Publications by authors named "Elizabeth E Palmer"

30 Publications

  • Page 1 of 1

Quantitative neurogenetics: applications in understanding disease.

Biochem Soc Trans 2021 Jul 20. Epub 2021 Jul 20.

BioMedical Machine Learning Lab (BML), The Graduate School of Biomedical Engineering, UNSW SYDNEY, Sydney, New South Wales 2052, Australia.

Neurodevelopmental and neurodegenerative disorders (NNDs) are a group of conditions with a broad range of core and co-morbidities, associated with dysfunction of the central nervous system. Improvements in high throughput sequencing have led to the detection of putative risk genetic loci for NNDs, however, quantitative neurogenetic approaches need to be further developed in order to establish causality and underlying molecular genetic mechanisms of pathogenesis. Here, we discuss an approach for prioritizing the contribution of genetic risk loci to complex-NND pathogenesis by estimating the possible impacts of these loci on gene regulation. Furthermore, we highlight the use of a tissue-specificity gene expression index and the application of artificial intelligence (AI) to improve the interpretation of the role of genetic risk elements in NND pathogenesis. Given that NND symptoms are associated with brain dysfunction, risk loci with direct, causative actions would comprise genes with essential functions in neural cells that are highly expressed in the brain. Indeed, NND risk genes implicated in brain dysfunction are disproportionately enriched in the brain compared with other tissues, which we refer to as brain-specific expressed genes. In addition, the tissue-specificity gene expression index can be used as a handle to identify non-brain contexts that are involved in NND pathogenesis. Lastly, we discuss how using an AI approach provides the opportunity to integrate the biological impacts of risk loci to identify those putative combinations of causative relationships through which genetic factors contribute to NND pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1042/BST20200732DOI Listing
July 2021

Siblings of young people with chronic illness: Caring responsibilities and psychosocial functioning.

J Child Health Care 2021 Jul 16:13674935211033466. Epub 2021 Jul 16.

School of Women's and Children's Health, 7800UNSW Sydney, Kensington, NSW, Australia.

Siblings of young people with chronic illness commonly undertake caring responsibilities for their affected brother/sister, which may encourage maturation, yet may also be perceived as a burden. Our study determined (1) siblings' caring responsibilities, (2) siblings' current emotional distress and psychosocial functioning, and (3) how siblings' caring responsibilities and psychosocial functioning related to familial relationships and coping strategies. Siblings completed questionnaires which contained Sibling Inventory of Behavior, Sibling Inventory of Differential Experiences, PedsQL, emotion thermometers, Brief COPE, and a checklist of caregiving responsibilities. We analyzed the data with -tests and multi-level models. Forty-five siblings (mean age = 15.40 years, = 3.31 years; 60.0% female) participated. Siblings who had caring responsibilities ( = 26, 57.8%) reported lower anxiety symptoms, lower need for help, greater use of problem-focused coping, and more companionship and teaching/directiveness with their affected brother/sister than siblings without caring responsibilities. Siblings reported lower psychosocial and physical functioning when they perceived their parents provided them with less affection than their affected brother/sister. Family-based psychosocial interventions may aim to improve the sibling-parent relationship (including expressing affection) and the sibling-sibling relationship. Future interventions may also focus on increasing siblings' use of problem-focused coping strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/13674935211033466DOI Listing
July 2021

CHEDDA syndrome is an underrecognized neurodevelopmental disorder with a highly restricted ATN1 mutation spectrum.

Clin Genet 2021 Jul 1. Epub 2021 Jul 1.

Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

We describe the clinical features of nine unrelated individuals with rare de novo missense or in-frame deletions/duplications within the "HX motif" of exon 7 of ATN1. We previously proposed that individuals with such variants should be considered as being affected by the syndromic condition of congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA), distinct from dentatorubral-pallidoluysian atrophy (DRPLA) secondary to expansion variants in exon 5 of ATN1. We confirm that the universal phenotypic features of CHEDDA are distinctive facial features and global developmental delay. Infantile hypotonia and minor hand and feet differences are common and can present as arthrogryposis. Common comorbidities include severe feeding difficulties, often requiring gastrostomy support, as well as visual and hearing impairments. Epilepsy and congenital malformations of the brain, heart, and genitourinary systems are frequent but not universal. Our study confirms the clinical entity of CHEDDA secondary to a mutational signature restricted to exon 7 of ATN1. We propose a clinical schedule for assessment upon diagnosis, surveillance, and early intervention including the potential of neuroimaging for prognostication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.14022DOI Listing
July 2021

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.

Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system.

Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder.

Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-021-01215-9DOI Listing
June 2021

Feasibility of a mental health informed physical activity intervention for the carers of children with developmental and epileptic encephalopathy.

Epilepsy Behav 2021 08 18;121(Pt A):108022. Epub 2021 May 18.

School of Psychiatry, University of New South Wales, Sydney, Australia; Black Dog Institute, Prince of Wales Hospital, Sydney, Australia.

Aim: Parents and carers of children with developmental and epileptic encephalopathies (DEEs) experience high rates of mental health disorders including depression and posttraumatic stress disorder. Physical activity is an evidence-based strategy which may help to improve the wellbeing of this population.

Method: We delivered a 4-week physical activity group program via a private Facebook group for carers of children with DEEs and their nominated support person. The facilitators provided education and motivation on different weekly topics (e.g. goal setting, overcoming barriers to exercise) and encouraged social support between participants. All participants were provided with a physical activity tracker (Fitbit). The primary outcome was feasibility and secondary outcomes included psychological distress, quality of life, physical activity levels, and PTSD symptoms.

Results: N=20 (parents and support partners) were recruited. All participants remained in the program for the full duration and 85% completed the post assessment questionnaires. High acceptability was observed in the qualitative interviews and exploratory analysis of pre-post outcomes found significant improvements in psychological distress and quality of life (ps < 0.01), while changes in physical activity levels and PTSD symptoms were non-significant.

Conclusion: A mental health informed physical activity program delivered via Facebook is feasible for carers of children with DEEs and may help improve wellbeing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2021.108022DOI Listing
August 2021

ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria.

Brain 2021 Jun;144(5):1435-1450

Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Meyer Children's Hospital, University of Florence, Florence, Italy.

Constitutional heterozygous mutations of ATP1A2 and ATP1A3, encoding for two distinct isoforms of the Na+/K+-ATPase (NKA) alpha-subunit, have been associated with familial hemiplegic migraine (ATP1A2), alternating hemiplegia of childhood (ATP1A2/A3), rapid-onset dystonia-parkinsonism, cerebellar ataxia-areflexia-progressive optic atrophy, and relapsing encephalopathy with cerebellar ataxia (all ATP1A3). A few reports have described single individuals with heterozygous mutations of ATP1A2/A3 associated with severe childhood epilepsies. Early lethal hydrops fetalis, arthrogryposis, microcephaly, and polymicrogyria have been associated with homozygous truncating mutations in ATP1A2. We investigated the genetic causes of developmental and epileptic encephalopathies variably associated with malformations of cortical development in a large cohort and identified 22 patients with de novo or inherited heterozygous ATP1A2/A3 mutations. We characterized clinical, neuroimaging and neuropathological findings, performed in silico and in vitro assays of the mutations' effects on the NKA-pump function, and studied genotype-phenotype correlations. Twenty-two patients harboured 19 distinct heterozygous mutations of ATP1A2 (six patients, five mutations) and ATP1A3 (16 patients, 14 mutations, including a mosaic individual). Polymicrogyria occurred in 10 (45%) patients, showing a mainly bilateral perisylvian pattern. Most patients manifested early, often neonatal, onset seizures with a multifocal or migrating pattern. A distinctive, 'profound' phenotype, featuring polymicrogyria or progressive brain atrophy and epilepsy, resulted in early lethality in seven patients (32%). In silico evaluation predicted all mutations to be detrimental. We tested 14 mutations in transfected COS-1 cells and demonstrated impaired NKA-pump activity, consistent with severe loss of function. Genotype-phenotype analysis suggested a link between the most severe phenotypes and lack of COS-1 cell survival, and also revealed a wide continuum of severity distributed across mutations that variably impair NKA-pump activity. We performed neuropathological analysis of the whole brain in two individuals with polymicrogyria respectively related to a heterozygous ATP1A3 mutation and a homozygous ATP1A2 mutation and found close similarities with findings suggesting a mainly neural pathogenesis, compounded by vascular and leptomeningeal abnormalities. Combining our report with other studies, we estimate that ∼5% of mutations in ATP1A2 and 12% in ATP1A3 can be associated with the severe and novel phenotypes that we describe here. Notably, a few of these mutations were associated with more than one phenotype. These findings assign novel, 'profound' and early lethal phenotypes of developmental and epileptic encephalopathies and polymicrogyria to the phenotypic spectrum associated with heterozygous ATP1A2/A3 mutations and indicate that severely impaired NKA pump function can disrupt brain morphogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awab052DOI Listing
June 2021

Different types of disease-causing noncoding variants revealed by genomic and gene expression analyses in families with X-linked intellectual disability.

