Distinct molecular profile of diffuse cerebellar gliomas.

Acta Neuropathol. 2017 Dec;134(6):941-956

Authors: Nomura M, Mukasa A, Nagae G, Yamamoto S, Tatsuno K, Ueda H, Fukuda S, Umeda T, Suzuki T, Otani R, Kobayashi K, Maruyama T, Tanaka S, Takayanagi S, Nejo T, Takahashi S, Ichimura K, Nakamura T, Muragaki Y, Narita Y, Nagane M, Ueki K, Nishikawa R, Shibahara J, Aburatani H, Saito N

Abstract
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the "RTK I (PDGFRA)" group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.

PMID: 28852847 [PubMed - indexed for MEDLINE]

Pharmacological and genomic profiling of neurofibromatosis type 1 plexiform neurofibroma-derived schwann cells.

Sci Data. 2018 Jun 12;5:180106

Authors: Ferrer M, Gosline SJC, Stathis M, Zhang X, Guo X, Guha R, Ryman DA, Wallace MR, Kasch-Semenza L, Hao H, Ingersoll R, Mohr D, Thomas C, Verma S, Guinney J, Blakeley JO

Abstract
Neurofibromatosis type I (NF1) is an autosomal dominant genetic condition characterized by peripheral nervous system tumors (PNSTs), including plexiform neurofibromas (pNFs) that cause nerve dysfunction, deformity, pain damage to adjacent structures, and can undergo malignant transformation. There are no effective therapies to prevent or treat pNFs. Drug discovery efforts are slowed by the 'benign' nature of the Schwann cells that are the progenitor cells of pNF. In this work we characterize a set of pNF-derived cell lines at the genomic level (via SNP Arrays, RNAseq, and Whole Exome- Sequencing), and carry out dose response-based quantitative high-throughput screening (qHTS) with a collection of 1,912 oncology-focused compounds in a 1536-well microplate cell proliferation assays. Through the characterization and screening of NF1-/-, NF1+/+ and NF1+/- Schwann cell lines, this resource introduces novel therapeutic avenues for the development for NF1 associated pNF as well as all solid tumors with NF1 somatic mutations. The integrated data sets are openly available for further analysis at http://www.synapse.org/pnfCellCulture.

PMID: 29893754 [PubMed - in process]

A case of inherited type 1 and type 2A von Willebrand disease confirmed by diagnostic exome sequencing.

Pediatr Blood Cancer. 2018 Jun 12;:e27279

Authors: Shim YJ, Park SY, Jung N, Kim HS, Ha JS, Jang JH

Abstract
A 10-year-old male and his family members visited a pediatric hematology clinic due to coagulopathy. Laboratory tests indicated von Willebrand disease (vWD) in all the family members. We conducted diagnostic exome sequencing for confirmation. The patient was confirmed to be a compound heterozygote for vWD: c.2574C > G (p.Cys858Trp) from his father (known variant of vWD type 1) and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (variant known to result in exon 26 skipping in vWD type 2A). He was managed with factor VIII and von Willebrand factor complex concentrate during palatoplasty due to bleeding despite pre-operative desmopressin injection. The operation was completed successfully.

PMID: 29893454 [PubMed - as supplied by publisher]

Congenital Myasthenic Syndromes in 2018.

Curr Neurol Neurosci Rep. 2018 Jun 12;18(8):46

Authors: Engel AG

Abstract
PURPOSE OF REVIEW: Summarize features of the currently recognized congenital myasthenic syndromes (CMS) with emphasis on novel findings identified in the past 6 years.
RECENT FINDINGS: Since the last review of the CMS in this journal in 2012, several novel CMS were identified. The identified disease proteins are SNAP25B, synaptotagmin 2, Munc13-1, synaptobrevin-1, GFPT1, DPAGT1, ALG2, ALG14, Agrin, GMPPB, LRP4, myosin 9A, collagen 13A1, the mitochondrial citrate carrier, PREPL, LAMA5, the vesicular ACh transporter, and the high-affinity presynaptic choline transporter. Exome sequencing has provided a powerful tool for identifying novel CMS. Identifying the disease genes is essential for determining optimal therapy. The landscape of the CMS is still unfolding.

PMID: 29892917 [PubMed - in process]

De novo truncating variants in WHSC1 recapitulate the Wolf-Hirschhorn (4p16.3 microdeletion) syndrome phenotype.

