Dr Anna Hackett

Conjoint Senior Lecturer

School of Biomedical Sciences and Pharmacy (Medical Genetics)

Career Summary

Biography

Research Expertise
X linked intellectual disability

Keywords

  • Clinical Sciences and Genetics
  • Intellectual Disability
  • Paediatrics and Reproduction
  • X Chromosome

Fields of Research

Code Description Percentage
060499 Genetics not elsewhere classified 35
110399 Clinical Sciences not elsewhere classified 30
060199 Biochemistry and Cell Biology not elsewhere classified 35
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Publications

For publications that are currently unpublished or in-press, details are shown in italics.


Journal article (37 outputs)

Year Citation Altmetrics Link
2017 Hocking DR, Birch RC, Bui QM, Menant JC, Lord SR, Georgiou-Karistianis N, et al., 'Cerebellar volume mediates the relationship between FMR1 mRNA levels and voluntary step initiation in males with the premutation', Neurobiology of Aging, 50 5-12 (2017) [C1]

© 2016 Elsevier Inc. Recent evidence indicates that adults with a premutation (PM: 55¿199 CGG repeats) expansion in the fragile X mental retardation 1 (FMR1) gene show postural ... [more]

© 2016 Elsevier Inc. Recent evidence indicates that adults with a premutation (PM: 55¿199 CGG repeats) expansion in the fragile X mental retardation 1 (FMR1) gene show postural control deficits that may reflect disruption to cerebellar motor regions. Less is known about the influence of reduced cerebellar volume and structural changes, and increase in CGG repeat and FMR1 mRNA levels on the attentional demands of step initiation in PM males. We investigated the effects of a concurrent cognitive task on choice stepping reaction time (CSRT) and explored the associations between CSRT performance, cerebellar volume, CGG size, and FMR1 mRNA levels in blood in PM males. We examined 19 PM males (ages 28¿75) and 23 matched controls (CGG < 44; ages 26¿77), who performed a verbal fluency task during CSRT performance and single-task stepping without a secondary cognitive task. Our results provide preliminary evidence that smaller cerebellar volume (ß = -2.73, p = 0.002) and increasing CGG repeat length (ß = 1.69, p = 0.003) were associated with greater dual-task step initiation times in PM males, but not in controls. There was evidence of a mediating effect of cerebellar volume on the relationship between FMR1 mRNA levels and single-task CSRT performance in PM males (estimate coefficient = 8.69, standard error = 4.42, p = 0.049). These findings suggest increasing CGG repeat and FMR1 mRNA levels have neurotoxic effects on cerebellar regions underlying anticipatory postural responses during stepping. Cerebellar postural changes may be predictive of the increased risk of falls in older PM males.

DOI 10.1016/j.neurobiolaging.2016.10.017
Co-authors A Hackett
2017 Donnio LM, Bidon B, Hashimoto S, May M, Epanchintsev A, Ryan C, et al., 'MED12-related XLID disorders are dose-dependent of immediate early genes (IEGs) expression', Human Molecular Genetics, 26 2062-2075 (2017)

© The Author 2017. Published by Oxford University Press. All rights reserved. Mediator occupies a key role in protein coding genes expression in mediating the contacts between ge... [more]

© The Author 2017. Published by Oxford University Press. All rights reserved. Mediator occupies a key role in protein coding genes expression in mediating the contacts between gene specific factors and the basal transcription machinery but little is known regarding the role of each Mediator subunits. Mutations in MED12 are linked with a broad spectrum of genetic disorders with X-linked intellectual disability that are difficult to range as Lujan, Opitz-Kaveggia or Ohdo syndromes. Here, we investigated several MED12 patients mutations (p. R206Q, p. N898D, p. R961W, p. N1007S, p. R1148H, p. S1165P and p. R1295H) and show that each MED12 mutations cause specific expression patterns of JUN, FOS and EGR1 immediate early genes (IEGs), reflected by the presence or absence of MED12 containing complex at their respective promoters. Moreover, the effect of MED12 mutations has cell-type specificity on IEG expression. As a consequence, the expression of late responsive genes such as the matrix metalloproteinase-3 and the RE1 silencing transcription factor implicated respectively in neural plasticity and the specific expression of neuronal genes is disturbed as documented for MED12/p. R1295H mutation. In such case, JUN and FOS failed to be properly recruited at their AP1-binding site. Our results suggest that the differences between MED12-related phenotypes are essentially the result of distinct IEGs expression patterns, the later ones depending on the accurate formation of the transcription initiation complex. This might challenge clinicia ns to rethink the traditional syndromes boundaries and to include genetic criterion in patients' diagnostic.

