A novel splicing mutation in SMPX is linked to nonsyndromic progressive hearing loss.

Int J Pediatr Otorhinolaryngol. 2018 Jan;104:47-50

Authors: Niu Z, Yan D, Bressler S, Mei L, Feng Y, Liu X

Abstract
OBJECTIVE: X-linked nonsyndromic hearing impairment is the rarest form of genetic hearing loss and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked nonsyndromic sensorineural hearing loss in a three-generation American family.
METHODS: Whole-exome sequencing and co-segregation analysis were used to identify disease-causing genes.
RESULTS: In this study, we described in detail the clinical characteristics of the family and identified a novel frameshift mutation creating a premature stop codon (c.133-1 G > A, p.(Gly45fs*36)) of SMPX. The loss-of-function mutation was co-segregated with the progressive hearing loss phenotype and was absent in 200 normal controls.
CONCLUSIONS: We report the first SMPX (DFNX4) mutation in a North American family. Our findings contribute to the existing genotypic and phenotypic spectrum of SMPX associated hearing loss. Furthermore, our data suggest that exome sequencing is promising in the genetic diagnosis of hearing loss.

PMID: 29287879 [PubMed - in process]

SLC52A2 mutations cause SCABD2 phenotype: A second report.

Int J Pediatr Otorhinolaryngol. 2018 Jan;104:195-199

Authors: Babanejad M, Adeli OA, Nikzat N, Beheshtian M, Azarafra H, Sadeghnia F, Mohseni M, Najmabadi H, Kahrizi K

Abstract
INTRODUCTION: Autosomal recessive cerebellar ataxias (ARCAs) are a large group of neurodegenerative disorders that manifest mainly in children and young adults. Most ARCAs are heterogeneous with respect to age at onset, severity of disease progression, and frequency of extracerebellar and systemic signs.
METHODS: The phenotype of a consanguineous Iranian family was characterized using clinical testing and pedigree analysis. Whole-exome sequencing was used to identify the disease-causing gene in this family.
RESULTS AND CONCLUSION: Using whole exome sequencing (WES), a novel missense mutation in SLC52A2 gene is reported in a consanguineous Iranian family with progressive severe hearing loss, optic atrophy and ataxia. This is the second report of the genotype-phenotype correlation between this syndrome named spinocerebellar ataxia with blindness and deafness type 2 (SCABD2) and SLC52A2 gene.

PMID: 29287867 [PubMed - in process]

A possible role of FANCM mutations in male breast cancer susceptibility: Results from a multicenter study in Italy.

Breast. 2017 Dec 26;38:92-97

Authors: Silvestri V, Rizzolo P, Zelli V, Valentini V, Zanna I, Bianchi S, Tibiletti MG, Varesco L, Russo A, Tommasi S, Coppa A, Capalbo C, Calistri D, Viel A, Cortesi L, Manoukian S, Bonanni B, Montagna M, Palli D, Radice P, Peterlongo P, Ottini L

Abstract
INTRODUCTION: Breast cancer (BC) in men is a rare disease, whose etiology appears to be associated with genetic factors. Inherited mutations in BRCA1/2 genes account for about 10-15% of all cases. FANCM, functionally linked to BRCA1/2, has been suggested as a novel BC susceptibility gene. Our aim was to test if FANCM germline mutations could further explain male BC (MBC) susceptibility.
METHODS: We screened the entire coding region of FANCM in 286 MBCs by a multi-gene panel analysis, and compared these data with available whole exome sequencing data from 415 men used as population controls. Moreover, we genotyped the two most frequent FANCM mutations (c.5101C>T and c.5791C>T) in 506 MBCs and 854 healthy male controls.
RESULTS: Two FANCM truncating mutations, the c.1432C>T (p.Arg478Ter) and c.1972C>T (p.Arg658Ter), were identified in two MBC cases (0.7%). When specifically considering cases at increased genetic risk for BC, FANCM mutation frequency raises up to 1%. One mutation, the c.2201_2202delCT (p.Ser734Terfs), was found among controls (0.24%). Mutation frequency in cases was higher than in controls, however this difference was not statistically significant. FANCM c.5101C>T was not present in any of the cases and controls analyzed, whereas FANCM c.5791C>T was found in two controls (0.23%).
CONCLUSION: Rare FANCM truncating mutations, other than c.5101C>T and c.5791C>T, may have a role in MBC susceptibility. The inclusion of FANCM in gene panels for research purpose would allow for the identification of a higher number of mutation carriers, thus helping estimate BC risk associated with FANCM mutations.

PMID: 29287190 [PubMed - as supplied by publisher]

CELSR2 is a candidate susceptibility gene in idiopathic scoliosis.

