01;:333102418761041

Authors: Hiekkala ME, Vuola P, Artto V, Häppölä P, Häppölä E, Vepsäläinen S, Cuenca-León E, Lal D, Gormley P, Hämäläinen E, Ilmavirta M, Nissilä M, Säkö E, Sumelahti ML, Harno H, Havanka H, Keski-Säntti P, Färkkilä M, Palotie A, Wessman M, Kaunisto MA, Kallela M

Abstract
Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

PMID: 29486580 [PubMed - as supplied by publisher]

Loss of Chromatin Remodeling Proteins and/or CDKN2A Associates With Metastasis of Pancreatic Neuroendocrine Tumors and Reduced Patient Survival Times.

Gastroenterology. 2018 Feb 24;:

Authors: Roy S, LaFramboise WA, Liu TC, Cao D, Luvison A, Miller C, Lyons MA, O'Sullivan RJ, Zureikat AH, Hogg ME, Tsung A, Lee KK, Bahary N, Brand RE, Chennat JS, Fasanella KE, McGrath K, Nikiforova MN, Papachristou GI, Slivka A, Zeh HJ, Singhi AD

Abstract
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified alterations in death domain-associated protein (DAXX) and ATRX chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single non-syndrome, non-functional PanNET. We found distant metastases contained alterations in MEN1 (n=8), ATRX (n=5), DAXX (n=5), TSC2 (n=3), and DEPDC5 (n=3). We found copy number loss of CDKN2A in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling including SETD2 (n=4), ARID1A (n=2), CHD8 (n=2), and DNMT1 (n=2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3K36me3), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3K36me3, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin remodeling genes and CDKN2A contribute to metastasis of PanNETs.

PMID: 29486199 [PubMed - as supplied by publisher]

Genetic and Structural Analysis of a SKIV2L Mutation Causing Tricho-hepato-enteric Syndrome.

Dig Dis Sci. 2018 Feb 26;:

Authors: Vardi I, Barel O, Sperber M, Schvimer M, Nunberg M, Field M, Ouahed J, Marek-Yagel D, Werner L, Haberman Y, Lahad A, Anikster Y, Rechavi G, Barshack I, McElwee JJ, Maranville J, Somech R, Snapper SB, Weiss B, Shouval DS

Abstract
BACKGROUND: Advances in genomics have facilitated the discovery of monogenic disorders in patients with unique gastro-intestinal phenotypes. Syndromic diarrhea, also called tricho-hepato-enteric (THE) syndrome, results from deleterious mutations in SKIV2L or TTC37 genes. The main features of this disorder are intractable diarrhea, abnormal hair, facial dysmorphism, immunodeficiency and liver disease.
AIM: To report on a patient with THE syndrome and present the genetic analysis that facilitated diagnosis.
METHODS: Whole-exome sequencing (WES) was performed in a 4-month-old female with history of congenital diarrhea and severe failure to thrive but without hair anomalies or dysmorphism. Since the parents were first-degree cousins, the analysis focused on an autosomal recessive model. Sanger sequencing was used to validate suspected variants. Mutated protein structure was modeled to assess the effect of the mutation on protein function.
RESULTS: We identified an autosomal recessive C.1891G > A missense mutation (NM_006929) in SKIV2L gene that was previously described only in a compound heterozygous state as causing THE syndrome. The mutation was determined to be deleterious in multiple prediction models. Protein modeling suggested that the mutation has the potential to cause structural destabilization of SKIV2L, either through conformational changes, interference with the protein's packing, or changes at the protein's interface.
CONCLUSIONS: THE syndrome can present with a broad range of clinical features in the neonatal period. WES is an important diagnostic tool in patients with congenital diarrhea and can facilitate diagnosis of various diseases presenting with atypical features.

PMID: 29484573 [PubMed - as supplied by publisher]

Whole Exome Sequencing Reveals a Monogenic Cause of Disease in ≈43% of 35 Families With Midaortic Syndrome.