DOI 10.1093/hmg/ddx099
Co-authors A Hackett
2016 Kumar R, Ha T, Pham D, Shaw M, Mangelsdorf M, Friend KL, et al., 'A non-coding variant in the 5? UTR of DLG3 attenuates protein translation to cause non-syndromic intellectual disability', European Journal of Human Genetics, 24 1612-1616 (2016)

© 2016 Macmillan Publishers Limited, part of Springer Nature. Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may... [more]

© 2016 Macmillan Publishers Limited, part of Springer Nature. Intellectual disability (ID) is a clinically complex and heterogeneous disorder, which has variable severity and may be associated with additional dysmorphic, metabolic, neuromuscular or psychiatric features. Although many coding variants have been implicated in ID, identification of pathogenic non-coding regulatory variants has only been achieved in a few cases to date. We identified a duplication of a guanine on chromosome X, NC-000023.10:g.69665044dupG 7 nucleotides upstream of the translational start site in the 5? untranslated region (UTR) of the known ID gene DLG3 that encodes synapse-associated protein 102 (SAP102). The dupG variant segregated with affected status in a large multigenerational family with non-syndromic X-linked ID and was predicted to disrupt folding of the mRNA. When tested on blood cells from the affected individuals, DLG3 mRNA levels were not altered, however, DLG3/SAP102 protein levels were. We also showed by dual luciferase reporter assay that the dupG variant interfered with translation. All currently known pathogenic DLG3 variants are predicted to be null, however the dupG variant likely leads to only a modest reduction of SAP102 levels accounting for the milder phenotype seen in this family.

DOI 10.1038/ejhg.2016.46
Citations Scopus - 1
Co-authors A Hackett
2016 Hu H, Haas SA, Chelly J, Van Esch H, Raynaud M, de Brouwer APM, et al., 'X-exome sequencing of 405 unresolved families identifies seven novel intellectual disability genes', MOLECULAR PSYCHIATRY, 21 133-148 (2016)
DOI 10.1038/mp.2014.193
Citations Scopus - 40Web of Science - 41
Co-authors A Hackett
2015 Corbett MA, Dudding-Byth T, Crock PA, Botta E, Christie LM, Nardo T, et al., 'A novel X-linked trichothiodystrophy associated with a nonsense mutation in RNF113A', Journal of Medical Genetics, 52 269-274 (2015) [C1]

Background: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnost... [more]

Background: Trichothiodystrophy (TTD) is a group of rare autosomal recessive disorders that variably affect a wide range of organs derived from the neuroectoderm. The key diagnostic feature is sparse, brittle, sulfur deficient hair that has a 'tiger-tail' banding pattern under polarising light microscopy. Patients and methods: We describe two male cousins affected by TTD associated with microcephaly, profound intellectual disability, sparse brittle hair, aged appearance, short stature, facial dysmorphism, seizures, an immunoglobulin deficiency, multiple endocrine abnormalities, cerebellar hypoplasia and partial absence of the corpus callosum, in the absence of cellular photosensitivity and ichthyosis. Obligate female carriers showed 100% skewed X-chromosome inactivation. Linkage analysis and Sanger sequencing of 737 X-chromosome exons and whole exome sequencing was used to find the responsible gene and mutation. Results: Linkage analysis localised the disease allele to a 7.75 Mb interval from Xq23-q25. We identified a nonsense mutation in the highly conserved RNF113A gene (c.901 C > T, p.Q301*). The mutation segregated with the disease in the family and was not observed in over 100 000 control X chromosomes. The mutation markedly reduced RNF113A protein expression in extracts from lymphoblastoid cell lines derived from the affected individuals. Conclusions: The association of RNF113A mutation with non-photosensitive TTD identifies a new locus for these disorders on the X chromosome. The extended phenotype within this family includes panhypopituitarism, cutis marmorata and congenital short oesophagus.

DOI 10.1136/jmedgenet-2014-102418
Citations Scopus - 7Web of Science - 6
Co-authors T Dudding, A Hackett
2015 Ishibashi M, Manning E, Shoubridge C, Krecsmarik M, Hawkins TA, Giacomotto J, et al., 'Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene', Human Genetics, 134 1163-1182 (2015)

© 2015, Springer-Verlag Berlin Heidelberg. Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy... [more]

© 2015, Springer-Verlag Berlin Heidelberg. Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.