Hum Mutat 2021 Jul 3;42(7):835-847. Epub 2021 May 3.

Adelaide Medical School and Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia.

The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of individuals worldwide; however, approximately 30% of XLID families still remain unresolved. We postulated that noncoding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different noncoding variants. We used comprehensive structural, single-nucleotide, and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, reverse-transcription polymerase chain reactions, Western blots, and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic noncoding variants: a retrotransposon insertion, a novel intronic splice donor, and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favor of a regulatory noncoding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic noncoding variant discovery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.24207DOI Listing
July 2021

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features.

Am J Hum Genet 2020 12 6;107(6):1157-1169. Epub 2020 Nov 6.

Genetics of Learning Disability Service, Waratah, NSW 2298, Australia.

Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820564PMC
December 2020

Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders.

Nat Commun 2020 10 1;11(1):4932. Epub 2020 Oct 1.

Oasi Research Institute-IRCCS, Troina, Italy.

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF < 0.01%) gene-disruptive mutations (FDR 5%), six of which reach family-wise error rate (FWER) significance (p < 1.25E-06). Among these 125 targeted genes, we also reevaluate DNM excess in 17,426 NDD trios with 6,499 new autism trios. We identify 90 genes enriched for DNMs (FDR 5%; e.g., GABRG2 and UIMC1); of which, 61 reach FWER significance (p < 3.64E-07; e.g., CASZ1). In addition to doubling the number of patients for many NDD risk genes, we present phenotype-genotype correlations for seven risk genes (CTCF, HNRNPU, KCNQ3, ZBTB18, TCF12, SPEN, and LEO1) based on this large-scale targeted sequencing effort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18723-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530681PMC
October 2020

The information needs of parents of children with early-onset epilepsy: A systematic review.

Epilepsy Behav 2020 11 24;112:107382. Epub 2020 Aug 24.

School of Women's and Children's Health, UNSW Medicine, UNSW Sydney, Australia; Centre for Clinical Genetics, Sydney Children's Hospital, Randwick, Australia.

Objective: Early-onset epilepsy has broad physical and psychosocial impacts, and parents have a wide variety of information needs. This systematic review set out to assess 1) whether parents of children with early-onset epilepsy have unmet information needs and 2) their preferences regarding information content and style of information delivery.

Methods: We searched Medline, Embase, PsychInfo, and CINAHL using keywords relating to information needs, information resources, and preferences for information delivery. We limited the search to parent populations and included all peer-reviewed publications published in English after the year 2005.

Results: Eleven studies met our inclusion criteria. Parents reported a clear need for understandable, realistic, and focused information, highlighting a particular need for content about comorbidities and emotional support. Parents reported limited availability of detailed information resources on early-onset epilepsy, which compromised their ability to access appropriate healthcare services. Unmet information needs were associated with greater levels of stress, poorer psychosocial outcomes, and lower satisfaction with healthcare services.

Significance: The results highlight the importance of detailed epilepsy information for families. Healthcare professionals should be aware of the impact of a lack of epilepsy information on family wellbeing. Multipronged and tailored interventions targeting the information needs of families are warranted.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107382DOI Listing
November 2020

Pre-genetics clinic resource evaluation for adults with intellectual disability: The pre-genetics clinic aid.

J Genet Couns 2020 08 4;29(4):668-677. Epub 2020 Apr 4.

Genetics of Learning Disability, Waratah, Hunter New England, Sydney, NSW, Australia.