PLoS One. 2017;12(12):e0189591

Authors: Einarsdottir E, Grauers A, Wang J, Jiao H, Escher SA, Danielsson A, Simony A, Andersen M, Christensen SB, Åkesson K, Kou I, Khanshour AM, Ohlin A, Wise C, Ikegawa S, Kere J, Gerdhem P

Abstract
A Swedish pedigree with an autosomal dominant inheritance of idiopathic scoliosis was initially studied by genetic linkage analysis, prioritising genomic regions for further analysis. This revealed a locus on chromosome 1 with a putative risk haplotype shared by all affected individuals. Two affected individuals were subsequently exome-sequenced, identifying a rare, non-synonymous variant in the CELSR2 gene. This variant is rs141489111, a c.G6859A change in exon 21 (NM_001408), leading to a predicted p.V2287I (NP_001399.1) change. This variant was found in all affected members of the pedigree, but showed reduced penetrance. Analysis of tagging variants in CELSR1-3 in a set of 1739 Swedish-Danish scoliosis cases and 1812 controls revealed significant association (p = 0.0001) to rs2281894, a common synonymous variant in CELSR2. This association was not replicated in case-control cohorts from Japan and the US. No association was found to variants in CELSR1 or CELSR3. Our findings suggest a rare variant in CELSR2 as causative for idiopathic scoliosis in a family with dominant segregation and further highlight common variation in CELSR2 in general susceptibility to idiopathic scoliosis in the Swedish-Danish population. Both variants are located in the highly conserved GAIN protein domain, which is necessary for the auto-proteolysis of CELSR2, suggesting its functional importance.

PMID: 29240829 [PubMed - indexed for MEDLINE]

Congenital Neuronal Ceroid Lipofuscinosis with a Novel CTSD Gene Mutation: A Rare Cause of Neonatal-Onset Neurodegenerative Disorder.

Neuropediatrics. 2017 Dec 28;:

Authors: Varvagiannis K, Hanquinet S, Billieux MH, De Luca R, Rimensberger P, Lidgren M, Guipponi M, Makrythanasis P, Blouin JL, Antonarakis SE, Steinfeld R, Kern I, Poretti A, Fluss J, Fokstuen S

Abstract
Neuronal ceroid lipofuscinoses represent a heterogeneous group of early onset neurodegenerative disorders that are characterized by progressive cognitive and motor function decline, visual loss, and epilepsy. The age of onset has been historically used for the phenotypic classification of this group of disorders, but their molecular genetic delineation has now enabled a better characterization, demonstrating significant genetic heterogeneity even among individuals with a similar phenotype. The rare Congenital Neuronal Ceroid Lipofuscinosis (CLN10) caused by mutations in the CTSD gene encoding for cathepsin D is associated with a dramatic presentation with onset before or around birth. We report on a female born to consanguineous parents who presented at birth with severe neonatal encephalopathy with massive cerebral and cerebellar shrinking on magnetic resonance imaging. Whole exome sequencing with targeted bioinformatic analysis of a panel of genes associated with prenatal/perinatal onset of neurodegenerative disease was performed and revealed the presence of a novel homozygous in-frame deletion in CTSD. Additional functional studies further confirmed the pathogenic character of this variant and established the diagnosis of CLN10 in the patient.

PMID: 29284168 [PubMed - as supplied by publisher]

Microvillus Inclusion Disease Variant in an Infant with Intractable Diarrhea.

Case Rep Gastroenterol. 2017 Sep-Dec;11(3):647-651

Authors: Alsaleem BMR, Ahmed ABM, Fageeh MA

Abstract
Microvillus inclusion disease (MVID) is a rare autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea. We report a case of MVID variant with a homozygous gene mutation in syntaxin 3 (STX3). The patient is a male Saudi infant who presented shortly after birth with severe vomiting, metabolic acidosis, and mild diarrhea. Electron microscopy study for small intestinal biopsy was consistent with MVID. MYO5B gene mutation was excluded; subsequently, whole exome sequencing (WES) was performed, which revealed homozygous gene mutation in STX3. Using WES in clinical environment can be a useful tool for diagnosing difficult and rare inherited congenital enteropathies.

PMID: 29282386 [PubMed]

Functional characterization of a novel loss-of-function mutation of PRPS1 related to early-onset progressive nonsyndromic hearing loss in Koreans (DFNX1): Potential implications on future therapeutic intervention.