Hypertension. 2018 Feb 26;:

Authors: Warejko JK, Schueler M, Vivante A, Tan W, Daga A, Lawson JA, Braun DA, Shril S, Amann K, Somers MJG, Rodig NM, Baum MA, Daouk G, Traum AZ, Kim HB, Vakili K, Porras D, Lock J, Rivkin MJ, Chaudry G, Smoot LB, Singh MN, Smith ER, Mane SM, Lifton RP, Stein DR, Ferguson MA, Hildebrandt F

Abstract
Midaortic syndrome (MAS) is a rare cause of severe childhood hypertension characterized by narrowing of the abdominal aorta in children and is associated with extensive vascular disease. It may occur as part of a genetic syndrome, such as neurofibromatosis, or as consequence of a pathological inflammatory disease. However, most cases are considered idiopathic. We hypothesized that in a high percentage of these patients, a monogenic cause of disease may be detected by evaluating whole exome sequencing data for mutations in 1 of 38 candidate genes previously described to cause vasculopathy. We studied a cohort of 36 individuals from 35 different families with MAS by exome sequencing. In 15 of 35 families (42.9%), we detected likely causal dominant mutations. In 15 of 35 (42.9%) families with MAS, whole exome sequencing revealed a mutation in one of the genes previously associated with vascular disease (NF1, JAG1, ELN, GATA6, and RNF213). Ten of the 15 mutations have not previously been reported. This is the first report of ELN, RNF213, or GATA6 mutations in individuals with MAS. Mutations were detected in NF1 (6/15 families), JAG1 (4/15 families), ELN (3/15 families), and one family each for GATA6 and RNF213 Eight individuals had syndromic disease and 7 individuals had isolated MAS. Whole exome sequencing can provide conclusive molecular genetic diagnosis in a high fraction of individuals with syndromic or isolated MAS. Establishing an etiologic diagnosis may reveal genotype/phenotype correlations for MAS in the future and should, therefore, be performed routinely in MAS.

PMID: 29483232 [PubMed - as supplied by publisher]

Genomic and functional fidelity of small cell lung cancer patient-derived xenografts.

Cancer Discov. 2018 Feb 26;:

Authors: Drapkin BJ, George J, Christensen CL, Mino-Kenudson M, Dries R, Sundaresan T, Phat S, Myers DT, Zhong J, Igo P, Hazar-Rethinam MH, LiCausi JA, Gomez-Caraballo M, Kem M, Jani KN, Azimi R, Abedpour N, Menon R, Lakis S, Heist RS, Büttner R, Haas S, Sequist LV, Shaw AT, Wong KK, Hata AN, Toner M, Maheswaran S, Haber DA, Peifer M, Dyson N, Thomas RK, Farago AF

Abstract
Small cell lung cancer (SCLC) patient-derived xenografts (PDXs) can be generated from biopsies or circulating tumor cells (CTCs), though scarcity of tissue and low efficiency of tumor growth have previously limited these approaches. Applying an established clinical-translational pipeline for tissue collection and an automated microfluidic platform for CTC-enrichment, we generated 17 biopsy-derived PDXs and 17 CTC-derived PDXs in a two-year timeframe, at 89% and 38% efficiency, respectively. Whole exome sequencing showed that somatic alterations are stably maintained between patient tumors and PDXs. Early-passage PDXs maintain the genomic and transcriptional profiles of the founder PDX. In vivo treatment with etoposide and cisplatin (EP) in 30 PDX models demonstrated greater sensitivity in PDXs from EP naïve patients, and resistance to EP corresponded to increased expression of a MYC gene signature. Finally, serial CTC-derived PDXs generated from an individual patient at multiple time points accurately recapitulated the evolving drug sensitivities of that patient's disease. Collectively, this work highlights the translational potential of this strategy.

PMID: 29483136 [PubMed - as supplied by publisher]

Transcriptome profiling reveals the immune response of goose T cells under selenium stimuli.

