Publications by authors named "Nayia Nicolaou"

18 Publications

  • Page 1 of 1

Goldberg-Shprintzen syndrome is determined by the absence, or reduced expression levels, of KIFBP.

Hum Mutat 2020 Nov 16;41(11):1906-1917. Epub 2020 Sep 16.

Department of Clinical Genetics, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Goldberg-Shprintzen syndrome (GOSHS) is caused by loss of function variants in the kinesin binding protein gene (KIFBP). However, the phenotypic range of this syndrome is wide, indicating that other factors may play a role. To date, 37 patients with GOSHS have been reported. Here, we document nine new patients with variants in KIFBP: seven with nonsense variants and two with missense variants. To our knowledge, this is the first time that missense variants have been reported in GOSHS. We functionally investigated the effect of the variants identified, in an attempt to find a genotype-phenotype correlation. We also determined whether common Hirschsprung disease (HSCR)-associated single nucleotide polymorphisms (SNPs), could explain the presence of HSCR in GOSHS. Our results showed that the missense variants led to reduced expression of KIFBP, while the truncating variants resulted in lack of protein. However, no correlation was found between the severity of GOSHS and the location of the variants. We were also unable to find a correlation between common HSCR-associated SNPs, and HSCR development in GOSHS. In conclusion, we show that reduced, as well as lack of KIFBP expression can lead to GOSHS, and our results suggest that a threshold expression of KIFBP may modulate phenotypic variability of the disease.
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http://dx.doi.org/10.1002/humu.24097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693350PMC
November 2020

First reported case of Steel syndrome in the European population: A novel homozygous mutation in COL27A1 and review of the literature.

Eur J Med Genet 2020 Jul 30;63(7):103939. Epub 2020 Apr 30.

Clinical Genetics Department, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus; The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus. Electronic address:

Steel syndrome is an autosomal recessive disorder that primarily affects the skeletal system causing a variety of manifestations. Sixteen individuals with Steel syndrome, mainly Puerto Ricans (11/16), were previously reported to carry bi-allelic mutations in the COL27A1 gene. Here, we present the first patient with Steel syndrome in Europe and the sixth non-Puerto Rican carrying a novel homozygous mutation in COL27A1. The patient is a 4-year-old boy born to non-consanguineous healthy parents, with dysmorphic facial features, absent hip ossification centres, external rotation of both feet, relatively short stature, mild skin syndactyly, short mid phalanges and bilateral sensorineural hearing loss. Whole exome sequencing (WES) revealed a novel homozygous missense variant p.(Gly802Glu) in COL27A1. The homozygous mutation was confirmed by Sanger sequencing in the proband and carrier status was confirmed in both parents and his unaffected sibling. According to online and in-house minor allele frequency (MAF) databases, this is the first COL27A1 mutation reported in the European population. Additional screening of healthy Greek-Cypriot individuals was thus performed, which did not reveal any additional carriers in the population for the variant in question.
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http://dx.doi.org/10.1016/j.ejmg.2020.103939DOI Listing
July 2020

Persistent generalized Grover disease: complete remission after treatment with oral acitretin.

Dermatol Online J 2019 Mar 15;25(3). Epub 2019 Mar 15.

Department of Dermatology, School of Medicine, University of Patras, Patras.

Grover disease (GD) is a disorder of unknown origin, clinically characterized by the occurrence of pruritic, erythematous or brownish papules and papulovesicles, which histologically reveal four different patterns of acantholysis. Usually, the eruption is self-limited and spontaneously remit within a few weeks. In some cases, however, it may persist for months or even years and show a therapy-resistant course. We report a 56-year-old woman with recalcitrant, persistent, and generalized GD who showed complete remission after 6 weeks of treatment with oral acitretin (0.8mg/kg/day). The treatment was well-tolerated and laboratory parameters remained unchanged. The patient remains free of any recurrence at 26 months. To the best of our knowledge, this is the first report of a complete remission of the persistent form of GD as a result of oral acitretin monotherapy.
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March 2019

Aniridia due to a novel microdeletion affecting regulatory enhancers: case report and review of the literature.

J Genet 2018 06;97(2):555-562

Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, 2370 Nicosia, Cyprus.