J Gene Med. 2016 Nov;18(11-12):353-358

Authors: Kim SY, Kim AR, Kim NK, Lee C, Han JH, Kim MY, Jeon EH, Park WY, Mittal R, Yan D, Liu XZ, Choi BY

Abstract
BACKGROUND: The symptoms of phosphoribosyl pyrophosphate synthetase 1 (PRPS1) deficiency diseases have been reported to be alleviated by medication. In the present study, we report biochemical data that favor PRPS1 deficiency-related hearing loss as a potential target for pharmaceutical treatment.
METHODS: We recruited 42 probands from subjects aged less than 15 years with a moderate degree of nonsyndromic autosomal-recessive or sporadic sensorineural hearing loss (SNHL) in at least one side. Molecular genetic testing, including targeted exome sequencing (TES) of 129 genes for deafness, and in silico prediction were performed.
RESULTS: A strong candidate variant (p.A82P) of PRPS1 is co-segregated with SNHL in X-linked recessive inheritance from one Korean multiplex SNHL family. Subsequent measurement of in vitro enzymatic activities of PRPS1 from erythrocytes of affected and unaffected family members, as well as unrelated normal controls, confirmed a pathogenic role of this variant. In detail, compared to normal hearing controls (0.23-0.26 nmol/ml/h), the proband, the affected sibling and their normal hearing mother demonstrated a significantly decreased PRPS1 enzymatic activity (0.07, 0.03 and 0.11 nmol/ml/h, respectively). This novel loss-of-function mutation of PRPS1 (p.A82P) is the ninth and sixth most reported mutation in the world and in Asia, respectively.
CONCLUSIONS: DFNX1 was found to account for approximately 2.4% (1/42) of moderate SNHL in a Korean pediatric population. Confirmation of PRPS1 activity deficiency and an audiologic phenotype that initially begins in a milder form of SNHL, as in our family, should indicate the need for rigorous genetic screening as early as possible.

PMID: 27886419 [PubMed - indexed for MEDLINE]

Novel De Novo Mutations in KIF1A as a Cause of Hereditary Spastic Paraplegia With Progressive Central Nervous System Involvement.

J Child Neurol. 2016 Aug;31(9):1114-9

Authors: Hotchkiss L, Donkervoort S, Leach ME, Mohassel P, Bharucha-Goebel DX, Bradley N, Nguyen D, Hu Y, Gurgel-Giannetti J, Bönnemann CG

Abstract
Hereditary spastic paraplegias are a clinically and genetically heterogeneous group of disorders characterized by lower extremity spasticity and weakness. Recently, the first de novo mutations in KIF1A were identified in patients with an early-onset severe form of complicated hereditary spastic paraplegia. We report two additional patients with novel de novo mutations in KIF1A, hereby expanding the genetic spectrum of KIF1A-related hereditary spastic paraplegia. Both children presented with spastic paraplegia and additional findings of optic nerve atrophy, structural brain abnormalities, peripheral neuropathy, cognitive/language impairment, and never achieved ambulation. In particular, we highlight the progressive nature of cerebellar involvement as captured on sequential magnetic resonance images (MRIs), thus linking the neurodegenerative and spastic paraplegia phenotypes. Exome sequencing in patient 1 and patient 2 identified novel heterozygous missense mutations in KIF1A at c.902G>A (p.R307Q) and c.595G>A (p.G199 R), respectively. Therefore, our report contributes to expanding the genotypic and phenotypic spectrum of hereditary spastic paraplegia caused by mutations in KIF1A.

PMID: 27034427 [PubMed - indexed for MEDLINE]

Genetic Progression of High Grade Prostatic Intraepithelial Neoplasia to Prostate Cancer.

Eur Urol. 2016 May;69(5):823-30

Authors: Jung SH, Shin S, Kim MS, Baek IP, Lee JY, Lee SH, Kim TM, Lee SH, Chung YJ

Abstract
BACKGROUND: Although high grade prostatic intraepithelial neoplasia (HGPIN) is considered a neoplastic lesion that precedes prostate cancer (PCA), the genomic structures of HGPIN remain unknown.
OBJECTIVE: Identification of the genomic landscape of HGPIN and the genomic differences between HGPIN and PCA that may drive the progression to PCA.
DESIGN, SETTINGS, AND PARTICIPANTS: We analyzed 20 regions of paired HGPIN and PCA from six patients using whole-exome sequencing and array-comparative genomic hybridization.
OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Somatic mutation and copy number alteration (CNA) profiles of paired HGPIN and PCA were measured and compared.
RESULTS AND LIMITATIONS: The number of total mutations and CNAs of HGPINs were significantly fewer than those of PCAs. Mutations in FOXA1 and CNAs (1q and 8q gains) were detected in both HGPIN and PCA ('common'), suggesting their roles in early PCA development. Mutations in SPOP, KDM6A, and KMT2D were 'PCA-specific', suggesting their roles in HGPIN progression to PCA. The 8p loss was either 'common' or 'PCA-specific'. In-silico estimation of evolutionary ages predicted that HGPIN genomes were much younger than PCA genomes. Our data show that PCAs are direct descendants of HGPINs in most cases that require more genomic alterations to progress to PCA. The nature of heterogeneous HGPIN population that might attenuate genomic signals should further be studied.
CONCLUSIONS: HGPIN genomes harbor relatively fewer mutations and CNAs than PCA but require additional hits for the progression.
PATIENT SUMMARY: In this study, we suggest a systemic diagram from high grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PCA). Our results provide a clue to explain the long latency from HGPIN to PCA and provide useful information for the genetic diagnosis of HGPIN and PCA.