Genet Med. 2018 Jun 11;:

Authors: Derar N, Al-Hassnan ZN, Al-Owain M, Monies D, Abouelhoda M, Meyer BF, Moghrabi N, Alkuraya FS

Abstract
PURPOSE: Wolf-Hirschhorn syndrome (WHS) is a genomic disorder with a recognizable dysmorphology profile caused by hemizygosity at 4p16.3. Previous attempts have failed to map the minimal critical locus to a single gene, leaving open the possibility that the core phenotypic components of the syndrome are caused by the combined haploinsufficiency of multiple genes.
METHODS: Clinical exome sequencing and "reverse" phenotyping.
RESULTS: We identified two patients with de novo truncating variants in WHSC1, which maps to the WHS critical locus. The phenotype of these two individuals is consistent with WHS, which suggests that haploinsufficiency of WHSC1 is sufficient to recapitulate the core phenotype (characteristic facies, and growth and developmental delay) of this classic microdeletion syndrome.
CONCLUSION: Our study expands the list of microdeletion syndromes that are solved at the single-gene level, and establishes WHSC1 as a disease gene in humans. Given the severe nature of the reported variants, the full phenotypic expression of WHSC1 may be further expanded by future reports of milder variants.

PMID: 29892088 [PubMed - as supplied by publisher]

Broad phenotypes in heterozygous NR5A1 46,XY patients with a disorder of sex development: an oligogenic origin?

Eur J Hum Genet. 2018 Jun 11;:

Authors: Camats N, Fernández-Cancio M, Audí L, Schaller A, Flück CE

Abstract
SF-1/NR5A1 is a transcriptional regulator of adrenal and gonadal development. NR5A1 disease-causing variants cause disorders of sex development (DSD) and adrenal failure, but most affected individuals show a broad DSD/reproductive phenotype only. Most NR5A1 variants show in vitro pathogenic effects, but not when tested in heterozygote state together with wild-type NR5A1 as usually seen in patients. Thus, the genotype-phenotype correlation for NR5A1 variants remains an unsolved question. We analyzed heterozygous 46,XY SF-1/NR5A1 patients by whole exome sequencing and used an algorithm for data analysis based on selected project-specific DSD- and SF-1-related genes. The variants detected were evaluated for their significance in literature, databases and checked in silico using webtools. We identified 19 potentially deleterious variants (one to seven per patient) in 18 genes in four 46,XY DSD subjects carrying heterozygous NR5A1 disease-causing variants. We constructed a scheme of all these hits within the landscape of currently known genes involved in male sex determination and differentiation. Our results suggest that the broad phenotype in these heterozygous NR5A1 46,XY DSD subjects may well be explained by an oligogenic mode of inheritance, in which multiple hits, individually non-deleterious, may contribute to a DSD phenotype unique to each heterozygous SF-1/NR5A1 individual.

PMID: 29891883 [PubMed - as supplied by publisher]

Biallelic variants in the ciliary gene TMEM67 cause RHYNS syndrome.

Eur J Hum Genet. 2018 Jun 11;:

Authors: Brancati F, Camerota L, Colao E, Vega-Warner V, Zhao X, Zhang R, Bottillo I, Castori M, Caglioti A, Sangiuolo F, Novelli G, Perrotti N, Otto EA, Undiagnosed Disease Network Italy

Abstract
A rare syndrome was first described in 1997 in a 17-year-old male patient presenting with Retinitis pigmentosa, HYpopituitarism, Nephronophthisis and Skeletal dysplasia (RHYNS). In the single reported familial case, two brothers were affected, arguing for X-linked or recessive mode of inheritance. Up to now, the underlying genetic basis of RHYNS syndrome remains unknown. Here we applied whole-exome sequencing in the originally described family with RHYNS to identify compound heterozygous variants in the ciliary gene TMEM67. Sanger sequencing confirmed a paternally inherited nonsense c.622A > T, p.(Arg208*) and a maternally inherited missense variant c.1289A > G, p.(Asp430Gly), which perturbs the correct splicing of exon 13. Overall, TMEM67 showed one of the widest clinical continuum observed in ciliopathies ranging from early lethality to adults with liver fibrosis. Our findings extend the spectrum of phenotypes/syndromes resulting from biallelic TMEM67 variants to now eight distinguishable clinical conditions including RHYNS syndrome.

PMID: 29891882 [PubMed - as supplied by publisher]

Exome sequencing reveals a novel homozygous splice site variant in the WNT1 gene underlying osteogenesis imperfecta type 3.