Aniridia is a rare congenital ocular malformation that follows an autosomal dominant mode of inheritance. Most patients carry pathogenic point mutations in the paired box 6 gene (), but some carry deletions involving the 11p13 region, encompassing partly or completely or the region downstream. We identified a novel deletion, ~564 kb in size located about 46.5 kb downstream of in a family with bilateral aniridia and foveal hypoplasia using array-CGH and multiplex ligation-dependent probe amplification. We also reviewall of the reported deletions downstream of in patients with aniridia and/or other congenital malformations and define the overlapping region that leads to aniridia when deleted.
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June 2018

Molecular analysis of Cypriot families with aniridia reveals a novel PAX6 mutation.

Mol Med Rep 2018 Aug 5;18(2):1623-1627. Epub 2018 Jun 5.

Department of Clinical Genetics, The Cyprus Institute of Neurology and Genetics, 2370 Nicosia, Cyprus.

The present study investigated the clinical and mutational spectrum of aniridia in a cohort of 17 affected individuals from six families from Cyprus. Each proband was initially evaluated for copy number variants at the PAX6 locus and subsequently underwent PAX6 mutation screening. Sequence analysis of FOXC1 and PITX2 was performed in patients who did not carry a PAX6 mutation. The most common clinical features in the group of aniridia patients associated with aniridia were nystagmus, cataracts and glaucoma. PAX6 pathogenic mutations were identified in five out of six families (a diagnostic yield of 84%). Previously reported pathogenic mutations in PAX6 were identified in four families, which comprise p.R203*, p.R240* and p.R317*. In addition, a novel pathogenic variant (p.E220Gfs*23) was identified in a single family. No pathogenic mutations were detected in PAX6, FOXC1 or PITX2 in the only patient with a sporadic form of aniridia‑like phenotype, confirming the genetic heterogeneity associated with this disease. To the best of our knowledge this is the first report on the mutational spectrum of PAX6 in aniridia patients of Cypriot ancestry. Mutational screening of PAX6 serves a crucial role in distinguishing isolated from syndromic forms of aniridia, and it may therefore eliminate the need for renal ultrasound scan surveillance, delineate the phenotype and improve genetic counseling.
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http://dx.doi.org/10.3892/mmr.2018.9126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072148PMC
August 2018

Novel TBX3 mutation in a family of Cypriot ancestry with ulnar-mammary syndrome.

Clin Dysmorphol 2017 Apr;26(2):61-65

aDepartment of Clinical Genetics, Makarios Medical Centre, The Cyprus Institute of Neurology and Genetics bDivision of Pediatric Endocrinology, Paedi Center for Specialized Pediatrics cDepartment of Paediatrics, Medical School, St George's University London - University of Nicosia, Nicosia, Cyprus.

Ulnar-mammary syndrome (UMS) is an autosomal dominant disorder resulting from TBX3 haploinsufficiency. It typically affects limb, apocrine gland, hair, tooth and genital development and shows marked intrafamilial and interfamilial variability in phenotypic expression. We report a family (twin brothers and their father) affected with UMS because of a novel TBX3 mutation. The twin brothers showed classical features of UMS, whereas their father was mildly affected. The c.1423C>T (p.Q475*) nonsense mutation in exon 6 of the TBX3 gene identified in the patients by targeted Sanger sequencing is predicted to lead to premature termination of translation. This is the first report of a Cypriot family with UMS resulting from a novel TBX3 mutation. This report provides additional evidence in support of the rich variability in phenotypic expression, the mutational heterogeneity and ethnic diversity associated with this rare condition.
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http://dx.doi.org/10.1097/MCD.0000000000000170DOI Listing
April 2017

De novo 14q24.2q24.3 microdeletion including IFT43 is associated with intellectual disability, skeletal anomalies, cardiac anomalies, and myopia.

Am J Med Genet A 2016 06 19;170(6):1566-9. Epub 2016 Feb 19.

Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.