People with intellectual disability (PWID) consistently identify the importance of health service information that is accessible and relevant. Resources tailored to the information and support needs of PWID can facilitate inclusivity in their health care (including access to genomic medicine) and improve healthcare outcomes. Despite the fact that PWID are commonly referred to genetics services, there is a lack of appropriate resources to help them prepare for their appointments. We therefore aimed to evaluate the feasibility and acceptability of a booklet for PWID to read with their carers prior to their genetics appointment, to help them prepare for what they may experience. With input from Easy to Read experts and PWID who were members of the New South Wales (NSW) Council for Intellectual Disability, the information booklet 'Getting ready for your visit to the genetics clinic' was produced. Australian healthcare professionals (HCP) familiar with clinical genetics services were invited to complete an anonymous online survey designed to assess perceived relevance, readability, and utility of the resource. Recruitment of HCPs was pursued via affiliated clinical services and email distribution through clinical genetics organizations. Sixty-six HCPs completed and submitted the survey. The results demonstrated that HCPs believed the booklet represented a typical clinical genetics service appointment and that the majority would provide a copy of the resource to clients and their carers. They reported that the booklet was easy to understand and entailed appropriate content and images which were presented clearly and simply. Some minor modifications were recommended and incorporated into the resource. A model of customizable booklets such as this could be transferrable across clinical genetics services and guide development of other resources for PWID. This may help to reduce healthcare disparities, improve client satisfaction, and facilitate involvement of PWID in their own healthcare decisions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jgc4.1259DOI Listing
August 2020

Missense variants in TAF1 and developmental phenotypes: challenges of determining pathogenicity.

Hum Mutat 2019 Oct 23. Epub 2019 Oct 23.

Center for Medical Genetics Dr. Jacinto de Magalhães, Hospital and University Center of Porto, Porto, Portugal.

We recently described a new neurodevelopmental syndrome (TAF1/MRXS33 intellectual disability syndrome) (MIM# 300966) caused by pathogenic variants involving the X-linked gene TAF1, which participates in RNA polymerase II transcription. The initial study reported eleven families, and the syndrome was defined as presenting early in life with hypotonia, facial dysmorphia, and developmental delay that evolved into intellectual disability (ID) and/or autism spectrum disorder (ASD). We have now identified an additional 27 families through a genotype-first approach. Familial segregation analysis, clinical phenotyping, and bioinformatics were capitalized on to assess potential variant pathogenicity, and molecular modelling was performed for those variants falling within structurally characterized domains of TAF1. A novel phenotypic clustering approach was also applied, in which the phenotypes of affected individuals were classified using 51 standardized Human Phenotype Ontology (HPO) terms. Phenotypes associated with TAF1 variants show considerable pleiotropy and clinical variability, but prominent among previously unreported effects were brain morphological abnormalities, seizures, hearing loss, and heart malformations. Our allelic series broadens the phenotypic spectrum of TAF1/MRXS33 intellectual disability syndrome and the range of TAF1 molecular defects in humans. It also illustrates the challenges for determining the pathogenicity of inherited missense variants, particularly for genes mapping to chromosome X. This article is protected by copyright. All rights reserved.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23936DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187541PMC
October 2019

Significantly Elevated mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing.

Int J Mol Sci 2019 Aug 11;20(16). Epub 2019 Aug 11.

Diagnosis and Development, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC 3052, Australia.

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55-199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20163907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721168PMC
August 2019

encephalopathy: Connecting neurodevelopmental disorders with α-synucleinopathies?

Neurology 2019 07 20;93(3):114-123. Epub 2019 Jun 20.

From the Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute (V.L., Y.J.C., J.Z.B., F.A.M.), the University of Queensland, St. Lucia Campus, Brisbane, Australia; Neurogenetics Group (S.W.), University of Antwerp, Belgium; Laboratory of Neurogenetics (S.W.), Institute Born-Bunge, University of Antwerp; Department of Neurology (S.W.), Antwerp University Hospital, Belgium; School of Women's and Children's Health (E.E.P.), University of New South Wales, Sydney; Genetics of Learning Disability Service (E.E.P.), Hunter New England Health, Newcastle; Department of Clinical Genetics (E.E.P.), Sydney Children's Hospital; and Institute for Molecular Bioscience (B.M.C.), the University of Queensland, Brisbane, Australia.

De novo pathogenic variants in encoding syntaxin1-binding protein (STXBP1, also known as Munc18-1) lead to a range of early-onset neurocognitive conditions, most commonly early infantile epileptic encephalopathy type 4 (EIEE4, also called STXBP1 encephalopathy), a severe form of epilepsy associated with developmental delay/intellectual disability. Other neurologic features include autism spectrum disorder and movement disorders. The progression of neurologic symptoms has been reported in a few older affected individuals, with the appearance of extrapyramidal features, reminiscent of early onset parkinsonism. Understanding the pathologic process is critical to improving therapies, as currently available antiepileptic drugs have shown limited success in controlling seizures in EIEE4 and there is no precision medication approach for the other neurologic features of the disorder. Basic research shows that genetic knockout of STXBP1 or other presynaptic proteins of the exocytic machinery leads to widespread perinatal neurodegeneration. The mechanism that regulates this effect is under scrutiny but shares intriguing hallmarks with classical neurodegenerative diseases, albeit appearing early during brain development. Most critically, recent evidence has revealed that STXBP1 controls the self-replicating aggregation of α-synuclein, a presynaptic protein involved in various neurodegenerative diseases that are collectively known as synucleinopathies, including Parkinson disease. In this review, we examine the tantalizing link among STXBP1 function, EIEE, and the neurodegenerative synucleinopathies, and suggest that neural development in EIEE could be further affected by concurrent synucleinopathic mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007786DOI Listing
July 2019