Pediatr Res. 2017 Nov;82(5):753-758

Authors: Umair M, Alhaddad B, Rafique A, Jan A, Haack TB, Graf E, Ullah A, Ahmad F, Strom TM, Meitinger T, Ahmad W

Abstract
BackgroundOsteogenesis imperfecta (OI) is a heritable bone fragility disorder usually caused by dominant variants in COL1A1 or COL1A2 genes. Over the last few years, 17 genes including 12 autosomal recessive and five autosomal dominant forms of OI, involved in various aspects of bone formation, have been identified.MethodsWhole-exome sequencing followed by conventional Sanger sequencing was performed in a single affected individual (IV-3) in a family.ResultsHere, we report the clinical and genetic characterization of OI type 3 in a consanguineous family with four affected members. Clinical examinations revealed low bone density, short stature, severe vertebral compression fractures, and multiple long bone fractures in the affected members. Exome sequencing revealed a biallelic pathogenic splice acceptor site variant (c.359-3C>G) in a wingless-type mouse mammary tumor virus integration site family 1 (WNT1) gene located on chromosome 12q13.12.ConclusionWe report a biallelic splice site variant underlying OI type 3 and the first case from the Pakistani population.

PMID: 28665926 [PubMed - indexed for MEDLINE]

Association between vitamin D receptor gene polymorphism and ankylosing spondylitis in Han Chinese.

Int J Rheum Dis. 2017 Oct;20(10):1510-1516

Authors: Zhang P, Li Q, Qi J, Lv Q, Zheng X, Wu X, Gu J

Abstract
OBJECTIVES: To investigate whether vitamin D receptor (VDR) gene polymorphisms confer susceptibility to aankylosing spondylitis (AS) and study its polymorphisms in Han Chinese.
METHODS: We screened single nucleotide polymorphisms (SNPs) in the VDR region through genome-wide genotyping chips in AS cases and healthy controls, then used the exome sequencing result to analyze all the potential AS-associated SNPs in the VDR gene.
RESULTS: Thirty-two SNPs were found in the VDR gene in the genome-wide genotyping chips and the logistic regression result showed no significant difference between AS cases and controls. A total of 46 SNPs in the VDR region were genotyped through exome sequencing, including four functional SNPs (rs731236 [TaqI], rs2228570 [FokI], rs7975232 [ApaI], rs1544410 [BsmI]) and two newly discovered SNPs (12:48259222 and 12:48276730). To note, rs731236 and rs2228570 locate in the exons of VDR, which cause synonymous and missense mutation. The association test showed there was no significant difference between AS cases and controls in the allele frequency distribution, but haplotype analysis of rs11168266-rs11168267 show nominal significance (P = 0.01268).
CONCLUSION: Our preliminary study indicates the haplotypes (TG) of rs11168266-rs11168267 in the VDR gene confers susceptibility to AS, which is worth further research.

PMID: 27778467 [PubMed - indexed for MEDLINE]

Rare genetic mutations in Pakistani patients with dilated cardiomyopathy.

Gene. 2018 Jun 07;:

Authors: Shakeel M, Irfan M, Khan IA

Abstract
Dilated cardiomyopathy (DCM) is a leading cause of heart failure, and heart transplantation globally. There is enlargement of left ventricle of the heart impairing the systolic function in this disorder. The involvement of genetic factors in the pathogenesis of DCM has been reported in up to 50% of the cases. However, due to the complexity and heterogeneity of the disease, the complete pathophysiology remains unclear. In this study, whole exomes of five unrelated patients of idiopathic DCM were sequenced to an average depth of 100× using Illumina HiSeq4000 system. The analysis of the data with in silico tools SIFT, Polyphen2, and CADD showed 494 rare (AF < 1.0%) missense SNVs predicted as deleterious. Detrimental variants in genes highly expressed in cardiac tissue included 3 rare allele frequency loss-of-function SNVs in C2orf40, MYOM3, and TMED4 genes, a homozygous frameshift insertion in RTKN2, and a splice site homozygous deletion in SLC6A6 in at least one of the patients. The stop-gained SNV rs143187236 of MYOM3 (myomesin 3) was found in perfect linkage disequilibrium (r2 = 1.0) with its neighboring missense SNV rs149105212 in two of the patients, representing the role of myomesin 3 in pathophysiology of DCM. Allele frequency comparison showed three variants rs375563861 (C2orf40), rs143187236 (MYOM3), and rs564181443 (RTKN2) having 3 fold or higher allele frequency in South Asians than in the global populations. The identified pathogenic variants can be used in risk assessment and precision therapy in DCM patients.

