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ABSTRACT: Many children with chronic genetic diseases are followed by specialty clinics that provide genetic information as part of
the care. Health services restrictions in the Republic of Ireland (ROI) can make the wait for an appointment with a genetic
counsellor long. We examined whether genetic information was being adequately understood when presented by medical, but non-genetics
staff to long term patients, using our national metabolic service as an example. The aim was to inform health professionals
about the need or role of a genetic counsellor in a specialist setting. A questionnaire was used to assess knowledge among
parents and patients affected by galactosaemia and Maple Syrup Urine Disease (MSUD). Twenty seven families with galactosemia
and 10 with MSUD were interviewed in clinic. Comparative analysis showed significant differences in knowledge between parents
of children with galactosemia and adult patients (p = 0.001) and between ethnicities (p > 0.05). While parents are well informed, the majority expressed a wish for more information about the condition and its
transmission. Adult patients with galactosemia and parents from certain ethnic backgrounds could especially benefit from genetic
counselling. This study highlights the need for a genetic counsellor in specialist clinics.
KeywordsGalactosemia–Maple Syrup Urine Disease–Knowledge–Referral to genetic counselling
Journal of Genetic Counseling 04/2012; 20(2):192-203. · 1.77 Impact Factor
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Siddharth Banka,
Ratna Veeramachaneni,
William Reardon,
Emma Howard,
Sancha Bunstone,
Nicola Ragge,
Michael J Parker,
Yanick J Crow,
Bronwyn Kerr,
Helen Kingston, [......],
Deepthi C de Silva,
I Karen Temple,
Amanda L Collins,
Katherine Lachlan,
Frances Elmslie,
Meriel McEntagart,
Bruce Castle,
Jill Clayton-Smith,
Graeme C Black,
Dian Donnai
[show abstract]
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ABSTRACT: MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.
European journal of human genetics: EJHG 11/2011; 20(4):381-8. · 3.56 Impact Factor
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Jill Clayton-Smith,
James O'Sullivan,
Sarah Daly,
Sanjeev Bhaskar,
Ruth Day,
Beverley Anderson,
Anne K Voss,
Tim Thomas,
Leslie G Biesecker,
Philip Smith, [......],
May Tassabehji, Sally-Ann Lynch,
Malgorzata Krajewska-Walasek,
Shane McKee,
Janine Smith,
Elizabeth Sweeney,
Sahar Mansour,
Shehla Mohammed,
Dian Donnai,
Graeme Black
[show abstract]
[hide abstract]
ABSTRACT: Say-Barber-Biesecker-Young-Simpson syndrome (SBBYSS or Ohdo syndrome) is a multiple anomaly syndrome characterized by severe intellectual disability, blepharophimosis, and a mask-like facial appearance. A number of individuals with SBBYSS also have thyroid abnormalities and cleft palate. The condition usually occurs sporadically and is therefore presumed to be due in most cases to new dominant mutations. In individuals with SBBYSS, a whole-exome sequencing approach was used to demonstrate de novo protein-truncating mutations in the highly conserved histone acetyltransferase gene KAT6B (MYST4/MORF)) in three out of four individuals sequenced. Sanger sequencing was used to confirm truncating mutations of KAT6B, clustering in the final exon of the gene in all four individuals and in a further nine persons with typical SBBYSS. Where parental samples were available, the mutations were shown to have occurred de novo. During mammalian development KAT6B is upregulated specifically in the developing central nervous system, facial structures, and limb buds. The phenotypic features seen in the Qkf mouse, a hypomorphic Kat6b mutant, include small eyes, ventrally placed ears and long first digits that mirror the human phenotype. This is a further example of how perturbation of a protein involved in chromatin modification might give rise to a multisystem developmental disorder.
