NKX2-1 mutation in a family diagnosed with ataxic dyskinetic cerebral palsy

Benign hereditary chorea caused by mutations in the NK2 homeobox 1 gene (NKX2-1), shares clinical features with ataxic and dyskinetic cerebral palsy (CP), resulting in the possibility of misdiagnosis. A father and his two children were considered to have ataxic CP until a possible diagnosis of benign familial chorea was made in the children in early teenage. The father's neurological condition had not been appreciated prior to examination of the affected son. Whole exome sequencing of blood derived DNA and bioinformatics analysis were performed. A 7 bp deletion in exon 1 of NKX2-1, resulting in a frame shift and creation of a premature termination codon, was identified in all affected individuals. Screening of 60 unrelated individuals with a diagnosis of dyskinetic or ataxic CP did not identify NKX2-1 mutations. BHC can be confused with ataxic and dyskinetic CP. Occasionally these children have a mutation in NKX2-1.Gai McMichael, Eric Haan, Alison Gardner, Tzu Ying Yap, Suzanna Thompson, Robert Ouvrier, Russell C. Dale, Jozef Gecz, Alastair H. MacLenna

Single-nucleotide polymorphism associations with preterm delivery: a case-control replication study and meta-analysis

BackgroundThe aim of this study was to replicate single-nucleotide polymorphism (SNP) associations with preterm birth (PTB; birth at MethodsSpontaneous PTB cases and controls were selected from an existing cohort. Candidate SNPs were taken from an existing genotype panel. A systematic review was conducted for each SNP in the panel to determine suitability as a PTB candidate. Those with significant associations previously reported in Caucasians were selected for replication. Candidate SNPs were already genotyped in cases and controls and clinical data were accessed from state perinatal and cerebral palsy databases. Association analysis was conducted between each SNP and PTB, and meta-analysis was conducted if there were ≥ 3 studies in the literature. Maternal and fetal SNPs were considered as separate candidates.ResultsA cohort of 170 cases and 583 controls was formed. Eight SNPs from the original panel of genotyped SNPs were selected as PTB candidates and for replication on the basis of systematic literature review results. In our cohort, fetal factor V Leiden (FVL) was significantly associated with PTB (odds ratio (OR): 2.6, 95% confidence interval (CI): 1.31-5.17), and meta-analysis confirmed this association (OR: 2.71, 95% CI: 1.15-6.4).ConclusionReplication and meta-analysis support an increased risk of PTB in Caucasians with the fetal FVL mutation.Michael E. O’Callaghan, Alastair H. MacLennan, Gai L. McMichael, Eric A. Haan and Gustaaf A. Dekke

Rare copy number variation in cerebral palsy

As per publisher: published online 22 May 2013Recent studies have established the role of rare copy number variants (CNVs) in several neurological disorders but the contribution of rare CNVs to cerebral palsy (CP) is not known. Fifty Caucasian families having children with CP were studied using two microarray designs. Potentially pathogenic, rare (<1% population frequency) CNVs were identified, and their frequency determined, by comparing the CNVs found in cases with 8329 adult controls with no known neurological disorders. Ten of the 50 cases (20%) had rare CNVs of potential relevance to CP; there were a total of 14 CNVs, which were observed in <0.1% (<8/8329) of the control population. Eight inherited from an unaffected mother: a 751-kb deletion including FSCB, a 1.5-Mb duplication of 7q21.13, a 534-kb duplication of 15q11.2, a 446-kb duplication including CTNND2, a 219-kb duplication including MCPH1, a 169-kb duplication of 22q13.33, a 64-kb duplication of MC2R, and a 135-bp exonic deletion of SLC06A1. Three inherited from an unaffected father: a 386-kb deletion of 12p12.2-p12.1, a 234-kb duplication of 10q26.13, and a 4-kb exonic deletion of COPS3. The inheritance was unknown for three CNVs: a 157-bp exonic deletion of ACOX1, a 693-kb duplication of 17q25.3, and a 265-kb duplication of DAAM1. This is the first systematic study of CNVs in CP, and although it did not identify de novo mutations, has shown inherited, rare CNVs involving potentially pathogenic genes and pathways requiring further investigation.Gai McMichael, Santhosh Girirajan, Andres Moreno-De-Luca, Jozef Gecz, Chloe Shard, Lam Son Nguyen, Jillian Nicholl, Catherine Gibson, Eric Haan, Evan Eichler, Christa Lese Martin and Alastair MacLenna

The genomics of cerebral palsy : are copy number variants associated with cerebral palsy?