PMID: 29886034 [PubMed - as supplied by publisher]

Whole Exome Sequencing of Patients from Multicase Families with Systemic Lupus Erythematosus Identifies Multiple Rare Variants.

Sci Rep. 2018 Jun 08;8(1):8775

Authors: Delgado-Vega AM, Martínez-Bueno M, Oparina NY, López Herráez D, Kristjansdottir H, Steinsson K, Kozyrev SV, Alarcón-Riquelme ME

Abstract
In an effort to identify rare alleles associated with SLE, we have performed whole exome sequencing of the most distantly related affected individuals from two large Icelandic multicase SLE families followed by Ta targeted genotyping of additional relatives. We identified multiple rare likely pathogenic variants in nineteen genes co-segregating with the disease through multiple generations. Gene co-expression and protein-protein interaction analysis identified a network of highly connected genes comprising several loci previously implicated in autoimmune diseases. These genes were significantly enriched for immune system development, lymphocyte activation, DNA repair, and V(D)J gene recombination GO-categories. Furthermore, we found evidence of aggregate association and enrichment of rare variants at the FAM71E1/EMC10 locus in an independent set of 4,254 European SLE-cases and 4,349 controls. Our study presents evidence supporting that multiple rare likely pathogenic variants, in newly identified genes involved in known disease pathogenic pathways, segregate with SLE at the familial and population level.

PMID: 29884787 [PubMed - in process]

Metformin induces FOXO3-dependent fetal hemoglobin production in human primary erythroid cells.

Blood. 2018 Jun 08;:

Authors: Zhang Y, Paikari A, Sumazin P, Ginter Summarell CC, Crosby JR, Boerwinkle E, Weiss MJ, Sheehan VA

Abstract
Induction of red blood cell fetal hemoglobin (HbF, α2γ2) ameliorates the pathophysiology of sickle cell disease (SCD) by reducing the concentration of sickle hemoglobin (HbS, α2βS2) to inhibit its polymerization. Hydroxyurea (HU), the only FDA-approved drug for SCD, acts in part by inducing HbF, but is not fully effective, reflecting the need for new therapies. Whole exome sequence analysis of rare genetic variants in SCD patients identified FOXO3 as a candidate regulator of RBC HbF. We validated these genomic findings through loss and gain of function studies in normal human CD34+ hematopoietic stem and progenitor cells (HSPCs) induced to undergo erythroid differentiation. FOXO3 gene silencing reduced γ-globin RNA levels and HbF levels in erythroblasts, while overexpression of FOXO3 produced the opposite effect. Moreover, treatment of primary CD34+ cell-derived erythroid cultures with metformin, an FDA-approved drug known to enhance FOXO3 activity in non-erythroid cells, caused dose-related, FOXO3-dependent, increases in both percentage (%) HbF protein and the fraction of HbF-immunostaining cells (F-cells). Combined HU and metformin treatment induced HbF additively and reversed the erythroid maturation arrested caused by HU treatment alone. HbF induction in erythroid precursors by metformin was dependent on FOXO3 expression and did not alter expression of BCL11A, MYB or KLF1. Collectively, our data implicate FOXO3 as a positive regulator of γ-globin expression and identify metformin as a potential therapeutic agent for SCD.

PMID: 29884740 [PubMed - as supplied by publisher]

The role of protein methyltransferases as potential novel therapeutic targets in squamous cell carcinoma of the head and neck.

Oral Oncol. 2018 Jun;81:100-108

Authors: Saloura V, Vougiouklakis T, Sievers C, Burkitt K, Nakamura Y, Hager G, van Waes C

Abstract
Squamous cell carcinoma of the head and neck is a lethal disease with suboptimal survival outcomes and standard therapies with significant comorbidities. Whole exome sequencing data recently revealed an abundance of genetic and expression alterations in a family of enzymes known as protein methyltransferases in a variety of cancer types, including squamous cell carcinoma of the head and neck. These enzymes are mostly known for their chromatin-modifying functions through methylation of various histone substrates, though evidence supports their function also through methylation of non-histone substrates. This review summarizes the current knowledge on the function of protein methyltransferases in squamous cell carcinoma of the head and neck and highlights their promising potential as the next generation of therapeutic targets in this disease.