PMID: 26542946 [PubMed - indexed for MEDLINE]

Genomic Perturbations Reveal Distinct Regulatory Networks in Intrahepatic Cholangiocarcinoma.

Hepatology. 2017 Dec 26;:

Authors: Nepal C, O'Rourke CJ, Oliveira DV, Taranta A, Shema S, Gautam P, Calderaro J, Barbour A, Raggi C, Wennerberg K, Wang XW, Lautem A, Roberts LR, Andersen JB

Abstract
Intrahepatic cholangiocarcinoma (iCCA) remains a highly heterogeneous malignancy that has eluded effective patient stratification to date. The extent to which such heterogeneity can be influenced by individual driver mutations remains to be evaluated. Here, we analyzed genomic (whole-exome sequencing, targeted exome sequencing) and epigenomic data from 496 patients, and used the three most recurrently mutated genes to stratify patients (IDH, KRAS, TP53, 'undetermined'). Using this molecular dissection approach, each subgroup was determined to possess unique mutational signature preferences, co-mutation profiles and enriched pathways. High-throughput drug repositioning in seven patient-matched cell lines, chosen to reflect the genetic alterations specific for each patient group, confirmed in silico predictions of subgroup-specific vulnerabilities linked to enriched pathways. Intriguingly, patients lacking all 3 mutations ('undetermined') harbored the most extensive structural alterations while IDH mutant tumors displayed the most extensive DNA methylome dysregulation, consistent with previous findings.
CONCLUSION: Stratification of iCCA patients based on occurrence of mutations in three classifier genes (IDH, KRAS, TP53) revealed unique oncogenic programs (mutational, structural, epi-mutational) that influence pharmacologic response in drug repositioning protocols. This genome dissection approach highlights the potential of individual mutations to induce extensive molecular heterogeneity and could facilitate advancement of therapeutic response in this dismal disease. This article is protected by copyright. All rights reserved.

PMID: 29278425 [PubMed - as supplied by publisher]

Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF).

Reprod Sci. 2017 Jan 01;:1933719117749756

Authors: Sha YW, Wang X, Xu X, Su ZY, Cui Y, Mei LB, Huang XJ, Chen J, He XM, Ji ZY, Bao H, Yang X, Li P, Li L

Abstract
Multiple morphological abnormalities of the sperm flagella (MMAF) is a rare disease that causes primary infertility. However, the genetic causes for approximately half of MMAF cases are unknown. Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations (3 homozygous: c.2935_2944del: p.D979*, c.T1769A: p.L590Q, c.2005_2006del: p.M669Vfs*13; and putative compound heterozygous: c.G3262A: p.G1088S and c.C1718A: p.P573H.) and CFAP43 acceptor splice-site deletion (c.3661-2A>-) mutations in 5 and 1 patients, respectively. Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3, and CFAP43 expression was lower in P6 than in the control. Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control. This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF. These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF.

PMID: 29277146 [PubMed - as supplied by publisher]

lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling.

Nat Med. 2017 Nov;23(11):1331-1341

Authors: Lu Y, Zhao X, Liu Q, Li C, Graves-Deal R, Cao Z, Singh B, Franklin JL, Wang J, Hu H, Wei T, Yang M, Yeatman TJ, Lee E, Saito-Diaz K, Hinger S, Patton JG, Chung CH, Emmrich S, Klusmann JH, Fan D, Coffey RJ