Background Cerebral palsy describes a group of permanent disorders of the development of movement and posture that are attributed to non-progressive disturbances occurring in the developing fetal or infant brain. It is often accompanied by additional features including intellectual disability, autism, epilepsy and visual and hearing impairment. The overall incidence of cerebral palsy has not changed in the last 50 years despite major improvements in perinatal medicine, and remains at around 2- 2.5/1,000 deliveries world-wide. Treatment is symptomatic rather than curative. A child under 18 years of age is three times more likely to be diagnosed with cerebral palsy than cancer. There are major social, economic and quality of life issues for both the child with cerebral palsy and their family. In Australia, approximately 600 children are diagnosed with cerebral palsy each year. Several studies have suggested that genetic susceptibility factors and adverse environmental triggers such as perinatal viral infection can act both independently and in combination to contribute to the neuropathology of cerebral palsy. For the majority of cases the exact determinants responsible for injury to the child’s developing brain have not been defined. This thesis hypothesises that cerebral palsy is genetically highly heterogeneous and caused by many diverse and individually rare mutations of large effect in genes involving brain development, the most common of which are copy number variants (CNVs). Study design To explore the hypothesis that CNVs contribute to the aetiology of cerebral palsy, 50 DNA samples from individuals with cerebral palsy were tested on a custom-designed 180K chromosomal microarray with targeted plus whole genome coverage. The targeted coverage includes known clinically relevant regions such as microdeletion/duplication syndromes, telomeres and centromeres at a resolution of ~20-50 kb plus exon-level coverage of >1200 genes involved in neurodevelopmental disorders. The whole-genome backbone results in a resolution in unique DNA of ~225kb. These same samples were also separately assessed on a 135K custom designed array with targeted coverage of ~50kb in all genomic hotspots and backbone coverage of 350kb. Combined results were compared with 8,329 adult controls with no known neurological disorders. Results Three out of 50 cases were identified with a CNV that included candidate genes of special interest for the cerebral palsy phenotype; CTNND2 (446 kb duplication including the first exon), MCPH1 (219 kb duplication including exons 1-8) and COPS (4 kb deletion including exons 6-8). All three CNVs were shown to be inherited from an unaffected parent. Several additional CNVs of possible interest to the cerebral palsy phenotype were selected from 30 out of 50 cases, including the above three mentioned cases, as they encompassed genes expressed in the brain or were previously recognized in other neurodevelopmental disorders. These included Histone Cluster genes, 7q21 and 12p12.1p12.2, single-gene CNVs across CNTNAP3, MC2R, FSCB, PTCHD3, NPHP1 and TARP and intragenic CNVs in DLGAP2, PARK2, NBEA, PAK2, MACROD2, CNTN1, MPV17L, NF1, NCOR2, NOS3, SH3G13 and TBX1. Conclusion Copy number changes in cerebral palsy cases have been identified in this largest study to date. Amongst 50 cases there were three potential candidate genes for cerebral palsy and several additional variants involved in brain developmental genes. The pathogenicity of these rare CNVs is not currently resolved but these preliminary studies justify further evaluation of CNVs in a larger cohort of cerebral palsy families and functional studies. This is currently underway.Thesis (M.Med.Sc.) -- University of Adelaide, School of Paediatrics & Reproductive Health, 2011