PMID: 29884408 [PubMed - in process]

Integrated genomic characterization of oral carcinomas in post-hematopoietic stem cell transplantation survivors.

Oral Oncol. 2018 Jun;81:1-9

Authors: Hanna GJ, Kofman ER, Shazib MA, Woo SB, Reardon B, Treister NS, Haddad RI, Cutler CS, Antin JH, Van Allen EM, Uppaluri R, Soiffer RJ

Abstract
OBJECTIVES: Secondary oral squamous cell carcinoma (OSCC) is a late complication in allogeneic hematopoietic stem cell transplantation (HSCT) patients, but little is known about long-term outcomes and prognostication. Additionally, molecular alterations and immunologic insights unique to this disease remain largely unexplored.
METHODS: We present a cohort of 31 patients with post-HSCT OSCC and reported on clinicopathologic predictors of survival. Whole-exome sequencing was performed on 6 (19%) matched pairs of peripheral blood (post-conditioning, pre-HSCT) and tumor samples. The entire cohort had archival tumor available for immunoprofiling with PD-1/L1 immunohistochemistry.
RESULTS: Five-year overall survival (OS) was 57% (95% CI: 46.1-69.8) with a median disease-free survival (DFS) of 13.3 months. Advanced initial staging, a buccal or oral tongue subsite, chronic oral graft-versus-host disease (GVHD) and smoking all negatively impacted survival. High tumor mutational burden (TMB) (median 11.3 vs. 5.0) and unique mutational signatures were noted between unrelated and related donor groups - with a strong correlation between infiltrating PD-1+ lymphocytes and TMB (R = 0.98, p < 0.01). Some differences were observed when comparing commonly mutated genes among our cohort and TCGA, with a predominance of TP53 events.
CONCLUSION: Survival outcomes appear similar in HSCT survivors with OSCC compared with non-HSCT OSCC populations. We identified somatic alterations in genes with therapeutic potential unique to this subpopulation of oral cancers.

PMID: 29884406 [PubMed - in process]

Decoding the Heart through Next Generation Sequencing Approaches.

Genes (Basel). 2018 Jun 07;9(6):

Authors: Pawlak M, Niescierowicz K, Winata CL

Abstract
: Vertebrate organs develop through a complex process which involves interaction between multiple signaling pathways at the molecular, cell, and tissue levels. Heart development is an example of such complex process which, when disrupted, results in congenital heart disease (CHD). This complexity necessitates a holistic approach which allows the visualization of genome-wide interaction networks, as opposed to assessment of limited subsets of factors. Genomics offers a powerful solution to address the problem of biological complexity by enabling the observation of molecular processes at a genome-wide scale. The emergence of next generation sequencing (NGS) technology has facilitated the expansion of genomics, increasing its output capacity and applicability in various biological disciplines. The application of NGS in various aspects of heart biology has resulted in new discoveries, generating novel insights into this field of study. Here we review the contributions of NGS technology into the understanding of heart development and its disruption reflected in CHD and discuss how emerging NGS based methodologies can contribute to the further understanding of heart repair.

PMID: 29880785 [PubMed]

Identification of two novel compound heterozygous mutations of ADGRV1 in a Chinese family with Usher syndrome type IIC.

Ophthalmic Genet. 2018 Jun 08;:1-5

Authors: Zhang N, Wang J, Liu S, Liu M, Jiang F

Abstract
BACKGROUND: To describe the clinical and genetic findings in a Chinese family with three sibs diagnosed with Usher syndrome type IIC.
MATERIALS AND METHODS: Four members received ophthalmic and otologic tests to ascertain the clinical characteristics. According to the clinical phenotype, we focused attention on a total of 658 genes associated with them. We screened the possible pathogenic mutation sites, used Sanger to exclude the false positive and verified whether there were co-segregated among the family members.
RESULTS: Typical fundus features found in the proband supported the diagnosis of retinitis pigmentosa (RP). Audiometric test indicated moderate to severe sensorineural hearing impairment while the vestibular function was normal. Whole-exome sequencing identified the presence of two novel compound heterozygous mutations in ADGRV1, a known gene responsible for Usher syndrome type IIC. Mutationc.15008delG/p.Gly5003AlafsTer13 was inherited from the mother while c.18383_18386dupACAG/p.His6130GlnfsTer84 was inherited from the father, and they were co-segregated with the disease phenotype in the family.
CONCLUSIONS: The mutations found in our study not only broaden the mutation spectrum of ADGRV1, but also provide assistances for future genetic diagnosis and treatment for Usher syndrome patients.