De novo and biallelic DEAF1 variants cause a phenotypic spectrum.

Genet Med 2019 09 29;21(9):2059-2069. Epub 2019 Mar 29.

GW Institute for Neuroscience, Department of Pharmacology and Physiology, The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.

Purpose: To investigate the effect of different DEAF1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and on DEAF1 activity in vitro.

Methods: We assembled a cohort of 23 patients with de novo and biallelic DEAF1 variants, described the genotype-phenotype correlation, and investigated the differential effect of de novo and recessive variants on transcription assays using DEAF1 and Eif4g3 promoter luciferase constructs.

Results: The proportion of the most prevalent phenotypic features, including intellectual disability, speech delay, motor delay, autism, sleep disturbances, and a high pain threshold, were not significantly different in patients with biallelic and pathogenic de novo DEAF1 variants. However, microcephaly was exclusively observed in patients with recessive variants (p < 0.0001).

Conclusion: We propose that different variants in the DEAF1 gene result in a phenotypic spectrum centered around neurodevelopmental delay. While a pathogenic de novo dominant variant would also incapacitate the product of the wild-type allele and result in a dominant-negative effect, a combination of two recessive variants would result in a partial loss of function. Because the clinical picture can be nonspecific, detailed phenotype information, segregation, and functional analysis are fundamental to determine the pathogenicity of novel variants and to improve the care of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0473-6DOI Listing
September 2019

De Novo Variants Disrupting the HX Repeat Motif of ATN1 Cause a Recognizable Non-Progressive Neurocognitive Syndrome.

Am J Hum Genet 2019 03 28;104(3):542-552. Epub 2019 Feb 28.

Fundación para la Lucha contra las Enfermedades Neurológicas de la Infancia, Montañeses, Buenos Aires 2325, Argentina.

Polyglutamine expansions in the transcriptional co-repressor Atrophin-1, encoded by ATN1, cause the neurodegenerative condition dentatorubral-pallidoluysian atrophy (DRPLA) via a proposed novel toxic gain of function. We present detailed phenotypic information on eight unrelated individuals who have de novo missense and insertion variants within a conserved 16-amino-acid "HX repeat" motif of ATN1. Each of the affected individuals has severe cognitive impairment and hypotonia, a recognizable facial gestalt, and variable congenital anomalies. However, they lack the progressive symptoms typical of DRPLA neurodegeneration. To distinguish this subset of affected individuals from the DRPLA diagnosis, we suggest using the term CHEDDA (congenital hypotonia, epilepsy, developmental delay, digit abnormalities) to classify the condition. CHEDDA-related variants alter the particular structural features of the HX repeat motif, suggesting that CHEDDA results from perturbation of the structural and functional integrity of the HX repeat. We found several non-homologous human genes containing similar motifs of eight to 10 HX repeat sequences, including RERE, where disruptive variants in this motif have also been linked to a separate condition that causes neurocognitive and congenital anomalies. These findings suggest that perturbation of the HX motif might explain other Mendelian human conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2019.01.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407605PMC
March 2019

Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature.

Genet Med 2019 09 11;21(9):2036-2042. Epub 2019 Feb 11.

Spectrum Health Medical Genetics, Grand Rapids, MI, USA.

Purpose: To define the clinical characteristics of patients with variants in TCF20, we describe 27 patients, 26 of whom were identified via exome sequencing. We compare detailed clinical data with 17 previously reported patients.

Methods: Patients were ascertained through molecular testing laboratories performing exome sequencing (and other testing) with orthogonal confirmation; collaborating referring clinicians provided detailed clinical information.

Results: The cohort of 27 patients all had novel variants, and ranged in age from 2 to 68 years. All had developmental delay/intellectual disability. Autism spectrum disorders/autistic features were reported in 69%, attention disorders or hyperactivity in 67%, craniofacial features (no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Additional features affecting various organ systems were described in 93%. In a majority of patients, we did not observe previously reported findings of postnatal overgrowth or craniosynostosis, in comparison with earlier reports.