DOI 10.1007/s00439-015-1594-x
Citations Scopus - 3
Co-authors A Hackett
2015 Ramos-brossier M, Montani C, Lebrun N, Gritti L, Martin C, Seminatore-nole C, et al., 'Novel IL1RAPL1 mutations associated with intellectual disability impair synaptogenesis', Human Molecular Genetics, 24 1106-1118 (2015)

© The Author 2014. Published by Oxford University Press. All rights reserved. Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated wi... [more]

© The Author 2014. Published by Oxford University Press. All rights reserved. Mutations in interleukin-1 receptor accessory protein like 1 (IL1RAPL1) gene have been associated with non-syndromic intellectual disability (ID) and autism spectrum disorder. This protein interacts with synaptic partners like PSD-95 and PTPd, regulating the formation and function of excitatory synapses. The aim of this work was to characterize the synaptic consequences of three IL1RAPL1 mutations, two novel causing the deletion of exon 6 (¿ex6) and one point mutation (C31R), identified in patients with ID. Using immunofluorescence and electrophysiological recordings, we examined the effects of IL1RAPL1 mutant over-expression on synapse formation and function in cultured rodent hippocampal neurons. ¿ex6 but not C31R mutation leads to IL1RAPL1 protein instability and mislocalization within dendrites. Analysis of different markers of excitatory synapses and sEPSC recording revealed that both mutants fail to induce pre- and post-synaptic differentiation, contrary to WT IL1RAPL1 protein. Cell aggregation and immunoprecipitation assays in HEK293 cells showed a reduction of the interaction between IL1RAPL1 mutants and PTPd that could explain the observed synaptogenic defect in neurons. However, these mutants do not affect all cellular signaling because their over-expression still activates JNK pathway. We conclude that both mutations described in this study lead to a partial loss of function of the IL1RAPL1 protein through different mechanisms. Our work highlights the important function of the trans-synaptic PTPd/IL1RAPL1 interaction in synaptogenesis and as such in ID in the patients.

DOI 10.1093/hmg/ddu523
Citations Scopus - 6
Co-authors A Hackett
2015 Grozeva D, Carss K, Spasic-Boskovic O, Tejada MI, Gecz J, Shaw M, et al., 'Targeted Next-Generation Sequencing Analysis of 1,000 Individuals with Intellectual Disability', Human Mutation, 36 1197-1204 (2015)

© 2015 Wiley Periodicals, Inc. To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 ... [more]

© 2015 Wiley Periodicals, Inc. To identify genetic causes of intellectual disability (ID), we screened a cohort of 986 individuals with moderate to severe ID for variants in 565 known or candidate ID-associated genes using targeted next-generation sequencing. Likely pathogenic rare variants were found in ~11% of the cases (113 variants in 107/986 individuals: ~8% of the individuals had a likely pathogenic loss-of-function [LoF] variant, whereas ~3% had a known pathogenic missense variant). Variants in SETD5, ATRX, CUL4B, MECP2, and ARID1B were the most common causes of ID. This study assessed the value of sequencing a cohort of probands to provide a molecular diagnosis of ID, without the availability of DNA from both parents for de novo sequence analysis. This modeling is clinically relevant as 28% of all UK families with dependent children are single parent households. In conclusion, to diagnose patients with ID in the absence of parental DNA, we recommend investigation of all LoF variants in known genes that cause ID and assessment of a limited list of proven pathogenic missense variants in these genes. This will provide 11% additional diagnostic yield beyond the 10%-15% yield from array CGH alone.

DOI 10.1002/humu.22901
Citations Scopus - 29
Co-authors A Hackett
2015 Chatron N, Haddad V, Andrieux J, Désir J, Boute O, Dieux A, et al., 'Refinement of genotype-phenotype correlation in 18 patients carrying a 1q24q25 deletion', American Journal of Medical Genetics, Part A, 167 1008-1017 (2015)

© 2015 Wiley Periodicals, Inc. Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial ... [more]

© 2015 Wiley Periodicals, Inc. Interstitial deletion 1q24q25 is a rare rearrangement associated with intellectual disability, growth retardation, abnormal extremities and facial dysmorphism. In this study, we describe the largest series reported to date, including 18 patients (4M/14F) aged from 2 days to 67 years and comprising two familial cases. The patients presented with a characteristic phenotype including mild to moderate intellectual disability (100%), intrauterine (92%) and postnatal (94%) growth retardation, microcephaly (77%), short hands and feet (83%), brachydactyly (70%), fifth finger clinodactyly (78%) and facial dysmorphism with a bulbous nose (72%), abnormal ears (67%) and micrognathia (56%). Other findings were abnormal palate (50%), single transverse palmar crease (53%), renal (38%), cardiac (38%), and genital (23%) malformations. The deletions were characterized by chromosome microarray. They were of different sizes (490 kb to 20.95 Mb) localized within chromosome bands 1q23.3-q31.2 (chr1:160797550-192912120, hg19). The 490 kb deletion is the smallest deletion reported to date associated with this phenotype. We delineated three regions that may contribute to the phenotype: a proximal one (chr1:164,501,003-167,022,133), associated with cardiac and renal anomalies, a distal one (chr1:178,514,910-181,269,712) and an intermediate 490 kb region (chr1:171970575-172460683, hg19), deleted in the most of the patients, and containing DNM3, MIR3120 and MIR214 that may play an important role in the phenotype. However, this genetic region seems complex with multiple regions giving rise to the same phenotype.