PMID: 29883260 [PubMed - as supplied by publisher]

Episodic ataxia type 2 characterized by recurrent dizziness/vertigo: a report of four cases.

Int J Neurosci. 2018 Jun 08;:1-18

Authors: Ling X, Zhao DH, Zhao J, Shen B, Yang X

Abstract
PURPOSE: To report the clinical features and gene mutations in four episodic ataxia type 2 (EA2) patients whose main presentation was recurrent dizziness/vertigo.
METHODS: Clinical data of four EA2 patients (three familial EA2 cases and one sporadic case) with recurrent dizziness/vertigo were collected to assess nystagmus and eye movement. Gene mutations were identified by whole exome sequencing.
RESULTS: The three patients in family 1 experienced disease onset before 8 years of age, presented with a chief complaint of episodic dizziness, muscle weakness of the lower limbs and the inability to walk. These symptoms lasted a few hours and then subsided. The proband also had gaze-evoked nystagmus during attacks. Videonystagmography demonstrated that the saccade velocity was low, smooth pursuit was type III, and gain was abnormal at 0.1 Hz, 0.2 Hz, and 0.4 Hz. An optokinetic nystagmus test showed that the left eye optokinetic nystagmus disappeared, and the right eye optokinetic nystagmus weakened. A head shaking test produced a left horizontal nystagmus. Gene analysis identified a novel c.1558 + 2T > G splice site mutation in the CACNA1A gene in the proband and his mother. The fourth patient was sporadic, with an onset age of 3 years. He mainly suffered from episodic vertigo, accompanied by severe anxiety and depression. He carried a CACNA1A mutation, c.4636C > T, which is a previously reported pathogenic mutation.
CONCLUSIONS: The onset of symptoms in these EA2 patients was early. The patients mainly presented recurrent dizziness/vertigo, with the absence of characteristic episodic ataxia. Detection of CACNA1A mutations facilitates the diagnosis of EA2.

PMID: 29883219 [PubMed - as supplied by publisher]

Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases.

J Transl Med. 2018 Jun 07;16(1):158

Authors: Hamdi Y, Boujemaa M, Ben Rekaya M, Ben Hamda C, Mighri N, El Benna H, Mejri N, Labidi S, Daoud N, Naouali C, Messaoud O, Chargui M, Ghedira K, Boubaker MS, Mrad R, Boussen H, Abdelhak S, PEC Consortium

Abstract
BACKGROUND: A family history of breast cancer has long been thought to indicate the presence of inherited genetic events that predispose to this disease. In North Africa, many specific epidemio-genetic characteristics have been observed in breast cancer families when compared to Western populations. Despite these specificities, the majority of breast cancer genetics studies performed in North Africa remain restricted to the investigation of the BRCA1 and BRCA2 genes. Thus, comprehensive data at a whole exome or whole genome level from local patients are lacking.
METHODS: A whole exome sequencing (WES) of seven breast cancer Tunisian families have been performed using a family-based approach. We focused our analysis on BC-TN-F001 family that included two affected members that have been sequenced using WES. Relevant variants identified in BC-TN-F001 have been confirmed using Sanger sequencing. Then, we conducted an integrative analysis by combining our results with those from other WES studies in order to figure out the genetic transmission model of the newly identified genes. Biological network construction and protein-protein interactions analyses have been performed to decipher the molecular mechanisms likely accounting for the role of these genes in breast cancer risk.
RESULTS: Sequencing, filtering strategies, and validation analysis have been achieved. For BC-TN-F001, no deleterious mutations have been identified on known breast cancer genes. However, 373 heterozygous, exonic and rare variants have been identified on other candidate genes. After applying several filters, 12 relevant high-risk variants have been selected. Our results showed that these variants seem to be inherited in a family specific model. This hypothesis has been confirmed following a thorough analysis of the reported WES studies. Enriched biological process and protein-protein interaction networks resulted in the identification of four novel breast cancer candidate genes namely MMS19, DNAH3, POLK and KATB6.
CONCLUSIONS: In this first WES application on Tunisian breast cancer patients, we highlighted the impact of next generation sequencing technologies in the identification of novel breast cancer candidate genes which may bring new insights into the biological mechanisms of breast carcinogenesis. Our findings showed that the breast cancer predisposition in non-BRCA families may be ethnic and/or family specific.