The American Journal of Human Genetics 11/2011; 89(5):675-81. · 10.60 Impact Factor
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María Palomares,
Alicia Delicado,
Elena Mansilla,
María Luisa de Torres,
Elena Vallespín,
Luis Fernandez,
Victor Martinez-Glez,
Sixto García-Miñaur,
Julián Nevado,
Fernando Santos Simarro, [......],
Elga F Belligni,
María Luisa Martínez-Fernández,
Eva Bermejo,
Beata Nowakowska,
Anna Kutkowska-Kazmierczak,
Ewa Bocian,
Ewa Obersztyn,
María Luisa Martínez-Frías,
Raoul C M Hennekam,
Pablo Lapunzina
[show abstract]
[hide abstract]
ABSTRACT: We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.
The American Journal of Human Genetics 08/2011; 89(2):295-301. · 10.60 Impact Factor
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Carine Le Goff,
Clémentine Mahaut,
Lauren W Wang,
Slimane Allali,
Avinash Abhyankar,
Sacha Jensen,
Louise Zylberberg,
Gwenaelle Collod-Beroud,
Damien Bonnet,
Yasemin Alanay, [......],
Sheila Unger,
Bernhard Zabel,
Christine Bole-Feysot,
Patrick Nitschke,
Penny Handford,
Jean-Laurent Casanova,
Catherine Boileau,
Suneel S Apte,
Arnold Munnich,
Valérie Cormier-Daire
[show abstract]
[hide abstract]
ABSTRACT: Geleophysic (GD) and acromicric dysplasia (AD) belong to the acromelic dysplasia group and are both characterized by severe short stature, short extremities, and stiff joints. Although AD has an unknown molecular basis, we have previously identified ADAMTSL2 mutations in a subset of GD patients. After exome sequencing in GD and AD cases, we selected fibrillin 1 (FBN1) as a candidate gene, even though mutations in this gene have been described in Marfan syndrome, which is characterized by tall stature and arachnodactyly. We identified 16 heterozygous FBN1 mutations that are all located in exons 41 and 42 and encode TGFβ-binding protein-like domain 5 (TB5) of FBN1 in 29 GD and AD cases. Microfibrillar network disorganization and enhanced TGFβ signaling were consistent features in GD and AD fibroblasts. Importantly, a direct interaction between ADAMTSL2 and FBN1 was demonstrated, suggesting a disruption of this interaction as the underlying mechanism of GD and AD phenotypes. Although enhanced TGFβ signaling caused by FBN1 mutations can trigger either Marfan syndrome or GD and AD, our findings support the fact that TB5 mutations in FBN1 are responsible for short stature phenotypes.
The American Journal of Human Genetics 06/2011; 89(1):7-14. · 10.60 Impact Factor
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Clinical dysmorphology 01/2011; 20(1):21-5. · 0.47 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Many children with chronic genetic diseases are followed by specialty clinics that provide genetic information as part of the care. Health services restrictions in the Republic of Ireland (ROI) can make the wait for an appointment with a genetic counsellor long. We examined whether genetic information was being adequately understood when presented by medical, but non-genetics staff to long term patients, using our national metabolic service as an example. The aim was to inform health professionals about the need or role of a genetic counsellor in a specialist setting. A questionnaire was used to assess knowledge among parents and patients affected by galactosaemia and Maple Syrup Urine Disease (MSUD). Twenty seven families with galactosemia and 10 with MSUD were interviewed in clinic. Comparative analysis showed significant differences in knowledge between parents of children with galactosemia and adult patients (p=0.001) and between ethnicities (p>0.05). While parents are well informed, the majority expressed a wish for more information about the condition and its transmission. Adult patients with galactosemia and parents from certain ethnic backgrounds could especially benefit from genetic counselling. This study highlights the need for a genetic counsellor in specialist clinics.