Conclusion: We provide valuable data regarding the prognosis and clinical manifestations of patients with variants in TCF20.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0454-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171701PMC
September 2019

Expanding the spectrum of mutations and novel insights into disease mechanisms.

Mol Genet Metab Rep 2018 Sep 20;16:46-51. Epub 2018 Jul 20.

Department of Neurogenetics, Kolling Institute, Royal North Shore Hospital, St. Leonards, NSW, Australia.

Zellweger syndrome spectrum disorders are caused by mutations in any of at least 12 different genes. This includes , an important regulator of peroxisome biogenesis. Using whole genome sequencing, we detected previously unreported, biallelic variants in [NM_004813.2:c.658G>A, p.(Ala220Thr) and NM_004813.2:c.830G>A, p.(Arg277Gln)] in an individual with leukodystrophy, spastic paraplegia, cerebellar ataxia, and craniocervical dystonia with normal plasma very long chain fatty acids. Using olfactory-neurosphere derived cells, a population of neural stem cells, we showed patient cells had reduced peroxisome density and increased peroxisome size, replicating previously reported findings in cell lines. Along with alterations in peroxisome morphology, patient cells also had impaired peroxisome function with reduced catalase activity. Furthermore, patient cells had reduced oxidative stress levels after exposure to hydrogen-peroxide (HO), which may be a result of compensation by HO metabolising enzymes other than catalase to preserve peroxisome-related cell functions. Our findings of impaired catalase activity and altered oxidative stress response are novel. Our study expands the phenotype of mutations by including dystonia and provides further insights into the pathological mechanisms underlying -associated disorders. Additional studies of the full spectrum of peroxisomal dysfunction could improve our understanding of the mechanism underlying PEX16-associated disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ymgmr.2018.07.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072801PMC
September 2018

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery.

Hum Mutat 2018 08 14;39(8):1126-1138. Epub 2018 Jun 14.

Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW, Australia.

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and three maternally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins. We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such as mRNA export, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in humans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481655PMC
August 2018

Truncating Variants in NAA15 Are Associated with Variable Levels of Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies.

Am J Hum Genet 2018 05 12;102(5):985-994. Epub 2018 Apr 12.

Kennedy Krieger Institute, 801 North Broadway Baltimore, MD 21205, USA.

N-alpha-acetylation is a common co-translational protein modification that is essential for normal cell function in humans. We previously identified the genetic basis of an X-linked infantile lethal Mendelian disorder involving a c.109T>C (p.Ser37Pro) missense variant in NAA10, which encodes the catalytic subunit of the N-terminal acetyltransferase A (NatA) complex. The auxiliary subunit of the NatA complex, NAA15, is the dimeric binding partner for NAA10. Through a genotype-first approach with whole-exome or genome sequencing (WES/WGS) and targeted sequencing analysis, we identified and phenotypically characterized 38 individuals from 33 unrelated families with 25 different de novo or inherited, dominantly acting likely gene disrupting (LGD) variants in NAA15. Clinical features of affected individuals with LGD variants in NAA15 include variable levels of intellectual disability, delayed speech and motor milestones, and autism spectrum disorder. Additionally, mild craniofacial dysmorphology, congenital cardiac anomalies, and seizures are present in some subjects. RNA analysis in cell lines from two individuals showed degradation of the transcripts with LGD variants, probably as a result of nonsense-mediated decay. Functional assays in yeast confirmed a deleterious effect for two of the LGD variants in NAA15. Further supporting a mechanism of haploinsufficiency, individuals with copy-number variant (CNV) deletions involving NAA15 and surrounding genes can present with mild intellectual disability, mild dysmorphic features, motor delays, and decreased growth. We propose that defects in NatA-mediated N-terminal acetylation (NTA) lead to variable levels of neurodevelopmental disorders in humans, supporting the importance of the NatA complex in normal human development.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5986698PMC
May 2018

A Mild PUM1 Mutation Is Associated with Adult-Onset Ataxia, whereas Haploinsufficiency Causes Developmental Delay and Seizures.

Cell 2018 02;172(5):924-936.e11

Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia; St. Vincent's Clinical School, University of New South Wales, Sydney, NSW 2010, Australia.