We report an 11-year-old girl with mild intellectual disability, skeletal anomalies, congenital heart defect, myopia, and facial dysmorphisms including an extra incisor, cup-shaped ears, and a preauricular skin tag. Array comparative genomic hybridization analysis identified a de novo 4.5-Mb microdeletion on chromosome 14q24.2q24.3. The deleted region and phenotype partially overlap with previously reported patients. Here, we provide an overview of the literature on 14q24 microdeletions and further delineate the associated phenotype. We performed exome sequencing to examine other causes for the phenotype and queried genes present in the 14q24.2q24.3 microdeletion that are associated with recessive disease for variants in the non-deleted allele. The deleted region contains 65 protein-coding genes, including the ciliary gene IFT43. Although Sanger and exome sequencing did not identify variants in the second IFT43 allele or in other IFT complex A-protein-encoding genes, immunocytochemistry showed increased accumulation of IFT-B proteins at the ciliary tip in patient-derived fibroblasts compared to control cells, demonstrating defective retrograde ciliary transport. This could suggest a ciliary defect in the pathogenesis of this disorder. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37598DOI Listing
June 2016

Prioritization and burden analysis of rare variants in 208 candidate genes suggest they do not play a major role in CAKUT.

Kidney Int 2016 Feb;89(2):476-86

The leading cause of end-stage renal disease in children is attributed to congenital anomalies of the kidney and urinary tract (CAKUT). Familial clustering and mouse models support the presence of monogenic causes. Genetic testing is insufficient as it mainly focuses on HNF1B and PAX2 mutations that are thought to explain CAKUT in 5–15% of patients. To identify novel, potentially pathogenic variants in additional genes, we designed a panel of genes identified from studies on familial forms of isolated or syndromic CAKUT and genes suggested by in vitro and in vivo CAKUT models. The coding exons of 208 genes were analyzed in 453 patients with CAKUT using next-generation sequencing. Rare truncating, splice-site variants, and non-synonymous variants, predicted to be deleterious and conserved, were prioritized as the most promising variants to have an effect on CAKUT. Previously reported disease-causing mutations were detected, but only five were fully penetrant causal mutations that improved diagnosis. We prioritized 148 candidate variants in 151 patients, found in 82 genes, for follow-up studies. Using a burden test, no significant excess of rare variants in any of the genes in our cohort compared with controls was found. Thus, in a study representing the largest set of genes analyzed in CAKUT patients to date, the contribution of previously implicated genes to CAKUT risk was significantly smaller than expected, and the disease may be more complex than previously assumed.
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http://dx.doi.org/10.1038/ki.2015.319DOI Listing
February 2016

Genetic, environmental, and epigenetic factors involved in CAKUT.

Nat Rev Nephrol 2015 Dec 18;11(12):720-31. Epub 2015 Aug 18.

Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, PO Box 85090, 3508 AB, Utrecht, Netherlands.

Congenital anomalies of the kidney and urinary tract (CAKUT) refer to a spectrum of structural renal malformations and are the leading cause of end-stage renal disease in children. The genetic diagnosis of CAKUT has proven to be challenging due to genetic and phenotypic heterogeneity and incomplete genetic penetrance. Monogenic causes of CAKUT have been identified using different approaches, including single gene screening, and gene panel and whole exome sequencing. The majority of the identified mutations, however, lack substantial evidence to support a pathogenic role in CAKUT. Copy number variants or single nucleotide variants that are associated with CAKUT have also been identified. Numerous studies support the influence of epigenetic and environmental factors on kidney development and the natural history of CAKUT, suggesting that the pathogenesis of this syndrome is multifactorial. In this Review we describe the current knowledge regarding the genetic susceptibility underlying CAKUT and the approaches used to investigate the genetic basis of CAKUT. We outline the associated environmental risk factors and epigenetic influences on CAKUT and discuss the challenges and strategies used to fully address the involvement and interplay of these factors in the pathogenesis of the disease.
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http://dx.doi.org/10.1038/nrneph.2015.140DOI Listing
December 2015

Functional models for congenital anomalies of the kidney and urinary tract.

Nephron 2015 19;129(1):62-7. Epub 2014 Dec 19.

Congenital anomalies of the kidney and urinary tract (CAKUT) constitute one of the most common developmental diseases in humans; however, the cause for most patients remains unknown. Efforts to identify novel genetic causes for CAKUT through next-generation sequencing techniques have led to the discovery of new genes and risk factors. Concomitantly, these same efforts have generated large gene candidate lists requiring individual functional characterization. Appropriate model systems are needed to assess the functionality of genes and pathogenicity of genetic variants discovered in CAKUT patients. In this review, we discuss how cellular, animal, and personal (human) models are being used to study CAKUT candidate genes and what their major advantages and disadvantages are with respect to relevance and throughput.
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http://dx.doi.org/10.1159/000369313DOI Listing
September 2015

Assessment of common variability and expression quantitative trait loci for genome-wide associations for progressive supranuclear palsy.