Anim Sci J. 2017 Dec;88(12):2001-2009

Authors: Cao N, Li W, Li B, Tian Y, Xu D

Abstract
The goose is an economically important poultry species and a principal natural host of avian viruses. This study aimed to determine the effects of selenium on the immune response of geese. Under selenium stimulation, gene expression profiling was investigated using transcriptome sequencing. The selenoproteins were promoted by selenium stimulation, while the heat shock proteins, interleukin and interferons were mainly down-regulated. After comparison, 2228 differentially expressed genes were primarily involved in immune and environmental response, and infectious disease and genetic information processing related pathways were identified. Specifically, the enzymes of the lysosomes which acted as a safeguard in preventing pathogens were mostly up-regulated and six randomly selected differentially expressed genes were validated by quantitative polymerase chain reaction. In addition, the most proportional increased transcription factor family basic helix-loop-helix (bHLH) located in the 5' flank of selenoprotein P-like protein for selenium metabolism was identified by response to the selenium stimulation in this study. These analyses show that selenium can promote immune function by activating selenoproteins, transcript factors and lysosome pathway related genes, while weakening cytokine content genes in geese.

PMID: 28749043 [PubMed - indexed for MEDLINE]

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Progress in defining the genetic contribution to type 2 diabetes susceptibility.

Curr Opin Genet Dev. 2018 Feb 21;50:41-51

Authors: Morris AP

Abstract
Candidate gene, genome-wide association, exome array and sequencing studies have identified more than 140 loci associated with type 2 diabetes (T2D) susceptibility. In this review, progress in understanding the genetic architecture of T2D susceptibility across diverse populations and in localising potential causal variants for the disease through fine-mapping studies is discussed. The additional insights gained from these genetic studies into novel molecular mechanisms and pathophysiology underlying T2D susceptibility are described, and the prospects for future genomic investigations of the disease are considered.

PMID: 29477131 [PubMed - as supplied by publisher]

Pattern of TSC1 and TSC2 germline mutations in Russian patients with tuberous sclerosis.

J Hum Genet. 2018 Feb 23;:

Authors: Suspitsin EN, Yanus GA, Dorofeeva MY, Ledashcheva TA, Nikitina NV, Buyanova GV, Saifullina EV, Sokolenko AP, Imyanitov EN

Abstract
Tuberous sclerosis (TS) is a rare autosomal-dominant genetic disease. TS is manifested by the development of multiple hamartomas, which affect brain, kidneys, retina, skin and other organs. This study aimed to reveal specific features of molecular epidemiology of TS in Russia. Blood DNA samples from 61 patients with definite (n = 53) or probable (n = 8) clinical diagnosis of TS were tested for mutations in TSC1 and TSC2 genes using Sanger sequencing and MLPA analysis. Five TSC1/2 mutation-negative patients were further analyzed by exome sequencing. TSC1/2 mutations were detected in 53/61 patients (87%): 39 (74%) carried mutations in the TSC2 and 14 (26%) in the TSC1. Large rearrangements (exon deletions/duplications) affected exclusively TSC2, accounting for 15% of lesions of this gene. 6/8 (75%) patients with incomplete clinical manifestation of TS carried TSC1/2 gene lesion. Overall, 96% of detected germline TSC1/2 mutations occurred de novo. Patients with no mutation identified (NMI) differed from TSC1/2 mutation carriers, being lacking cortical tubers and subependymal nodules but having higher frequencies of renal angiomyolipomas, rhabdomyomas, and lymphangioleiomyomatosis. Exome sequencing failed to identify overt disease-causing mutation candidates among NMI patients. Russian patients with TS have increased frequency of TSC2 large gene rearrangements and TSC1/2 mutations occurring de novo as compared to other studies. Patients with suspected TS diagnosis but NMI status may represent a distinct disease entity.

PMID: 29476190 [PubMed - as supplied by publisher]

Genetics of dementia in a Finnish cohort.