Abstract
De novo and acquired resistance, which are largely attributed to genetic alterations, are barriers to effective anti-epidermal-growth-factor-receptor (EGFR) therapy. To generate cetuximab-resistant cells, we exposed cetuximab-sensitive colorectal cancer cells to cetuximab in three-dimensional culture. Using whole-exome sequencing and transcriptional profiling, we found that the long non-coding RNA MIR100HG and two embedded microRNAs, miR-100 and miR-125b, were overexpressed in the absence of known genetic events linked to cetuximab resistance. MIR100HG, miR-100 and miR-125b overexpression was also observed in cetuximab-resistant colorectal cancer and head and neck squamous cell cancer cell lines and in tumors from colorectal cancer patients that progressed on cetuximab. miR-100 and miR-125b coordinately repressed five Wnt/β-catenin negative regulators, resulting in increased Wnt signaling, and Wnt inhibition in cetuximab-resistant cells restored cetuximab responsiveness. Our results describe a double-negative feedback loop between MIR100HG and the transcription factor GATA6, whereby GATA6 represses MIR100HG, but this repression is relieved by miR-125b targeting of GATA6. These findings identify a clinically actionable, epigenetic cause of cetuximab resistance.

PMID: 29035371 [PubMed - indexed for MEDLINE]

Validating Candidate Congenital Heart Disease Genes in Drosophila.

Bio Protoc. 2017 Jun 20;7(12):

Authors: Zhu JY, Fu Y, Richman A, Han Z

Abstract
Genomic sequencing efforts can implicate large numbers of genes and de novo mutations as potential disease risk factors. A high throughput in vivo model system to validate candidate gene association with pathology is therefore useful. We present such a system employing Drosophila to validate candidate congenital heart disease (CHD) genes. The protocols exploit comprehensive libraries of UAS-GeneX-RNAi fly strains that when crossed into a 4×Hand-Gal4 genetic background afford highly efficient cardiac-specific knockdown of endogenous fly orthologs of human genes. A panel of quantitative assays evaluates phenotypic severity across multiple cardiac parameters. These include developmental lethality, larva and adult heart morphology, and adult longevity. These protocols were recently used to evaluate more than 100 candidate CHD genes implicated by patient whole-exome sequencing (Zhu et al., 2017).

PMID: 29276722 [PubMed]

Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity.