Neurobiol Aging 2014 Jun 13;35(6):1514.e1-12. Epub 2014 Jan 13.

Reta Lila Weston Institute, UCL Institute of Neurology, London, UK; Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK. Electronic address:

Progressive supranuclear palsy is a rare parkinsonian disorder with characteristic neurofibrillary pathology consisting of hyperphosphorylated tau protein. Common variation defining the microtubule associated protein tau gene (MAPT) H1 haplotype strongly contributes to disease risk. A recent genome-wide association study (GWAS) revealed 3 novel risk loci on chromosomes 1, 2, and 3 that primarily implicate STX6, EIF2AK3, and MOBP, respectively. Genetic associations, however, rarely lead to direct identification of the relevant functional allele. More often, they are in linkage disequilibrium with the causative polymorphism(s) that could be a coding change or affect gene expression regulatory motifs. To identify any such changes, we sequenced all coding exons of those genes directly implicated by the associations in progressive supranuclear palsy cases and analyzed regional gene expression data from control brains to identify expression quantitative trait loci within 1 Mb of the risk loci. Although we did not find any coding variants underlying the associations, GWAS-associated single-nucleotide polymorphisms at these loci are in complete linkage disequilibrium with haplotypes that completely overlap with the respective genes. Although implication of EIF2AK3 and MOBP could not be fully assessed, we show that the GWAS single-nucleotide polymorphism rs1411478 (STX6) is a strong expression quantitative trait locus with significantly lower expression of STX6 in white matter in carriers of the risk allele.
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http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104112PMC
June 2014

Analysis of genome-wide association studies of Alzheimer disease and of Parkinson disease to determine if these 2 diseases share a common genetic risk.

JAMA Neurol 2013 Oct;70(10):1268-76

Importance: Despite Alzheimer disease (AD) and Parkinson disease (PD) being clinically distinct entities, there is a possibility of a pathological overlap, with some genome-wide association (GWA) studies suggesting that the 2 diseases represent a biological continuum. The application of GWA studies to idiopathic forms of AD and PD have identified a number of loci that contain genetic variants that increase the risk of these disorders.

Objective: To assess the genetic overlap between PD and AD by testing for the presence of potentially pleiotropic loci in 2 recent GWA studies of PD and AD.

Design: Combined GWA analysis.

Setting: Data sets from the United Kingdom, Germany, France, and the United States.

Participants: Thousands of patients with AD or PD and their controls.

Main Outcomes And Measures: Meta-analysis of GWA studies of AD and PD.

Methods: To identify evidence for potentially pleiotropic alleles that increased the risk for both PD and AD, we performed a combined PD-AD meta-analysis and compared the results with those obtained in the primary GWA studies.We also tested for a net effect of potentially polygenic alleles that were shared by both disorders by performing a polygenic score analysis. Finally, we also performed a gene-based association analysis that was aimed at detecting genes that harbor multiple disease-causing single-nucleotide polymorphisms, some of which confer a risk of PD and some a risk of AD.

Results: Detailed interrogation of the single-nucleotide polymorphism, polygenic, and gene-based analyses resulted in no significant evidence that supported the presence of loci that increase the risk of both PD and AD.

Conclusions And Relevance: Our findings therefore imply that loci that increase the risk of both PD and AD are not widespread and that the pathological overlap could instead be “downstream” of the primary susceptibility genes that increase the risk of each disease.
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http://dx.doi.org/10.1001/jamaneurol.2013.448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978422PMC
October 2013

A pathway-based analysis provides additional support for an immune-related genetic susceptibility to Parkinson's disease.

Hum Mol Genet 2013 Mar 7;22(5):1039-49. Epub 2012 Dec 7.

Department of Psychological Medicine and Neurology, Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre in Neuropsychiatric Genetics and Genomics, Cardiff University School of Medicine, Cardiff CF14 4XN, UK.