Eur J Hum Genet. 2018 Feb 23;:

Authors: Pasanen P, Myllykangas L, Pöyhönen M, Kiviharju A, Siitonen M, Hardy J, Bras J, Paetau A, Tienari PJ, Guerreiro R, Verkkoniemi-Ahola A

Abstract
Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias. Variants in APP, PSEN1 and PSEN2 are typically linked to early-onset AD, and several genetic risk loci are associated with late-onset AD. Inherited FTD can be caused by hexanucleotide expansions in C9orf72, or variants in GRN, MAPT or CHMP2B. Several other genes have also been linked to FTD or FTD with motor neuron disease. Here we describe a cohort of 60 Finnish families with possible inherited dementia. Our aim was to clarify the genetic background of dementia in this cohort by analysing both known dementia-associated genes (APOE, APP, C9ORF72, GRN, PSEN1 and PSEN2) and searching for rare or novel segregating variants with exome sequencing. C9orf72 repeat expansions were detected in 12 (20%) of the 60 families, including, in addition to FTD, a family with neuropathologically verified AD. Twelve families (10 with AD and 2 with FTD) with representative samples from affected and unaffected subjects and without C9orf72 expansions were selected for whole-exome sequencing. Exome sequencing did not reveal any variants that could be regarded unequivocally causative, but revealed potentially damaging variants in UNC13C and MARCH4.

PMID: 29476165 [PubMed - as supplied by publisher]

MANAGEMENT OF ENDOCRINE DISEASE: Adrenocortical carcinoma: differentiating the good from the poor prognosis tumors.

Eur J Endocrinol. 2018 Feb 23;:

Authors: Jouinot A, Bertherat J

Abstract
Adrenocortical carcinoma (ACC) is a rare malignancy with a poor prognosis, the five-years overall survival being below 40%. However there is great variability of outcomes and we have now a better view of the heterogeneity of tumor aggressiveness. The extent of the disease at the time of diagnosis, best assayed by the European Network for the Study of Adrenal Tumors (ENSAT) staging score, is a major determinant of survival. The tumor grade, including the mitotic count and the Ki67 proliferation index, also appears as a strong prognostic factor. The assessment of tumor grade, even by expert pathologists, still suffers from inter-observer reproducibility. The emergence of genomics in the last decade has revolutionized the knowledge of molecular biology and genetics of cancers. In ACC, genomic approaches -including pan-genomic studies of gene expression (transcriptome), recurrent mutations (exome or whole-genome sequencing), chromosome alterations, DNA methylation (methylome), miRNA expression (miRnome)- converge in a new classification of ACC, characterized by distinct molecular profiles and very different outcomes. Targeted measurements of a few discriminant molecular alterations have been developed in the perspective of clinical routine, and thus may help defining therapeutic strategy. By individualizing patients' prognosis and tumor biology, these recent progresses appear as an important step forward towards precision medicine.

PMID: 29475877 [PubMed - as supplied by publisher]

A novel mutation of dipeptidyl aminopeptidase-like protein-6 in a family with suspicious idiopathic ventricular fibrillation.

QJM. 2018 Feb 20;:

Authors: Ding DB, Fan LL, Xiao Z, Huang H, Chen YQ, Guo S, Liu ZH, Xiang R

Abstract
Background: Sudden cardiac death (SCD) occurs in a broad spectrum of cardiac pathologies and is an important cause of mortality in the general population. Idiopathic ventricular fibrillation (IVF) is a rare but important factor resulting in SCD. It is diagnosed in a resuscitated cardiac arrest victim underlying unknown cause, with documented ventricular fibrillation. Previous studies have demonstrated that mutations in dipeptidyl aminopeptidase-like protein-6 (DPP6) and cardiac sodium channel Nav1.5 (SCN5A) are the most important genetic factors involve in IVF.
Methods: In this study, we employed whole-exome sequencing in combination with arrhythmia-related gene filtering to identify the genetic lesion for a family suffering from suspicious IVF, syncope and SCD. We then generated the plasmids of DPP6-pcDNA3.1 + (WT and c.1578G>C/p.Q526H). Kv4.3-pcDNA3.1+ was co-transfected together with/without DPP6-pcDNA3.1 + (WT and/or c.1578G>C/p.Q526H) into HEK293 cells to perform the patch clamp experiments.
Results: A novel missense mutation (c.1578G>C/p.Q526H) of DPP6 was identified and co-segregated with affected patients in this family. Patch clamp experiments suggested that this novel mutation might result in a gain of function and disturb the efflux of potassium ion.
Conclusion: Our study not only reported the second missense mutation of DPP6 in heart disease and expanded the spectrum of DPP6 mutations, but also contribute to the genetic diagnosis and counseling of families with suspicious IVF, syncope and SCD.