Certain mutations can cause proteins to accumulate in neurons, leading to neurodegeneration. We recently showed, however, that upregulation of a wild-type protein, Ataxin1, caused by haploinsufficiency of its repressor, the RNA-binding protein Pumilio1 (PUM1), also causes neurodegeneration in mice. We therefore searched for human patients with PUM1 mutations. We identified eleven individuals with either PUM1 deletions or de novo missense variants who suffer a developmental syndrome (Pumilio1-associated developmental disability, ataxia, and seizure; PADDAS). We also identified a milder missense mutation in a family with adult-onset ataxia with incomplete penetrance (Pumilio1-related cerebellar ataxia, PRCA). Studies in patient-derived cells revealed that the missense mutations reduced PUM1 protein levels by ∼25% in the adult-onset cases and by ∼50% in the infantile-onset cases; levels of known PUM1 targets increased accordingly. Changes in protein levels thus track with phenotypic severity, and identifying posttranscriptional modulators of protein expression should identify new candidate disease genes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cell.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5832058PMC
February 2018

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness.

Mol Genet Genomic Med 2018 03 4;6(2):186-199. Epub 2018 Jan 4.

Sydney Children's Hospital, Randwick, NSW, Australia.

Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways.

Methods: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after "first-tier" testing. Sensitivity analysis was included with a range of commercial exome and multigene panels.

Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95% confidence intervals $2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported.

Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902395PMC
March 2018

A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

Am J Hum Genet 2017 Dec 30;101(6):995-1005. Epub 2017 Nov 30.

Paris Descartes-Sorbonne Paris Cité University, Institut Imagine, 75015 Paris, France; Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Institut Imagine, 75015 Paris, France.

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.10.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812890PMC
December 2017

Current use of chromosomal microarray by Australian paediatricians and implications for the implementation of next generation sequencing.

J Paediatr Child Health 2017 Jul 27;53(7):650-656. Epub 2017 Apr 27.

Department of General Medicine, Royal Children's Hospital, Melbourne, Victoria, Australia.

Aim: Chromosomal microarray (CMA) is an important diagnostic test for children with multiple congenital anomalies or certain developmental behavioural problems suggestive of an underlying genetic diagnosis. However, there are medical and ethical complexities to its use and few Australian policies to guide practice. We aimed to describe the current practice of Australian paediatricians in relation to CMA testing. We hypothesised that there are knowledge gaps in their use of CMA.

Methods: Online survey completed between September 2015 and January 2016 by paediatricians in secondary care settings. Participants were members of the Australian Paediatric Research Network. One hundred and sixty five (43%) of 383 active members responded. Our main outcome measures comprised: (i) the indications for which paediatricians request CMA; (ii) their approach to consent; (iii) their interpretation of results; and (iv) their understanding of the impact on patient management.

Results: A significant proportion of paediatricians (21-52%) did not regularly use CMA for conditions with established evidence of diagnostic yield. Paediatricians under-estimated the potential for CMA findings to alter patient management. There was wide variability in paediatricians' approach to consent, and low use of consent forms and fact sheets. Paediatricians reported difficulties interpreting CMA results, with high rates of referral to clinical genetics services.

Conclusions: The reported practice of Australian paediatricians is not consistent with international standards on CMA. Australian practice could be improved by a standardised approach to ordering CMA, consenting patients and interpreting results. We provide resources for CMA ordering and make recommendations about preparation for next generation sequencing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jpc.13523DOI Listing
July 2017

Eight further individuals with intellectual disability and epilepsy carrying bi-allelic CNTNAP2 aberrations allow delineation of the mutational and phenotypic spectrum.

J Med Genet 2016 12 20;53(12):820-827. Epub 2016 Jul 20.

Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Background: Heterozygous copy number variants (CNVs) or sequence variants in the contactin-associated protein 2 gene CNTNAP2 have been discussed as risk factors for a wide spectrum of neurodevelopmental and neuropsychiatric disorders. Bi-allelic aberrations in this gene are causative for an autosomal-recessive disorder with epilepsy, severe intellectual disability (ID) and cortical dysplasia (CDFES). As the number of reported individuals is still limited, we aimed at a further characterisation of the full mutational and clinical spectrum.

Methods: Targeted sequencing, chromosomal microarray analysis or multigene panel sequencing was performed in individuals with severe ID and epilepsy.