PMID: 29879995 [PubMed - in process]

Arid1b Haploinsufficiency Causes Abnormal Brain Gene Expression and Autism-Related Behaviors in Mice.

Int J Mol Sci. 2017 Aug 30;18(9):

Authors: Shibutani M, Horii T, Shoji H, Morita S, Kimura M, Terawaki N, Miyakawa T, Hatada I

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with core symptoms that include poor social communication, restricted interests, and repetitive behaviors. Several ASD mouse models exhibit impaired social interaction, anxiety-like behavior, and elevated perseveration. Large-scale whole exome sequencing studies identified many genes putatively associated with ASD. Like chromodomain helicase DNA binding protein 8 (CHD8), the most frequently mutated gene in individuals with ASD, the candidate gene AT-rich interaction domain 1B (ARID1B) encodes a chromatin remodeling factor. Arid1b heterozygous knockout (hKO) mice exhibited ASD-like traits related to social behavior, anxiety, and perseveration, in addition to associated features reported in some cases of ASD, such as reduced weight, impaired motor coordination, and hydrocephalus. Hydrocephalus was present in 5 of 91 hKO mice, while it was not observed in wild-type littermates (0 of 188). Genome-wide gene expression patterns in Arid1b hKO mice were similar to those in ASD patients and Chd8-haploinsufficient mice, an ASD model, and to developmental changes in gene expression in fast-spiking cells in the mouse brain. Our results suggest that Arid1b haploinsufficiency causes ASD-like phenotypes in mice.

PMID: 28867767 [PubMed - indexed for MEDLINE]

De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene.

Brain. 2018 Jun 05;:

Authors: Chemin J, Siquier-Pernet K, Nicouleau M, Barcia G, Ahmad A, Medina-Cano D, Hanein S, Altin N, Hubert L, Bole-Feysot C, Fourage C, Nitschké P, Thevenon J, Rio M, Blanc P, Vidal C, Bahi-Buisson N, Desguerre I, Munnich A, Lyonnet S, Boddaert N, Fassi E, Shinawi M, Zimmerman H, Amiel J, Faivre L, Colleaux L, Lory P, Cantagrel V

Abstract
Cerebellar atrophy is a key neuroradiological finding usually associated with cerebellar ataxia and cognitive development defect in children. Unlike the adult forms, early onset cerebellar atrophies are classically described as mostly autosomal recessive conditions and the exact contribution of de novo mutations to this phenotype has not been assessed. In contrast, recent studies pinpoint the high prevalence of pathogenic de novo mutations in other developmental disorders such as intellectual disability, autism spectrum disorders and epilepsy. Here, we investigated a cohort of 47 patients with early onset cerebellar atrophy and/or hypoplasia using a custom gene panel as well as whole exome sequencing. De novo mutations were identified in 35% of patients while 27% had mutations inherited in an autosomal recessive manner. Understanding if these de novo events act through a loss or a gain of function effect is critical for treatment considerations. To gain a better insight into the disease mechanisms causing these cerebellar defects, we focused on CACNA1G, a gene not yet associated with the early-onset form. This gene encodes the Cav3.1 subunit of T-type calcium channels highly expressed in Purkinje neurons and deep cerebellar nuclei. We identified four patients with de novo CACNA1G mutations. They all display severe motor and cognitive impairment, cerebellar atrophy as well as variable features such as facial dysmorphisms, digital anomalies, microcephaly and epilepsy. Three subjects share a recurrent c.2881G>A/p.Ala961Thr variant while the fourth patient has the c.4591A>G/p.Met1531Val variant. Both mutations drastically impaired channel inactivation properties with significantly slower kinetics (∼5 times) and negatively shifted potential for half-inactivation (>10 mV). In addition, these two mutations increase neuronal firing in a cerebellar nuclear neuron model and promote a larger window current fully inhibited by TTA-P2, a selective T-type channel blocker. This study highlights the prevalence of de novo mutations in early-onset cerebellar atrophy and demonstrates that A961T and M1531V are gain of function mutations. Moreover, it reveals that aberrant activity of Cav3.1 channels can markedly alter brain development and suggests that this condition could be amenable to treatment.

PMID: 29878067 [PubMed - as supplied by publisher]