Journal of Genetic Counseling 01/2011; 20(2):192-203. · 1.77 Impact Factor
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Sally Ann Lynch,
Nicola Foulds,
Ann-Charlotte Thuresson,
Amanda L Collins,
Göran Annerén,
Bernt-Oves Hedberg,
Carol A Delaney,
James Iremonger,
Caroline M Murray,
John A Crolla,
Colm Costigan,
Wayne Lam,
David R Fitzpatrick,
Regina Regan,
Sean Ennis,
Freddie Sharkey
[show abstract]
[hide abstract]
ABSTRACT: We report six patients with array deletions encompassing 12q14. Out of a total of 2538 array investigations carried out on children with developmental delay and dysmorphism in three diagnostic testing centres, six positive cases yielded a frequency of 1 in 423 for this deletion syndrome. The deleted region in each of the six cases overlaps significantly with previously reported cases with microdeletions of this region. The chromosomal range of the deletions extends from 12q13.3q15. In the current study, we report overlapping deletions of variable extent and size but primarily comprising chromosomal bands 12q13.3q14.1. Four of the six deletions were confirmed as de novo events. Two cases had deletions that included HMGA2, and both children had significant short stature. Neither case had osteopoikilosis despite both being deleted for LEMD3. Four cases had deletions that ended proximal to HMGA2 and all of these had much better growth. Five cases had congenital heart defects, including two with atrial septal defects, one each with pulmonary stenosis, sub-aortic stenosis and a patent ductus. Four cases had moderate delay, two had severe developmental delay and a further two had a diagnosis of autism. All six cases had significant speech delay with subtle facial dysmorphism.
European journal of human genetics: EJHG 01/2011; 19(5):534-9. · 3.56 Impact Factor
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Jennifer J. Johnston,
Julie C. Sapp,
Joyce T. Turner,
David Amor,
Salim Aftimos,
Kyrieckos A. Aleck,
Maureen Bocian,
Joann N. Bodurtha,
Gerald F. Cox,
Cynthia J. Curry, [......],
Susan Tomkins,
Pamela Trapane,
Anne Chun-Hui Tsai,
Margot I. Van Allen,
Pradeep C. Vasudevan,
Bernhard Zabel,
Janice Zunich,
Graeme C.M. Black,
Leslie G. Biesecker,
John M. Graham
[show abstract]
[hide abstract]
ABSTRACT: A range of phenotypes including Greig cephalopolysyndactyly and Pallister-Hall syndromes (GCPS, PHS) are caused by pathogenic mutation of the GLI3 gene. To characterize the clinical variability of GLI3 mutations, we present a subset of a cohort of 174 probands referred for GLI3 analysis. Eighty-one probands with typical GCPS or PHS were previously reported, and we report the remaining 93 probands here. This includes 19 probands (12 mutations) who fulfilled clinical criteria for GCPS or PHS, 48 probands (16 mutations) with features of GCPS or PHS but who did not meet the clinical criteria (sub-GCPS and sub-PHS), 21 probands (6 mutations) with features of PHS or GCPS and oral-facial-digital syndrome, and 5 probands (1 mutation) with nonsyndromic polydactyly. These data support previously identified genotype–phenotype correlations and demonstrate a more variable degree of severity than previously recognized. The finding of GLI3 mutations in patients with features of oral–facial–digital syndrome supports the observation that GLI3 interacts with cilia. We conclude that the phenotypic spectrum of GLI3 mutations is broader than that encompassed by the clinical diagnostic criteria, but the genotype–phenotype correlation persists. Individuals with features of either GCPS or PHS should be screened for mutations in GLI3 even if they do not fulfill clinical criteria. Hum Mutat 31:1142–1154, 2010. © 2010 Wiley-Liss, Inc.
Human Mutation 09/2010; 31(10):1142 - 1154. · 5.69 Impact Factor
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Roberto Giorda,
M Clara Bonaglia,
Silvana Beri,
Marco Fichera,
Francesca Novara,
Pamela Magini,
Jill Urquhart,
Freddie H Sharkey,
Claudio Zucca,
Rita Grasso, [......],
Elena Fontana, Sally Ann Lynch,
Jill Clayton-Smith,
Graeme Black,
Philippe Jonveaux,
Bruno Leheup,
Marco Seri,
Corrado Romano,
Bernardo dalla Bernardina,
Orsetta Zuffardi
[show abstract]
[hide abstract]
ABSTRACT: Submicroscopic copy-number variations make a considerable contribution to the genetic etiology of human disease. We have analyzed subjects with idiopathic mental retardation (MR) by using whole-genome oligonucleotide-based array comparative genomic hybridization (aCGH) and identified familial and de novo recurrent Xp11.22-p11.23 duplications in males and females with MR, speech delay, and a peculiar electroencephalographic (EEG) pattern in childhood. The size of the duplications ranges from 0.8-9.2 Mb. Most affected females show preferential activation of the duplicated X chromosome. Carriers of the smallest duplication show X-linked recessive inheritance. All other affected individuals present dominant expression and comparable clinical phenotypes irrespective of sex, duplication size, and X-inactivation pattern. The majority of the rearrangements are mediated by recombination between flanking complex segmental duplications. The identification of common clinical features, including the typical EEG pattern, predisposing genomic structure, and peculiar X-inactivation pattern, suggests that duplication of Xp11.22-p11.23 constitutes a previously undescribed syndrome.
