Dr Anna Hackett
Conjoint Senior Lecturer
School of Biomedical Sciences and Pharmacy (Medical Genetics)
- Phone:(02) 4925 3100
X linked intellectual disability
- Clinical Sciences and Genetics
- Intellectual Disability
- Paediatrics and Reproduction
- X Chromosome
Fields of Research
|060499||Genetics not elsewhere classified||35|
|110399||Clinical Sciences not elsewhere classified||30|
|060199||Biochemistry and Cell Biology not elsewhere classified||35|
For publications that are currently unpublished or in-press, details are shown in italics.
Journal article (42 outputs)
Rafehi H, Szmulewicz DJ, Bennett MF, Sobreira NLM, Pope K, Smith KR, et al., 'Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS', American Journal of Human Genetics, 105 151-165 (2019) [C1]
© 2019 The Authors Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have pr... [more]
© 2019 The Authors Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
Srivastava S, Niranjan T, May MM, Tarpey P, Allen W, Hackett A, et al., 'Dysregulations of sonic hedgehog signaling in MED12-related X-linked intellectual disability disorders', Molecular Genetics and Genomic Medicine, 7 (2019)
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Mutations in mediator of RNA polymerase II transcription subunit 1... [more]
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Mutations in mediator of RNA polymerase II transcription subunit 12 homolog (MED12, OMIM 300188) cause X-linked intellectual disability (XLID) disorders including FG, Lujan, and Ohdo syndromes. The Gli3-dependent Sonic Hedgehog (SHH) signaling pathway has been implicated in the original FG syndrome and Lujan syndrome. How are SHH-signaling defects related to the complex clinical phenotype of MED12-associated XLID syndromes are not fully understood. Methods: Quantitative RT-PCR was used to study expression levels of three SHH-signaling genes in lymophoblast cell lines carrying four MED12 mutations from four unrelated XLID families. Genotype and phenotype correlation studies were performed on these mutations. Results: Three newly identified and one novel MED12 mutations in six affected males from four unrelated XLID families were studied. Three mutations (c.2692A>G; p.N898D, c.3640C>T; p.R1214C, and c.3884G>A; p.R1295H) are located in the LS domain and one (c.617G>A; p.R206Q) is in the L domain of MED12. These mutations involve highly conserved amino acid residues and segregate with ID and related congenital malformations in respective probands families. Patients with the LS-domain mutations share many features of FG syndrome and some features of Lujan syndrome. The patient with the L-domain mutation presented with ID and predominant neuropsychiatric features but little dysmorphic features of either FG or Lujan syndrome. Transcript levels of three Gli3-dependent SHH-signaling genes, CREB5, BMP4, and NEUROG2, were determined by quantitative RT-PCR and found to be significantly elevated in lymphoblasts from patients with three mutations in the MED12-LS domain. Conclusions: These results support a critical role of MED12 in regulating Gli3-dependent SHH signaling and in developing ID and related congenital malformations in XLID syndromes. Differences in the expression profile of SHH-signaling genes potentially contribute to variability in clinical phenotypes in patients with MED12-related XLID disorders.
Khayat W, Hackett A, Shaw M, Ilie A, Dudding-Byth T, Kalscheuer VM, et al., 'A recurrent missense variant in SLC9A7 causes nonsyndromic X-linked intellectual disability with alteration of Golgi acidification and aberrant glycosylation', Human Molecular Genetics, 28 598-614 (2019)
© The Author(s) 2018. We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.15... [more]
© The Author(s) 2018. We report two unrelated families with multigenerational nonsyndromic intellectual disability (ID) segregating with a recurrent de novo missense variant (c.1543CT:p.Leu515Phe) in the alkali cation/proton exchanger gene SLC9A7 (also commonly referred to as NHE7). SLC9A7 is located on human X chromosome at Xp11.3 and has not yet been associated with a human phenotype. The gene is widely transcribed, but especially abundant in brain, skeletal muscle and various secretory tissues.Within cells, SLC9A7 resides in the Golgi apparatus, with prominent enrichment in the trans-Golgi network (TGN) and post-Golgi vesicles. In transfected Chinese hamster ovary AP-1 cells, the Leu515Phe mutant protein was correctly targeted to the TGN/post-Golgi vesicles, but its N-linked oligosaccharide maturation as well as that of a co-transfected secretory membrane glycoprotein, vesicular stomatitis virus G (VSVG) glycoprotein, was reduced compared to cells co-expressing SLC9A7 wild-type and VSVG. This correlated with alkalinization of the TGN/post-Golgi compartments, suggestive of a gain-of-function. Membrane trafficking of glycosylation-deficient Leu515Phe and co-transfected VSVG to the cell surface, however, was relatively unaffected. Mass spectrometry analysis of patient sera also revealed an abnormal.
Jansen S, Hoischen A, Coe BP, Carvill GL, Van Esch H, Bosch DGM, et al., 'A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency', European Journal of Human Genetics, 26 54-63 (2018) [C1]
© 2017 European Society of Human Genetics. Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next genera... [more]
© 2017 European Society of Human Genetics. Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID. Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype. Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome.
Dudding-Byth T, Baxter A, Holliday EG, Hackett A, O'Donnell S, White SM, et al., 'Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability', BMC Biotechnology, 17 (2017) [C1]
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 co... [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.
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.
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)
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.
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.
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 wit... [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.
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 k... [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.
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 d... [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.
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 & Sons Ltd and International Behavioural and Neural Genetics Society. Recent evidence suggests that early changes in postural control may be discernible am... [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.
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)
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)
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.
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.
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.
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]
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]
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]
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]
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]
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]
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]
Hackett AK, Rowe LJ, 'FGFR1 Pfeiffer syndrome without craniosynostosis: an additional case report', Clinical Dysmorphology, 15 207-210 (2006) [C3]
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]
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]
|Show 39 more journal articles|
Conference (4 outputs)
|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]|
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]
|2005||Hackett AK, Gillard J, 'n=1 trial for an ornithine transcarbamylase deficiency carrier', Human Genetics Society of Australasia, Newcastle (2005) [E3]|
|2004||Field M, Hackett AK, 'Utilisation and cost of genetic testing for the Hunter Genetics Service', Conference Abstract, Fremantle, Western Australia (2004) [E3]|
|Show 1 more conference|
Dr Anna Hackett
Conjoint Senior Lecturer
School of Biomedical Sciences and Pharmacy
Faculty of Health and Medicine
|Phone||(02) 4925 3100|
|Fax||(02) 4925 3133|
|Building||Newcastle Western Suburbs Hospital|