Nat Genet. 2018 Jan;50(1):26-41

Authors: Turcot V, Lu Y, Highland HM, Schurmann C, Justice AE, Fine RS, Bradfield JP, Esko T, Giri A, Graff M, Guo X, Hendricks AE, Karaderi T, Lempradl A, Locke AE, Mahajan A, Marouli E, Sivapalaratnam S, Young KL, Alfred T, Feitosa MF, Masca NGD, Manning AK, Medina-Gomez C, Mudgal P, Ng MCY, Reiner AP, Vedantam S, Willems SM, Winkler TW, Abecasis G, Aben KK, Alam DS, Alharthi SE, Allison M, Amouyel P, Asselbergs FW, Auer PL, Balkau B, Bang LE, Barroso I, Bastarache L, Benn M, Bergmann S, Bielak LF, Blüher M, Boehnke M, Boeing H, Boerwinkle E, Böger CA, Bork-Jensen J, Bots ML, Bottinger EP, Bowden DW, Brandslund I, Breen G, Brilliant MH, Broer L, Brumat M, Burt AA, Butterworth AS, Campbell PT, Cappellani S, Carey DJ, Catamo E, Caulfield MJ, Chambers JC, Chasman DI, Chen YI, Chowdhury R, Christensen C, Chu AY, Cocca M, Collins FS, Cook JP, Corley J, Corominas Galbany J, Cox AJ, Crosslin DS, Cuellar-Partida G, D'Eustacchio A, Danesh J, Davies G, Bakker PIW, Groot MCH, Mutsert R, Deary IJ, Dedoussis G, Demerath EW, Heijer M, Hollander AI, Ruijter HM, Dennis JG, Denny JC, Angelantonio E, Drenos F, Du M, Dubé MP, Dunning AM, Easton DF, Edwards TL, Ellinghaus D, Ellinor PT, Elliott P, Evangelou E, Farmaki AE, Farooqi IS, Faul JD, Fauser S, Feng S, Ferrannini E, Ferrieres J, Florez JC, Ford I, Fornage M, Franco OH, Franke A, Franks PW, Friedrich N, Frikke-Schmidt R, Galesloot TE, Gan W, Gandin I, Gasparini P, Gibson J, Giedraitis V, Gjesing AP, Gordon-Larsen P, Gorski M, Grabe HJ, Grant SFA, Grarup N, Griffiths HL, Grove ML, Gudnason V, Gustafsson S, Haessler J, Hakonarson H, Hammerschlag AR, Hansen T, Harris KM, Harris TB, Hattersley AT, Have CT, Hayward C, He L, Heard-Costa NL, Heath AC, Heid IM, Helgeland Ø, Hernesniemi J, Hewitt AW, Holmen OL, Hovingh GK, Howson JMM, Hu Y, Huang PL, Huffman JE, Ikram MA, Ingelsson E, Jackson AU, Jansson JH, Jarvik GP, Jensen GB, Jia Y, Johansson S, Jørgensen ME, Jørgensen T, Jukema JW, Kahali B, Kahn RS, Kähönen M, Kamstrup PR, Kanoni S, Kaprio J, Karaleftheri M, Kardia SLR, Karpe F, Kathiresan S, Kee F, Kiemeney LA, Kim E, Kitajima H, Komulainen P, Kooner JS, Kooperberg C, Korhonen T, Kovacs P, Kuivaniemi H, Kutalik Z, Kuulasmaa K, Kuusisto J, Laakso M, Lakka TA, Lamparter D, Lange EM, Lange LA, Langenberg C, Larson EB, Lee NR, Lehtimäki T, Lewis CE, Li H, Li J, Li-Gao R, Lin H, Lin KH, Lin LA, Lin X, Lind L, Lindström J, Linneberg A, Liu CT, Liu DJ, Liu Y, Lo KS, Lophatananon A, Lotery AJ, Loukola A, Luan J, Lubitz SA, Lyytikäinen LP, Männistö S, Marenne G, Mazul AL, McCarthy MI, McKean-Cowdin R, Medland SE, Meidtner K, Milani L, Mistry V, Mitchell P, Mohlke KL, Moilanen L, Moitry M, Montgomery GW, Mook-Kanamori DO, Moore C, Mori TA, Morris AD, Morris AP, Müller-Nurasyid M, Munroe PB, Nalls MA, Narisu N, Nelson CP, Neville M, Nielsen SF, Nikus K, Njølstad PR, Nordestgaard BG, Nyholt DR, O'Connel JR, O'Donoghue ML, Olde Loohuis LM, Ophoff RA, Owen KR, Packard CJ, Padmanabhan S, Palmer CNA, Palmer ND, Pasterkamp G, Patel AP, Pattie A, Pedersen O, Peissig PL, Peloso GM, Pennell CE, Perola M, Perry JA, Perry JRB, Pers TH, Person TN, Peters A, Petersen ERB, Peyser PA, Pirie A, Polasek O, Polderman TJ, Puolijoki H, Raitakari OT, Rasheed A, Rauramaa R, Reilly DF, Renström F, Rheinberger M, Ridker PM, Rioux JD, Rivas MA, Roberts DJ, Robertson NR, Robino A, Rolandsson O, Rudan I, Ruth KS, Saleheen D, Salomaa V, Samani NJ, Sapkota Y, Sattar N, Schoen RE, Schreiner PJ, Schulze MB, Scott RA, Segura-Lepe MP, Shah SH, Sheu WH, Sim X, Slater AJ, Small KS, Smith AV, Southam L, Spector TD, Speliotes EK, Starr JM, Stefansson K, Steinthorsdottir V, Stirrups KE, Strauch K, Stringham HM, Stumvoll M, Sun L, Surendran P, Swift AJ, Tada H, Tansey KE, Tardif JC, Taylor KD, Teumer A, Thompson DJ, Thorleifsson G, Thorsteinsdottir U, Thuesen BH, Tönjes A, Tromp G, Trompet S, Tsafantakis E, Tuomilehto J, Tybjaerg-Hansen A, Tyrer JP, Uher R, Uitterlinden AG, Uusitupa M, Laan SW, Duijn CM, Leeuwen N, van Setten J, Vanhala M, Varbo A, Varga TV, Varma R, Velez Edwards DR, Vermeulen SH, Veronesi G, Vestergaard H, Vitart V, Vogt TF, Völker U, Vuckovic D, Wagenknecht LE, Walker M, Wallentin L, Wang F, Wang CA, Wang S, Wang Y, Ware EB, Wareham NJ, Warren HR, Waterworth DM, Wessel J, White HD, Willer CJ, Wilson JG, Witte DR, Wood AR, Wu Y, Yaghootkar H, Yao J, Yao P, Yerges-Armstrong LM, Young R, Zeggini E, Zhan X, Zhang W, Zhao JH, Zhao W, Zhou W, Zondervan KT, CHD Exome+ Consortium, EPIC-CVD Consortium, ExomeBP Consortium, Global Lipids Genetic Consortium, GoT2D Genes Consortium, EPIC InterAct Consortium, INTERVAL Study, ReproGen Consortium, T2D-Genes Consortium, MAGIC Investigators, Understanding Society Scientific Group, Rotter JI, Pospisilik JA, Rivadeneira F, Borecki IB, Deloukas P, Frayling TM, Lettre G, North KE, Lindgren CM, Hirschhorn JN, Loos RJF

Abstract
Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are ~10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed ~7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.