Results: We identified homozygous mutations, compound heterozygous CNVs or CNVs and mutations in CNTNAP2 in eight individuals from six unrelated families. All aberrations were inherited from healthy, heterozygous parents and are predicted to be deleterious for protein function. Epilepsy occurred in all affected individuals with onset in the first 3.5 years of life. Further common aspects were ID (severe in 6/8), regression of speech development (5/8) and behavioural anomalies (7/8). Interestingly, cognitive impairment in one of two affected brothers was, in comparison, relatively mild with good speech and simple writing abilities. Cortical dysplasia that was previously reported in CDFES was not present in MRIs of six individuals and only suspected in one.

Conclusions: By identifying novel homozygous or compound heterozygous, deleterious CNVs and mutations in eight individuals from six unrelated families with moderate-to-severe ID, early onset epilepsy and behavioural anomalies, we considerably broaden the mutational and clinical spectrum associated with bi-allelic aberrations in CNTNAP2.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2016-103880DOI Listing
December 2016

Neuronal deficiency of ARV1 causes an autosomal recessive epileptic encephalopathy.

Hum Mol Genet 2016 07 6;25(14):3042-3054. Epub 2016 Jun 6.

Department of Molecular Physiology and Biophysics

We report an individual who presented with severe neurodevelopmental delay and an intractable infantile-onset seizure disorder. Exome sequencing identified a homozygous single nucleotide change that abolishes a splice donor site in the ARV1 gene (c.294 + 1G > A homozygous). This variant completely prevented splicing in minigene assays, and resulted in exon skipping and an in-frame deletion of 40 amino acids in primary human fibroblasts (NP_073623.1: p.(Lys59_Asn98del). The p.(Lys59_Asn98del) and previously reported p.(Gly189Arg) ARV1 variants were evaluated for protein expression and function. The p.(Gly189Arg) variant partially rescued the temperature-dependent growth defect in arv1Δ yeast, while p.(Lys59-Asn98del) completely failed to rescue at restrictive temperature. In contrast to wild type human ARV1, neither variant expressed detectable levels of protein in mammalian cells. Mice with a neuronal deletion of Arv1 recapitulated the human phenotype, exhibiting seizures and a severe survival defect in adulthood. Our data support ARV1 deficiency as a cause of autosomal recessive epileptic encephalopathy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddw157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5181598PMC
July 2016

THOC2 Mutations Implicate mRNA-Export Pathway in X-Linked Intellectual Disability.

Am J Hum Genet 2015 Aug 9;97(2):302-10. Epub 2015 Jul 9.

Department of Human Molecular Genetics, Max Planck Institute for Molecular Genetics, Ihnestrasse 63-73, 14195 Berlin, Germany.

Export of mRNA from the cell nucleus to the cytoplasm is essential for protein synthesis, a process vital to all living eukaryotic cells. mRNA export is highly conserved and ubiquitous. Mutations affecting mRNA and mRNA processing or export factors, which cause aberrant retention of mRNAs in the nucleus, are thus emerging as contributors to an important class of human genetic disorders. Here, we report that variants in THOC2, which encodes a subunit of the highly conserved TREX mRNA-export complex, cause syndromic intellectual disability (ID). Affected individuals presented with variable degrees of ID and commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. X chromosome exome sequencing revealed four missense variants in THOC2 in four families, including family MRX12, first ascertained in 1971. We show that two variants lead to decreased stability of THOC2 and its TREX-complex partners in cells derived from the affected individuals. Protein structural modeling showed that the altered amino acids are located in the RNA-binding domains of two complex THOC2 structures, potentially representing two different intermediate RNA-binding states of THOC2 during RNA transport. Our results show that disturbance of the canonical molecular pathway of mRNA export is compatible with life but results in altered neuronal development with other comorbidities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2015.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573269PMC
August 2015

Chromosome microarray in Australia: a guide for paediatricians.

J Paediatr Child Health 2012 Feb;48(2):E59-67

Department of Medical Genetics, Sydney Children's Hospital, Randwick, Sydney, New South Wales, Australia.

Chromosomal microarray or molecular karyotype has become the first-line genetic investigation for children with intellectual disability, autistic spectrum disorder or multiple congenital anomalies. Chromosomal microarray increases the detection rate of pathogenic chromosome imbalances including submicroscopic deletions or duplications in patients with undiagnosed intellectual disability to approximately 15% compared with 3% with conventional cytogenetics. This review article summarises the diagnostic technique and highlights the advantages and limitations of chromosomal microarray. Our aim is to assist clinicians in providing pretest counselling and with interpretation of the result.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/j.1440-1754.2011.02081.xDOI Listing
February 2012
-->