DOI 10.1002/ajmg.a.36856
Citations Scopus - 5
Co-authors A Hackett
2015 Birch RC, Hocking DR, Cornish KM, Menant JC, Georgiou-Karistianis N, Godler DE, et al., 'Preliminary evidence of an effect of cerebellar volume on postural sway in FMR1 premutation males', Genes, Brain and Behavior, 14 251-259 (2015)

© 2015 John Wiley &amp; Sons Ltd and International Behavioural and Neural Genetics Society. Recent evidence suggests that early changes in postural control may be discernible a... [more]

© 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society. Recent evidence suggests that early changes in postural control may be discernible among females with premutation expansions (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene at risk of developing fragile X-associated tremor ataxia syndrome (FXTAS). Cerebellar dysfunction is well described in males and females with FXTAS, yet the interrelationships between cerebellar volume, CGG repeat length, FMR1 messenger RNA (mRNA) levels and changes in postural control remain unknown. This study examined postural sway during standing in a cohort of 22 males with the FMR1 premutation (ages 26-80) and 24 matched controls (ages 26-77). The influence of cerebellar volume, CGG repeat length and FMR1 mRNA levels on postural sway was explored using multiple linear regression. The results provide preliminary evidence that increasing CGG repeat length and decreasing cerebellar volume were associated with greater postural sway among premutation males. The relationship between CGG repeat length and postural sway was mediated by a negative association between CGG repeat size and cerebellar volume. While FMR1 mRNA levels were significantly elevated in the premutation group and correlated with CGG repeat length, FMR1 mRNA levels were not significantly associated with postural sway scores. These findings show for the first time that greater postural sway among males with the FMR1 premutation may reflect CGG repeat-mediated disruption in vulnerable cerebellar circuits implicated in postural control. However, longitudinal studies in larger samples are required to confirm whether the relationships between cerebellar volume, CGG repeat length and postural sway indicate greater risk for neurological decline. Cerebellar volume as a mediator of the effect of CGG repeat length on postural sway in FMR1 premutation males.

DOI 10.1111/gbb.12204
Citations Scopus - 7
Co-authors A Hackett
2015 Shaw M, Yap TY, Henden L, Bahlo M, Gardner A, Kalscheuer VM, et al., 'Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome', EUROPEAN JOURNAL OF MEDICAL GENETICS, 58 364-368 (2015)
DOI 10.1016/j.ejmg.2015.04.004
Citations Scopus - 4Web of Science - 4
Co-authors A Hackett
2015 Kumar R, Corbett MA, van Bon BWM, Woenig JA, Weir L, Douglas E, et al., 'THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability', AMERICAN JOURNAL OF HUMAN GENETICS, 97 302-310 (2015)
DOI 10.1016/j.ajhg.2015.05.021
Citations Scopus - 6Web of Science - 5
Co-authors A Hackett
2014 Grozeva D, Carss K, Spasic-Boskovic O, Parker MJ, Archer H, Firth HV, et al., 'De novo loss-of-function mutations in SETD5, encoding a methyltransferase in a 3p25 microdeletion syndrome critical region, cause intellectual disability', American Journal of Human Genetics, 94 618-624 (2014)

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targe... [more]

To identify further Mendelian causes of intellectual disability (ID), we screened a cohort of 996 individuals with ID for variants in 565 known or candidate genes by using a targeted next-generation sequencing approach. Seven loss-of-function (LoF) mutations - four nonsense (c.1195A > T [p.Lys399 & z.ast;], c.1333C > T [p.Arg445 & z.ast;], c.1866C > G [p.Tyr622 & z.ast;], and c.3001C > T [p.Arg1001 & z.ast;]) and three frameshift (c.2177-2178del [p.Thr726Asnfs & z.ast;39], c.3771dup [p.Ser1258Glufs & z.ast;65], and c.3856del [p.Ser1286Leufs & z.ast;84]) - were identified in SETD5, a gene predicted to encode a methyltransferase. All mutations were compatible with de novo dominant inheritance. The affected individuals had moderate to severe ID with additional variable features of brachycephaly; a prominent high forehead with synophrys or striking full and broad eyebrows; a long, thin, and tubular nose; long, narrow upslanting palpebral fissures; and large, fleshy low-set ears. Skeletal anomalies, including significant leg-length discrepancy, were a frequent finding in two individuals. Congenital heart defects, inguinal hernia, or hypospadias were also reported. Behavioral problems, including obsessive-compulsive disorder, hand flapping with ritualized behavior, and autism, were prominent features. SETD5 lies within the critical interval for 3p25 microdeletion syndrome. The individuals with SETD5 mutations showed phenotypic similarity to those previously reported with a deletion in 3p25, and thus loss of SETD5 might be sufficient to account for many of the clinical features observed in this condition. Our findings add to the growing evidence that mutations in genes encoding methyltransferases regulating histone modification are important causes of ID. This analysis provides sufficient evidence that rare de novo LoF mutations in SETD5 are a relatively frequent (0.7%) cause of ID. © 2014 The American Society of Human Genetics.