PMID: 29273807 [PubMed - in process]

B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype-phenotype associations in the muscular dystrophy-dystroglycanopathies.

Genome Med. 2017 Dec 22;9(1):118

Authors: Maroofian R, Riemersma M, Jae LT, Zhianabed N, Willemsen MH, Wissink-Lindhout WM, Willemsen MA, de Brouwer APM, Mehrjardi MYV, Ashrafi MR, Kusters B, Kleefstra T, Jamshidi Y, Nasseri M, Pfundt R, Brummelkamp TR, Abbaszadegan MR, Lefeber DJ, van Bokhoven H

Abstract
BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients.
METHODS: Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2.
RESULTS: The first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes.
CONCLUSIONS: In conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.

PMID: 29273094 [PubMed - in process]

Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis.

Pediatr Blood Cancer. 2017 Dec 22;:

Authors: Alsultan A, Basher E, Alqanatish J, Mohammed R, Alfadhel M

Abstract
Adenosine deaminase-2 (ADA2) deficiency (DADA2) is associated with early onset polyarteritis nodosa and vasculopathy. Classic presentation includes livedo reticularis, vasculitis, and stroke. However, the phenotype and disease severity are variable. We present a 5-year-old female who presented with features that mimicked autoimmune lymphoproliferative syndrome (ALPS) in the absence of classic features of DADA2. Exome sequencing identified a novel homozygous splicing variant in ADA2 c.882-2A > G. Patient responded to anti- tumor necrosis factor medication and is in complete remission. Hematologists should be aware of various hematological presentations of DADA2, including ALPS-like disorder, that might lack vasculitis and livedo reticularis to prevent delay in initiating optimal therapy.

PMID: 29271561 [PubMed - as supplied by publisher]

A new association between CDK5RAP2 microcephaly and congenital cataracts.

Ann Hum Genet. 2017 Dec 22;:

Authors: Alfares A, Alhufayti I, Alsubaie L, Alowain M, Almass R, Alfadhel M, Kaya N, Eyaid W

Abstract
INTRODUCTION: Primary microcephaly type 3 is a genetically heterogeneous condition caused by a homozygous or compound heterozygous mutation in CDK5 regulatory subunit associated protein 2 (CDK5RAP2) and characterized by reduced head circumference (<5th percentile) with additional phenotypes varying from pigmentary abnormalities to sensorineural hearing loss. Until now, congenital cataracts have not been reported in patients with primary microcephaly type 3.
CLINICAL REPORT: We report multiple affected family members from a consanguineous Saudi family with microcephaly and congenital cataracts. We utilized a next-generation sequencing-based microcephaly gene panel that revealed a CDK5RAP2 variant (c.4055A>G; p.Glu1352Gly) as the most plausible candidate for the likely etiology in this family. Then we performed family segregation analysis using Sanger sequencing, autozygosity mapping, and whole exome sequencing, all of which revealed no other possible disease-causing variants.
CONCLUSION: Here we report on a new clinical manifestation of CDK5RAP2 and expand the phenotype of primary microcephaly type 3.

PMID: 29271474 [PubMed - as supplied by publisher]

[Molecular Pathogenesis of Testicular Germ Cell Tumors].

Klin Onkol. 2017;30(6):412-419

Authors: Bakardjieva-Mihaylova V, Škvárová Kramarzová K, Slámová M, Büchler T, Boublíková L

Abstract
BACKGROUND: Testicular germ cell tumors (TGCT) are the most frequently diagnosed solid tumors in young men and their incidence has been increasing over the past decades. Several factors may combine and play a role in the TGCT etiology, including environmental factors and genetic predispositions at multiple genomic loci that affect both testicular germ cells and stromal cells, and their interactions within the testicular microenvironment. The pathogenesis of TGCT starts prenatally with primordial germ cell arrest, and further proceeds postnatally, giving rise to in situ germ cell neoplasia and, finally, to invasive TGCT with the characteristic 12p chromosome amplification. Apart from the genes localized here, further molecular mechanisms have been linked to TGCT pathogenesis, such as the activation of the KIT/KITL signaling pathway, and aberrations in genes involved in DNA reparation, regulation of cellular differentiation, proliferation, and survival. Despite the relatively good prognosis and known etiopathogenesis of these tumors, neither targeted therapy nor molecular prognostic/predictive factors have yet been implemented in the management of TGCT, because there is not enough information about the molecular pathways or molecules involved in TGCT development that could be used for patient stratification and treatment. Current high-throughput technologies, such as next generation sequencing at the exome or transcriptome level could provide this missing information on genetic predispositions and other factors influencing the clinical course of the disease and treatment response in TGCT.
AIM: In this review, we summarize the main molecular characteristics of TGCT and the probable mechanisms participating in tumor initiation and progression.Key words: testicular germ cell tumors - signaling pathways - molecular aberrations - predictive factors - prognostic factors The work was supported by the Czech Ministry of Education, Youth and Sports NPU I nr.LO 1604. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 20. 3. 2017Accepted: 23. 7. 2017.