The genetic determinants of cerebral palsy

The main goal of genetic evaluation of individuals living with cerebral palsy is to understand the underlying origin of the disorder, so that those affected, their families and the wider community can benefit from further research leading to prevention, better management and ultimately, treatment. The advent of next generation sequencing technologies (NGS), in particular massively parallel sequencing, is a promising way forward in identifying the causes of, or contribution of genetic variation to, cerebral palsy. These technologies have been successful in increasing understanding of the causes of neurodevelopmental disorders whose phenotypes overlap with cerebral palsy (e.g. intellectual disability, autism and epilepsy), and provide an excellent way forward for cerebral palsy genetic research. However, they also bring with them new challenges, including determining which variants/genes are potentially pathogenic for cerebral palsy. We took an unbiased whole-exome sequencing approach to identify potential pathogenic variants for cerebral palsy in two groups of individuals with cerebral palsy: sporadic cases (no previous family history of cerebral palsy) and families with more than one individual with a confirmed diagnosis of cerebral palsy. Until our work, WES had only been performed in a small number of familial cases. Our overall findings suggest that cerebral palsy is genetically heterogeneous, involving mutations, mainly de novo, in previously known neurodevelopmental genes and novel candidate cerebral palsy genes. The de novo origin of these mutations may explain the typically sporadic nature of cerebral palsy, with most affected individuals having no apparent family history. De novo mutations are also associated with a sizable proportion of sporadic cases of ID and ASD and represent an important cause for both disorders.Thesis (Ph.D.) (Research by Publication) -- University of Adelaide, School of Medicine, 2016

Atrial Fibrillation Health Literacy Questionnaire (AFHLQ): The development of an AF-specific health literacy questionnaire

Background: Health literacy is a key enabler of effective behavioural modification in chronic diseases. While patient reported outcome measures (PROMs) exists for patient with atrial fibrillation (AF), none address risk factors comprehensively. The aim of the study was to develop and qualitatively validate a disease specific PROM that incorporates knowledge on risk factors and assesses interactive and critical health literacy of people living with AF. Methods: The 47-item Atrial Fibrillation Health Literacy Questionnaire (AFHLQ) was developed and validated through a qualitative research design. Expert and Consumer focus groups, each consisting of seven participants provided opinion. Results: The 47-item questionnaire consists of 5 domains: (1) what is AF, (2) what are the symptoms of AF, (3) why do people get AF, (4) management of AF, and (5) what measures can slow or prevent the progression of AF. Recommendations resulted in several changes to the original 47 item list during the qualitative validation process: 13 original items were removed, and 13 new items were added. The response categories were also simplified from a Likert scale to “yes”, “no” or “don't know”. Conclusion: A 47-item AFHLQ instrument was developed and validated with modifications made through clinical expert and consumer opinion. This tool has a potential to be used to evaluate and guide interventions at a clinical and population level to understand and improve AF health literacy and outcomes

Cytomegalovirus and Epstein–Barr virus may be associated with some cases of cerebral palsy

Objective: Intrauterine infection is a risk factor for cerebral palsy. Previous work reported a high frequency of viral DNA in newborn screening cards from cerebral palsy cases and controls possibly due to contamination. Methods: Retrospective case-control study using improved methodologies to minimize contamination during PCR-based detection of viral DNA sequences. Newborn screening cards of 339 Caucasian children with cerebral palsy and 594 controls were examined. Viruses tested were herpes simplex viruses 1 and 2 (HSV1 and 2), varicella zoster virus (VZV), Epstein–Barr virus (EBV), cytomegalovirus (CMV), human herpes viruses 6, 7 and 8 (HHV6, HHV7 and HHV8), and parvovirus B19. Genotyping was performed on DNA extracted from dried blood spots. Results: CMV and EBV were detected in 5 (1.5%) and 3 (0.9%) of 339 cases, respectively, but not in controls (p  = 0.047 and 0.006). Frequencies of detection of the other viruses examined were similar for cases and controls. DNA from at least one of the nine viruses tested was found in 4.4% of cases and 3.1% of controls [OR 1.4 95% CI (0.71–2.76)]. Conclusion: Evidence of congenital viral infection was uncommon in cases of cerebral palsy and controls. However, CMV and EBV were significantly associated with cerebral palsy.Gai McMichael, Alastair MacLennan, Catherine Gibson, Emily Alvino, Paul Goldwater, Eric Haan, Gustaaf Dekke