DOI 10.1016/j.ajhg.2014.03.006
Citations Scopus - 30
Co-authors A Hackett
2013 Ellaway CJ, Ho G, Bettella E, Knapman A, Collins F, Hackett A, et al., '14q12 microdeletions excluding FOXG1 give rise to a congenital variant Rett syndrome-like phenotype', European Journal of Human Genetics, 21 522-527 (2013)

Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP... [more]

Rett syndrome is a clinically defined neurodevelopmental disorder almost exclusively affecting females. Usually sporadic, Rett syndrome is caused by mutations in the X-linked MECP2 gene in B90-95% of classic cases and 40-60% of individuals with atypical Rett syndrome. Mutations in the CDKL5 gene have been associated with the early-onset seizure variant of Rett syndrome and mutations in FOXG1 have been associated with the congenital Rett syndrome variant. We report the clinical features and array CGH findings of three atypical Rett syndrome patients who had severe intellectual impairment, early-onset developmental delay, postnatal microcephaly and hypotonia. In addition, the females had a seizure disorder, agenesis of the corpus callosum and subtle dysmorphism. All three were found to have an interstitial deletion of 14q12. The deleted region in common included the PRKD1 gene but not the FOXG1 gene. Gene expression analysis suggested a decrease in FOXG1 levels in two of the patients. Screening of 32 atypical Rett syndrome patients did not identify any pathogenic mutations in the PRKD1 gene, although a previously reported frameshift mutation affecting FOXG1 (c.256dupC, p.Gln86ProfsX35) was identified in a patient with the congenital Rett syndrome variant. There is phenotypic overlap between congenital Rett syndrome variants with FOXG1 mutations and the clinical presentation of our three patients with this 14q12 microdeletion, not encompassing the FOXG1 gene. We propose that the primary defect in these patients is misregulation of the FOXG1 gene rather than a primary abnormality of PRKD1. © 2013 Macmillan Publishers Limited All rights reserved.

DOI 10.1038/ejhg.2012.208
Citations Scopus - 14
Co-authors A Hackett
2013 Roscioli T, Elakis G, Cox TC, Moon DJ, Venselaar H, Turner AM, et al., 'Genotype and clinical care correlations in craniosynostosis: Findings from a cohort of 630 australian and new zealand patients', American Journal of Medical Genetics, Part C: Seminars in Medical Genetics, 163 259-270 (2013)

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndro... [more]

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis. © 2013 Wiley Periodicals, Inc.

DOI 10.1002/ajmg.c.31378
Citations Scopus - 16
Co-authors A Hackett
2012 Voineagu I, Huang L, Winden K, Lazaro M, Haan E, Nelson J, et al., 'CCDC22: A novel candidate gene for syndromic X-linked intellectual disability', Molecular Psychiatry, 17 4-7 (2012) [C1]
Citations Scopus - 19
Co-authors A Hackett
2012 Huang L, Jolly LA, Willis-Owen S, Gardner A, Kumar R, Douglas E, et al., 'A Noncoding, Regulatory Mutation Implicates HCFC1 in Nonsyndromic Intellectual Disability', AMERICAN JOURNAL OF HUMAN GENETICS, 91 694-702 (2012)
DOI 10.1016/j.ajhg.2012.08.011
Citations Scopus - 30Web of Science - 31
Co-authors A Hackett
2012 Shoubridge C, Gardner A, Schwartz CE, Hackett A, Field M, Gecz J, 'Is there a Mendelian transmission ratio distortion of the c.429_452dup(24bp) polyalanine tract ARX mutation?', EUROPEAN JOURNAL OF HUMAN GENETICS, 20 1311-1314 (2012)
DOI 10.1038/ejhg.2012.61
Citations Scopus - 4Web of Science - 3
Co-authors A Hackett
2012 Rujirabanjerd S, Nelson J, Tarpey PS, Hackett A, Edkins S, Raymond FL, et al., 'Erratum: Identification and characterization of two novel JARID1C mutations: Suggestion of an emerging genotype-phenotype correlation (European Journal of Human Genetics (2010) 18 (330-335) DOI: 10.1038/ejhg.2009.175)', European Journal of Human Genetics, 20 1010 (2012)
DOI 10.1038/ejhg.2012.114
Co-authors A Hackett
2012 Nguyen LS, Jolly L, Shoubridge C, Chan WK, Huang L, Laumonnier F, et al., 'Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability', MOLECULAR PSYCHIATRY, 17 1103-1115 (2012)
DOI 10.1038/mp.2011.163
Citations Scopus - 35Web of Science - 32
Co-authors A Hackett
2011 Jensen LR, Chen W, Moser B, Lipkowitz B, Schroeder C, Musante L, et al., 'Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1', European Journal of Human Genetics, 19 717-720 (2011) [C1]
Citations Scopus - 13Web of Science - 12
Co-authors A Hackett
2011 Fullston T, Finnis M, Hackett A, Hodgson B, Brueton L, Baynam G, et al., 'Screening and cell-based assessment of mutations in the Aristaless-related homeobox (ARX) gene', Clinical Genetics, 80 510-522 (2011)

ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcriptio... [more]

ARX mutations cause a diverse spectrum of human disorders, ranging from severe brain and genital malformations to non-syndromic intellectual disability (ID). ARX is a transcription factor with multiple domains that include four polyalanine (pA) tracts, the first two of which are frequently expanded by mutations. We progressively screened DNA samples from 613 individuals with ID initially for the most frequent ARX mutations (c.304ins(GCG) 7 'expansion' of pA1 and c.429-452dup 'dup24bp' of pA2). Five hundred samples without pA1 or pA2 mutations had the entire ARX ORF screened by single stranded polymorphism conformation (SSCP) and/or denaturing high pressure liquid chromatography (dHPLC) analysis. Overall, eight families with six mutations in ARX were identified (1.31%): five duplication mutations in pA2 (0.82%) with three new clinical reports of families with the dup24bp and two duplications larger than the dup24bp mutation discovered (dup27bp, dup33bp); and three point mutations (0.6%), including one novel mutation in the homeodomain (c.1074G > T). Four ultraconserved regions distal to ARX (uc466-469) were also screened in a subset of 94 patients, with three unique nucleotide changes identified in two (uc466, uc467). The subcellular localization of full length ARX proteins was assessed for 11 variants. Protein mislocalization increased as a function of pA2 tract length and phenotypic severity, as has been previously suggested for pA1. Similarly, protein mislocalization of the homeodomain mutations also correlated with clinical severity, suggesting an emerging genotype vs cellular phenotype correlation. © 2011 John Wiley & Sons A/S.

DOI 10.1111/j.1399-0004.2011.01685.x
Citations Scopus - 12
Co-authors A Hackett
2010 Hackett A, Tarpey PS, Licata A, Cox J, Whibley A, Boyle J, et al., 'CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes', European Journal of Human Genetics, 18 544-552 (2010) [C1]
DOI 10.1038/ejhg.2009.220
Citations Scopus - 46Web of Science - 37
Co-authors A Hackett
2010 Rujirabanjerd S, Nelson J, Tarpey PS, Hackett A, Edkins S, Raymond FL, et al., 'Identification and characterization of two novel JARID1C mutations: Suggestion of an emerging genotype-phenotype correlation', European Journal of Human Genetics, 18 330-335 (2010) [C1]
DOI 10.1038/ejhg.2009.175
Citations Scopus - 33Web of Science - 27
Co-authors A Hackett
2010 Whibley AC, Plagnol V, Tarpey PS, Abidi F, Fullston T, Choma MK, et al., 'Fine-scale survey of X chromosome copy number variants and indels underlying intellectual disability', American Journal of Human Genetics, 87 173-188 (2010)

Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-den... [more]

Copy number variants and indels in 251 families with evidence of X-linked intellectual disability (XLID) were investigated by array comparative genomic hybridization on a high-density oligonucleotide X chromosome array platform. We identified pathogenic copy number variants in 10% of families, with mutations ranging from 2 kb to 11 Mb in size. The challenge of assessing causality was facilitated by prior knowledge of XLID-associated genes and the ability to test for cosegregation of variants with disease through extended pedigrees. Fine-scale analysis of rare variants in XLID families leads us to propose four additional genes, PTCHD1, WDR13, FAAH2, and GSPT2, as candidates for XLID causation and the identification of further deletions and duplications affecting X chromosome genes but without apparent disease consequences. Breakpoints of pathogenic variants were characterized to provide insight into the underlying mutational mechanisms and indicated a predominance of mitotic rather than meiotic events. By effectively bridging the gap between karyotype-level investigations and X chromosome exon resequencing, this study informs discussion of alternative mutational mechanisms, such as noncoding variants and non-X-linked disease, which might explain the shortfall of mutation yield in the well-characterized International Genetics of Learning Disability (IGOLD) cohort, where currently disease remains unexplained in two-thirds of families. © 2010 The American Society of Human Genetics.