PMID: 29271211 [PubMed - in process]

Genetic testing including targeted gene panel in a diverse clinical population of children with autism spectrum disorder: Findings and implications.

Mol Genet Genomic Med. 2017 Dec 21;:

Authors: Kalsner L, Twachtman-Bassett J, Tokarski K, Stanley C, Dumont-Mathieu T, Cotney J, Chamberlain S

Abstract
BACKGROUND: Genetic testing of children with autism spectrum disorder (ASD) is now standard in the clinical setting, with American College of Medical Genetics and Genomics (ACMGG) guidelines recommending microarray for all children, fragile X testing for boys and additional gene sequencing, including PTEN and MECP2, in appropriate patients. Increasingly, testing utilizing high throughput sequencing, including gene panels and whole exome sequencing, are offered as well.
METHODS: We performed genetic testing including microarray, fragile X testing and targeted gene panel, consistently sequencing 161 genes associated with ASD risk, in a clinical population of 100 well characterized children with ASD. Frequency of rare variants identified in individual genes was compared with that reported in the Exome Aggregation Consortium (ExAC) database.
RESULTS: We did not diagnose any conditions with complete penetrance for ASD; however, copy number variants believed to contribute to ASD risk were identified in 12%. Eleven children were found to have likely pathogenic variants on gene panel, yet, after careful analysis, none was considered likely causative of disease. KIRREL3 variants were identified in 6.7% of children compared to 2% in ExAC, suggesting a potential role for KIRREL3 variants in ASD risk. Children with KIRREL3 variants more often had minor facial dysmorphism and intellectual disability. We also observed an increase in rare variants in TSC2. However, analysis of variant data from the Simons Simplex Collection indicated that rare variants in TSC2 occur more commonly in specific racial/ethnic groups, which are more prevalent in our population than in the ExAC database.
CONCLUSION: The yield of genetic testing including microarray, fragile X (boys) and targeted gene panel was 12%. Gene panel did not increase diagnostic yield; however, we found an increase in rare variants in KIRREL3. Our findings reinforce the need for racial/ethnic diversity in large-scale genomic databases used to identify variants that contribute to disease risk.

PMID: 29271092 [PubMed - as supplied by publisher]

A novel splice variant in EMC1 is associated with cerebellar atrophy, visual impairment, psychomotor retardation with epilepsy.

Mol Genet Genomic Med. 2017 Dec 22;:

Authors: Geetha TS, Lingappa L, Jain AR, Govindan H, Mandloi N, Murugan S, Gupta R, Vedam R

Abstract
BACKGROUND: Several genes have been implicated in a highly variable presentation of developmental delay with psychomotor retardation. Mutations in EMC1 gene have recently been reported. Herein, we describe a proband born of a consanguineous marriage, who presented with early infantile onset epilepsy, scaphocephaly, developmental delay, central hypotonia, muscle wasting, and severe cerebellar and brainstem atrophy.
METHODS: Genetic testing in the proband was performed using custom clinical exome and targeted next-generation sequencing. This was followed by segregation analysis of the variant in the parents by Sanger sequencing and evaluation of the splice variant by RNA sequencing.
RESULTS: Clinical exome sequencing identified a novel homozygous intronic splice variant in the EMC1 gene (chr1:19564510C>T, c.1212 + 1G>A, NM_015047.2). Neither population databases (ExAC and 1000 genomes) nor our internal database (n = 1,500) had reported this rare variant, predicted to affect the splicing. RNA sequencing data from the proband confirmed aberrant splicing with intron 11 retention, thereby introducing a stop codon in the resultant mRNA. This nonsense mutation is predicted to result in the premature termination of protein synthesis leading to loss of function of the EMC1 protein.
CONCLUSION: We report, for the first time the role of aberrant EMC1RNA splicing as a potential cause of disease pathogenesis. The severe epilepsy observed in our study expands the disease-associated phenotype and also emphasizes the need for comprehensive screening of intronic splice mutations.

PMID: 29271071 [PubMed - as supplied by publisher]