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1-2% in people >60 and 3-4% in people >80. Genome-wide association (GWA) studies have now implicated significant evidence for association in at least 18 genomic regions. We have studied a large PD-meta analysis and identified a significant excess of SNPs (P < 1 × 10(-16)) that are associated with PD but fall short of the genome-wide significance threshold. This result was independent of variants at the 18 previously implicated regions and implies the presence of additional polygenic risk alleles. To understand how these loci increase risk of PD, we applied a pathway-based analysis, testing for biological functions that were significantly enriched for genes containing variants associated with PD. Analysing two independent GWA studies, we identified that both had a significant excess in the number of functional categories enriched for PD-associated genes (minimum P = 0.014 and P = 0.006, respectively). Moreover, 58 categories were significantly enriched for associated genes in both GWA studies (P < 0.001), implicating genes involved in the 'regulation of leucocyte/lymphocyte activity' and also 'cytokine-mediated signalling' as conferring an increased susceptibility to PD. These results were unaltered by the exclusion of all 178 genes that were present at the 18 genomic regions previously reported to be strongly associated with PD (including the HLA locus). Our findings, therefore, provide independent support to the strong association signal at the HLA locus and imply that the immune-related genetic susceptibility to PD is likely to be more widespread in the genome than previously appreciated.
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http://dx.doi.org/10.1093/hmg/dds492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561909PMC
March 2013

Gain of glycosylation in integrin α3 causes lung disease and nephrotic syndrome.

J Clin Invest 2012 Dec 1;122(12):4375-87. Epub 2012 Nov 1.

Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.

Integrins are transmembrane αβ glycoproteins that connect the extracellular matrix to the cytoskeleton. The laminin-binding integrin α3β1 is expressed at high levels in lung epithelium and in kidney podocytes. In podocytes, α3β1 associates with the tetraspanin CD151 to maintain a functional filtration barrier. Here, we report on a patient homozygous for a novel missense mutation in the human ITGA3 gene, causing fatal interstitial lung disease and congenital nephrotic syndrome. The mutation caused an alanine-to-serine substitution in the integrin α3 subunit, thereby introducing an N-glycosylation motif at amino acid position 349. We expressed this mutant form of ITGA3 in murine podocytes and found that hyperglycosylation of the α3 precursor prevented its heterodimerization with β1, whereas CD151 association with the α3 subunit occurred normally. Consequently, the β1 precursor accumulated in the ER, and the mutant α3 precursor was degraded by the ubiquitin-proteasome system. Thus, these findings uncover a gain-of-glycosylation mutation in ITGA3 that prevents the biosynthesis of functional α3β1, causing a fatal multiorgan disorder.
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http://dx.doi.org/10.1172/JCI64100DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533548PMC
December 2012

Using genome-wide complex trait analysis to quantify 'missing heritability' in Parkinson's disease.

Hum Mol Genet 2012 Nov 13;21(22):4996-5009. Epub 2012 Aug 13.

Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.

Genome-wide association studies (GWASs) have been successful at identifying single-nucleotide polymorphisms (SNPs) highly associated with common traits; however, a great deal of the heritable variation associated with common traits remains unaccounted for within the genome. Genome-wide complex trait analysis (GCTA) is a statistical method that applies a linear mixed model to estimate phenotypic variance of complex traits explained by genome-wide SNPs, including those not associated with the trait in a GWAS. We applied GCTA to 8 cohorts containing 7096 case and 19 455 control individuals of European ancestry in order to examine the missing heritability present in Parkinson's disease (PD). We meta-analyzed our initial results to produce robust heritability estimates for PD types across cohorts. Our results identify 27% (95% CI 17-38, P = 8.08E - 08) phenotypic variance associated with all types of PD, 15% (95% CI -0.2 to 33, P = 0.09) phenotypic variance associated with early-onset PD and 31% (95% CI 17-44, P = 1.34E - 05) phenotypic variance associated with late-onset PD. This is a substantial increase from the genetic variance identified by top GWAS hits alone (between 3 and 5%) and indicates there are substantially more risk loci to be identified. Our results suggest that although GWASs are a useful tool in identifying the most common variants associated with complex disease, a great deal of common variants of small effect remain to be discovered.
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http://dx.doi.org/10.1093/hmg/dds335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3576713PMC
November 2012

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

Lancet Neurol 2012 Apr 9;11(4):323-30. Epub 2012 Mar 9.

Molecular Genetics Unit, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.

Background: We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).

Methods: We screened 4448 patients diagnosed with ALS (El Escorial criteria) and 1425 patients with FTD (Lund-Manchester criteria) from 17 regions worldwide for the GGGGCC hexanucleotide expansion using a repeat-primed PCR assay. We assessed familial disease status on the basis of self-reported family history of similar neurodegenerative diseases at the time of sample collection. We compared haplotype data for 262 patients carrying the expansion with the known Finnish founder risk haplotype across the chromosomal locus. We calculated age-related penetrance using the Kaplan-Meier method with data for 603 individuals with the expansion.