DOI 10.1016/j.ajhg.2010.06.017
Citations Scopus - 68
Co-authors A Hackett
2010 Hackett A, Tarpey PS, Licata A, Cox J, Whibley A, Boyle J, et al., 'Erratum: CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes (European Journal of Human Genetics (2010) 18 (554-552) doi:10.1038/ejhg.2009.220)', European Journal of Human Genetics, 18 552 (2010)
DOI 10.1038/ejhg.2010.24
Co-authors A Hackett
2010 Shoubridge C, Tarpey PS, Abidi F, Ramsden SL, Rujirabanjerd S, Murphy JA, et al., 'Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability', NATURE GENETICS, 42 486-488 (2010)
DOI 10.1038/ng.588
Citations Scopus - 67Web of Science - 61
Co-authors A Hackett
2010 Jensen LR, Bartenschlager H, Rujirabanjerd S, Tzschach A, Nümann A, Janecke AR, et al., 'A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C', PathoGenetics, 3 (2010)

Background. Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority ... [more]

Background. Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. Results. By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development. We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. Conclusions. Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder. © 2010 Jensen et al; licensee BioMed Central Ltd.

DOI 10.1186/1755-8417-3-2
Citations Scopus - 23
Co-authors A Hackett
2009 Tarpey PS, Smith R, Pleasance E, Whibley A, Edkins S, Hardy C, et al., 'A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation', Nature Genetics, 41 535-543 (2009) [C1]
DOI 10.1038/ng.367
Citations Scopus - 334Web of Science - 313
Co-authors A Hackett
2008 Hackett AK, Gillard J, Wilcken B, 'n of 1 trial for an ornithine transcarbamylase deficiency carrier', Molecular Genetics and Metabolism, 94 157-161 (2008) [C1]
DOI 10.1016/j.ymgme.2008.02.001
Citations Scopus - 4Web of Science - 5
Co-authors A Hackett
2008 Froyen G, Corbett M, Vandewalle J, Jarvela I, Lawrence O, Meldrum C, et al., 'Submicroscopic duplications of the hydroxysteroid dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated with mental retardation', American Journal of Human Genetics, 82 432-443 (2008) [C1]
DOI 10.1016/j.ajhg.2007.11.002
Citations Scopus - 115Web of Science - 112
Co-authors Rodney Scott, A Hackett
2008 Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJL, Goldenberg A, et al., 'Clinical and molecular delineation of the 17q21.31 microdeletion syndrome', Journal of Medical Genetics, 45 710-720 (2008)

Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with u... [more]

Background: The chromosome 17q21.31 microdeletion syndrome is a novel genomic disorder that has originally been identified using high resolution genome analyses in patients with unexplained mental retardation. Aim: We report the molecular and/or clinical characterisation of 22 individuals with the 17q21.31 microdeletion syndrome. Results: We estimate the prevalence of the syndrome to be 1 in 16 000 and show that it is highly underdiagnosed. Extensive clinical examination reveals that developmental delay, hypotonia, facial dysmorphisms including a long face, a tubular or pear-shaped nose and a bulbous nasal tip, and a friendly/amiable behaviour are the most characteristic features. Other clinically important features include epilepsy, heart defects and kidney/urologic anomalies. Using high resolution oligonucleotide arrays we narrow the 17q21.31 critical region to a 424 kb genomic segment (007: 41046729-41470954, hg17) encompassing at least six genes, among which is the gene encoding microtubule associated protein tau IMAM Mutation screening of MAPT in 122 individuals with a phenotype suggestive of 17q21.31 deletion carriers, but who do not carry the recurrent deletion, failed to identify any disease associated variants. In five deletion carriers we identify a < 500 bp rearrangement hotspot at the proximal breakpoint contained within an L2 LINE motif and show that in every case examined the parent originating the deletion carries a common 900 kb 17q21.31 inversion polymorphism, indicating that this inversion is a necessary factor for deletion to occur (p < 10 -5 ). Conclusion: Our data establish the 17q21.31 microdeletion syndrome as a clinically and molecularly well recognisable genomic disorder.