The American Journal of Human Genetics 10/2009; 85(3):394-400. · 10.60 Impact Factor
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ABSTRACT: Rubinstein-Taybi syndrome (RSTS) is a heterogeneous disorder with approximately 45-55% of patients showing mutations in the CREB binding protein and a further 3% of patients having mutations in EP300. We report a male child with a deletion of exons 3-8 of the EP300 gene who has RSTS. He has a milder skeletal phenotype, a finding that has been described in other cases with EP300 mutations. The mother suffered from pre-eclampsia and HELLP syndrome in the pregnancy. She subsequently developed a mullerian tumor of her cervix 6 years after the birth of her son.
American Journal of Medical Genetics Part A 05/2009; 149A(5):997-1000. · 2.39 Impact Factor
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ABSTRACT: Langer-Giedion syndrome results from a microdeletion at 8q24.1 encompassing the EXT1 and the adjacent TRPS1 gene. We report on a boy with an oligo array-cgh characterized small microdeletion involving EXT1 alone but with some features of Langer-Giedion syndrome suggesting a functional disturbance of TRPS1. This boy, in addition to a mild Langer-Giedion like phenotype, also had some unusual features including prominent toe pads and fat pads on the soles of his feet similar to those described in Pierpont syndrome.
American Journal of Medical Genetics Part A 07/2008; 146A(12):1587-92. · 2.39 Impact Factor
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ABSTRACT: Mucopolysaccharidosis type 1 (MPS1) is an autosomal recessive disorder with severe, moderate and mild phenotypes: Hurler, Hurler-Scheie and Scheie syndromes. We estimated incidence (2001-2006) and prevalence (2002 census) of MPS1 in the Irish Republic (ROI) using population data, database and chart review of all live MPS1 patients attending two specialised centres. Patient genotypes, ethnicity, province of origin, age at diagnosis and presenting features were recorded. Thirty-one patients (14 females, 17 males) were alive, 27 of whom were <15 years. Twenty-six patients had Hurler syndrome, four had Hurler-Scheie and one had Scheie syndrome. The birth incidence was 1 in 26 206 births with a carrier frequency of 1 in 81. Of note, 19/26 (73%) Hurler patients were Irish Travellers. Amongst Irish Travellers the incidence was 1 in 371 with a carrier frequency of 1 in 10. This is the highest recorded incidence worldwide. Given the morbidity and mortality associated with delayed treatment we recommend targeted newborn screening for this population.