Findings: In patients with sporadic ALS, we identified the repeat expansion in 236 (7·0%) of 3377 white individuals from the USA, Europe, and Australia, two (4·1%) of 49 black individuals from the USA, and six (8·3%) of 72 Hispanic individuals from the USA. The mutation was present in 217 (39·3%) of 552 white individuals with familial ALS from Europe and the USA. 59 (6·0%) of 981 white Europeans with sporadic FTD had the mutation, as did 99 (24·8%) of 400 white Europeans with familial FTD. Data for other ethnic groups were sparse, but we identified one Asian patient with familial ALS (from 20 assessed) and two with familial FTD (from three assessed) who carried the mutation. The mutation was not carried by the three Native Americans or 360 patients from Asia or the Pacific Islands with sporadic ALS who were tested, or by 41 Asian patients with sporadic FTD. All patients with the repeat expansion had (partly or fully) the founder haplotype, suggesting a one-off expansion occurring about 1500 years ago. The pathogenic expansion was non-penetrant in individuals younger than 35 years, 50% penetrant by 58 years, and almost fully penetrant by 80 years.

Interpretation: A common Mendelian genetic lesion in C9orf72 is implicated in many cases of sporadic and familial ALS and FTD. Testing for this pathogenic expansion should be considered in the management and genetic counselling of patients with these fatal neurodegenerative diseases.

Funding: Full funding sources listed at end of paper (see Acknowledgments).
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http://dx.doi.org/10.1016/S1474-4422(12)70043-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3322422PMC
April 2012

The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions.

Brain 2012 Mar 1;135(Pt 3):723-35. Epub 2012 Feb 1.

Department of Clinical Genetics, VU University Medical Centre, 1007 MB Amsterdam, The Netherlands.

There is increasing evidence that frontotemporal dementia and amyotrophic lateral sclerosis are part of a disease continuum. Recently, a hexanucleotide repeat expansion in C9orf72 was identified as a major cause of both sporadic and familial frontotemporal dementia and amyotrophic lateral sclerosis. The aim of this study was to investigate clinical and neuropathological characteristics of hexanucleotide repeat expansions in C9orf72 in a large cohort of Dutch patients with frontotemporal dementia. Repeat expansions were successfully determined in a cohort of 353 patients with sporadic or familial frontotemporal dementia with or without amyotrophic lateral sclerosis, and 522 neurologically normal controls. Immunohistochemistry was performed in a series of 10 brains from patients carrying expanded repeats using a panel of antibodies. In addition, the presence of RNA containing GGGGCC repeats in paraffin-embedded sections of post-mortem brain tissue was investigated using fluorescence in situ hybridization with a locked nucleic acid probe targeting the GGGGCC repeat. Hexanucleotide repeat expansions in C9orf72 were found in 37 patients with familial (28.7%) and five with sporadic frontotemporal dementia (2.2%). The mean age at onset was 56.9 ± 8.3 years (range 39-76), and disease duration 7.6 ± 4.6 years (range 1-22). The clinical phenotype of these patients varied between the behavioural variant of frontotemporal dementia (n = 34) and primary progressive aphasia (n = 8), with concomitant amyotrophic lateral sclerosis in seven patients. Predominant temporal atrophy on neuroimaging was present in 13 of 32 patients. Pathological examination of the 10 brains from patients carrying expanded repeats revealed frontotemporal lobar degeneration with neuronal transactive response DNA binding protein-positive inclusions of variable type, size and morphology in all brains. Fluorescence in situ hybridization analysis of brain material from patients with the repeat expansion, a microtubule-associated protein tau or a progranulin mutation, and controls did not show RNA-positive inclusions specific for brains with the GGGGCC repeat expansion. The hexanucleotide repeat expansion in C9orf72 is an important cause of frontotemporal dementia with and without amyotrophic lateral sclerosis, and is sometimes associated with primary progressive aphasia. Neuropathological hallmarks include neuronal and glial inclusions, and dystrophic neurites containing transactive response DNA binding protein. Future studies are needed to explain the wide variation in clinical presentation.
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http://dx.doi.org/10.1093/brain/awr353DOI Listing
March 2012