DOI 10.1136/jmg.2008.058701
Citations Scopus - 135
Co-authors A Hackett
2007 Ali A, Christie PT, Grigorieva IV, Harding B, Van Esch H, Ahmed SF, et al., 'Functional characterization of GATA3 mutations causing the hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome: Insight into mechanisms of DNA binding by the GATA3 transcription factor', Human Molecular Genetics, 16 265-275 (2007)

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We invest... [more]

The hypoparathyroidism-deafness-renal (HDR) dysplasia syndrome is an autosomal dominant disorder caused by mutations of the dual zinc finger transcription factor, GATA3. We investigated 21 HDR probands and 14 patients with isolated hypoparathyroidism for GATA3 abnormalities. Thirteen different heterozygous germline mutations were identified in patients with HDR. These consisted of three nonsense mutations, six frameshifting deletions, two frameshifting insertions, one missense (Leu348Arg) mutation and one acceptor splice site mutation. The splice site mutation was demonstrated to cause a pre-mRNA processing abnormality leading to the use of an alternative acceptor site 8 bp downstream of the normal site, resulting in a frameshift and prematurely terminated protein. Electrophoretic mobility shift assays (EMSAs) revealed three classes of GATA3 mutations: those that lead to a loss of DNA binding which represent over 90% of all mutations, and involved a loss of the carboxy-terminal zinc finger; those that resulted in a reduced DNA-binding affinity; and those (e.g. Leu348Arg) that did not alter DNA binding or the affinity but likely altered the conformational change that occurs during binding in the DNA major groove as predicted by a three-dimensional modeling. These results elucidate further the molecular mechanisms underlying the altered functions of mutants of this zinc finger transcription factor and their role in causing this developmental anomaly. No mutations were identified in patients with isolated hypoparathyroidism, thereby indicating that GATA3 abnormalities are more likely to result in two or more of the phenotypic features of the HDR syndrome and not in one, such as isolated hypoparathyroidism. © 2007 Oxford University Press.

DOI 10.1093/hmg/ddl454
Citations Scopus - 76
Co-authors A Hackett
2007 Tarpey PS, Raymond FL, Nguyen LS, Rodriguez J, Hackett A, Vandeleur L, et al., 'Mutations in UPF3B, a member of the nonsense-mediated mRNA decay complex, cause syndromic and nonsyndromic mental retardation', NATURE GENETICS, 39 1127-1133 (2007)
DOI 10.1038/ng2100
Citations Scopus - 123Web of Science - 123
Co-authors A Hackett
2006 Hackett AK, Rowe LJ, 'FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report', Clinical Dysmorphology, 15 207-210 (2006) [C3]
Citations Scopus - 15Web of Science - 13
Co-authors A Hackett
2001 Biswas S, Munier F, Yardley J, Hart-Holden N, Perveen R, Cousin P, et al., 'Missense mutation in COL8A2, the gene encoding the 2 chain type of type VIII collagen, cause two forms of corneal endothelial dystrophy', Human Molecular Genetics, 10 (21) 2415-2423 (2001) [C1]
Citations Scopus - 226Web of Science - 215
Co-authors A Hackett
2000 Hackett AK, Giles W, James S, 'Successful vaginal delivery in a woman with amyoplasia', Australian and New Zealand Journal of Obstetrics and Gynaecology, 40;4 461-463 (2000) [C1]
Citations Scopus - 1
Co-authors A Hackett
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Conference (4 outputs)

Year Citation Altmetrics Link
2009 Shoubridge C, Tarpey P, Abidi F, Rujirabanjerd S, Boyle J, Shaw M, et al., 'Mutations in IQSEC2, a guanine nucleotide exchange factor for ARF6, cause non-syndromic mental retardation', 14th International Workshop on Fragile X and X-Linked Mental Retardation: Abstracts, Bahia, Brazil (2009) [E3]
Co-authors A Hackett
2005 McKenzie F, Dudding TE, Edwards MJ, Giles WB, Hackett AK, Somerset D, Woodford P, 'Review of late fetal loss in the Hunter and proposed strategies for investigation', Human Genetics Society of Australasia, Newcastle (2005) [E3]
Co-authors T Dudding, A Hackett
2005 Hackett AK, Gillard J, 'n=1 trial for an ornithine transcarbamylase deficiency carrier', Human Genetics Society of Australasia, Newcastle (2005) [E3]
Co-authors A Hackett
2004 Field M, Hackett AK, 'Utilisation and cost of genetic testing for the Hunter Genetics Service', Conference Abstract, Fremantle, Western Australia (2004) [E3]
Co-authors A Hackett
Show 1 more conference
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Dr Anna Hackett

Position

Conjoint Senior Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine

Focus area

Medical Genetics

Contact Details

Email anna.hackett@newcastle.edu.au
Phone (02) 4925 3100
Fax (02) 4925 3133

Office

Building Newcastle Western Suburbs Hospital
Location Other

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