Archives of Disease in Childhood 05/2008; 94(1):52-4. · 2.88 Impact Factor
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John C K Barber,
Viv K Maloney,
Shuwen Huang,
David J Bunyan,
Lara Cresswell,
Esther Kinning,
Anna Benson,
Tim Cheetham,
Jonathan Wyllie, Sally Ann Lynch,
Simon Zwolinski,
Laura Prescott,
Yanick Crow,
Rob Morgan,
Emma Hobson
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[hide abstract]
ABSTRACT: The 8p23.1 deletion syndrome is established but not an equivalent duplication syndrome. Here, we report five patients; a de novo prenatal case and two families in which 8p23.1 duplications have been directly transmitted from mothers to children. Dual-colour fluorescent in situ hybridisation, multiplex ligation-dependent probe amplification analysis and customised oligonucleotide array comparative genomic hybridisation (oaCGH) indicated an approximately 3.75 Mb duplication of most of band 8p23.1 between the olfactory receptor/defensin repeats (ORDRs) in all cases. However, oaCGH revealed an additional duplication of 500 kb adjacent to the proximal ORDR in Family 1 and an additional deletion of 3.14 Mb within the Nablus Mask-Like Facial Syndrome region of 8q22.1 in Family 2. Copy number variation at introns 4-5 of the GATA4 gene was also identified. This 8p23.1 duplication syndrome is associated with a characteristic facial phenotype including a prominent forehead and arched eyebrows. Adrenal insufficiency, Tetralogy of Fallot, partial 2/3 syndactyly of the toes and cleft palate in some individuals may be explained by ascertainment bias, incomplete penetrance and/or the presence of the microdeletion in Family 2. The duplication is compatible with normal early childhood development but, although our adult cases live independent lives with varying degrees of support, learning difficulties have been experienced by some family members. We conclude that the 8p23.1 duplication syndrome is a genomic condition with an emerging but variable phenotype that may be under-diagnosed. Our results demonstrate that direct transmission does not distinguish genuine duplications from euchromatic variants and illustrate the power of array CGH to reveal unexpected additional imbalances in affected patients.
European Journal of HumanGenetics 02/2008; 16(1):18-27. · 4.40 Impact Factor
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Clinical Dysmorphology 11/2007; 16(4):257-9. · 0.54 Impact Factor
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ABSTRACT: A girl with aniridia, microphthalmia, microcephaly and café au lait macules was found to have mutations in PAX6, NF1 and OTX2. A novel PAX6 missense mutation (p.R38W) was inherited from her mother whose iris phenotype had not been evident because of ocular neurofibromatosis. Analysis of the NF1 gene in the proband, prompted by the mother's diagnosis and the presence of café au lait spots, revealed a nonsense mutation (p.R192X). Subsequently an OTX2 nonsense mutation (p.Y179X) was identified and shown to be inherited from her father who was initially diagnosed with Leber's congenital amaurosis. Since individual mutations in PAX6, OTX2 or NF1 can cause a variety of severe developmental defects, the proband's phenotype is surprisingly mild. This case shows that patients with complex phenotypes should not be eliminated from subsequent mutation analysis after one or even two mutations are found.
European Journal of HumanGenetics 09/2007; 15(8):898-901. · 4.40 Impact Factor
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Clinical Dysmorphology 11/2006; 15(4):253-4. · 0.54 Impact Factor
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Clinical Dysmorphology 08/2006; 15(3):149-51. · 0.54 Impact Factor
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Yanick J Crow,
Bruce E Hayward,
Rekha Parmar,
Peter Robins,
Andrea Leitch,
Manir Ali,
Deborah N Black,
Hans van Bokhoven,
Han G Brunner,
Ben C Hamel, [......],
Roger F Massey,
Jean François Meritet,
Jacques L Michaud,
Gerard Ponsot,
Thomas Voit,
Pierre Lebon,
David T Bonthron,
Andrew P Jackson,
Deborah E Barnes,
Tomas Lindahl
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[hide abstract]
ABSTRACT: Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
Nature Genetics 08/2006; 38(8):917-20. · 35.53 Impact Factor
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Yanick J Crow,
Bruce E Hayward,
Rekha Parmar,
Peter Robins,
Andrea Leitch,
Manir Ali,
Deborah N Black,
Hans van Bokhoven,
Han G Brunner,
Ben C Hamel, [......],
Roger F Massey,
Jean Fran|[ccedil]|ois Meritet,
Jacques L Michaud,
Gerard Ponsot,
Thomas Voit,
Pierre Lebon,
David T Bonthron,
Andrew P Jackson,
Deborah E Barnes,
Tomas Lindahl
[show abstract]
[hide abstract]
ABSTRACT: Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection1,
2. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype3. Here, we show that TREX1, encoding the major mammalian 3' 5' DNA exonuclease4, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1
-/- mouse leads to an inflammatory phenotype5. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.
Nature Genetics. 07/2006; 38(8):917-920.