PMID: 29474731 [PubMed - as supplied by publisher]

AP4 deficiency: A novel form of neurodegeneration with brain iron accumulation?

Neurol Genet. 2018 Feb;4(1):e217

Authors: Roubertie A, Hieu N, Roux CJ, Leboucq N, Manes G, Charif M, Echenne B, Goizet C, Guissart C, Meyer P, Marelli C, Rivier F, Burglen L, Horvath R, Hamel CP, Lenaers G

Abstract
Objective: To describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation.
Methods: The 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients.
Results: In the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein.
Conclusions: Our results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.

PMID: 29473051 [PubMed]

Familial monophasic acute transverse myelitis due to the pathogenic variant in VPS37A.

Neurol Genet. 2018 Feb;4(1):e213

Authors: Mealy MA, Nam TS, Pardo SJ, Pardo CA, Sobreira NL, Avramopoulos D, Valle D, Burns KH, Levy M

Abstract
Objective: To identify genetic differences among siblings with a family history of idiopathic transverse myelitis (ITM).
Methods: We compared whole-exome sequencing (WES) on germline samples from the 2 affected sisters with ITM with 3 of their healthy siblings.
Results: The 2 sisters with ITM both had acute onset of sensory loss in the legs, weakness, and bowel/bladder dysfunction. The first developed ITM at age 15 years with a clinical nadir of complete paralysis, which slowly recovered over a few years. MRI demonstrated a persistent T2 lesion in the lower thoracic cord. The second developed ITM at age 50 years with a nadir of sensory loss from T6 down and paraparesis in the legs, associated with an MRI lesion at T6. She also made a partial recovery with treatment. Both sisters are homozygous for a missense variant in VPS37A (c.700C>A, p.Leu234Ile) identified by WES. We performed targeted sequencing of VPS37A in an additional 86 samples from patients with ITM and 175 with other diseases to investigate the p.Leu234Ile variant. We identified another patient with ITM homozygous for the same rare variant. No patients with multiple sclerosis, neuromyelitis optica, other neurologic conditions, or any healthy controls in public databases were homozygous for this variant.
Conclusions: A rare missense variant in VPS37A may predispose to development of ITM. Further studies are necessary to determine the frequency of this variant in the patient population and the mechanism through which it contributes to the risk of disease.

PMID: 29473047 [PubMed]

Modeling Genomic Instability and Selection Pressure in a Mouse Model of Melanoma.

Cell Rep. 2017 May 16;19(7):1304-1312

Authors: Kwong LN, Zou L, Chagani S, Pedamallu CS, Liu M, Jiang S, Protopopov A, Zhang J, Getz G, Chin L

Abstract
Tumor evolution is an iterative process of selection for pro-oncogenic aberrations. This process can be accelerated by genomic instability, but how it interacts with different selection bottlenecks to shape the evolving genomic landscape remains understudied. Here, we assessed tumor initiation and therapy resistance bottlenecks in mouse models of melanoma, with or without genomic instability. At the initiation bottleneck, whole-exome sequencing revealed that drug-naive tumors were genomically silent, and this was surprisingly unaffected when genomic instability was introduced via telomerase inactivation. We hypothesize that the strong engineered alleles created low selection pressure. At the therapy resistance bottleneck, strong selective pressure was applied using a BRAF inhibitor. In the absence of genomic instability, tumors acquired a non-genomic drug resistance mechanism. By contrast, telomerase-deficient, drug-resistant melanomas acquired highly recurrent copy number gains. These proof-of-principle experiments demonstrate how different selection pressures can interact with genomic instability to impact tumor evolution.

PMID: 28514651 [PubMed - indexed for MEDLINE]