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Background: Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. Methods: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. Results: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. Conclusion: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. Methods: We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. Results: We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. Conclusion: Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

Background Pallister-Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects. Methods We describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS. Results We reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region-specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS. Conclusion Our study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

© 2016 Wiley Periodicals, Inc. Copy Number Variations (CNVs) comprising the distal 1q region 1q43-q44 are associated with neurological impairments, structural brain disorder, and intellectual disability. Here, we report an extremely rare, de novo case of a 1q43-q44 deletion with an adjacent duplication, associated with severe seizures, microcephaly, agenesis of the corpus callosum, and pachygyria, a consequence of defective neuronal migration disorder. We conducted a literature survey to find that our patient is only the second case of such a 1q43-q44 CNV ever to be described. Our data support an association between 1q43-q44 deletions and microcephaly, as well as an association between 1q43-q44 duplications and macrocephaly. We compare and contrast our findings with previous studies reporting on critical 1q43-q44 regions and their constituent genes associated with seizures, microcephaly, and corpus callosum abnormalities [Ballif et al., 2012; Hum Genet 131:145-156; Nagamani et al., 2012; Eur J Hum Genet 20:176-179]. Taken together, our study reinforces the association between 1q43-q44 CNVs and brain disorder.

Objectives - Some associations between antiepileptic drugs (AEDs) and fracture risk have been reported in the general population. This study investigated the relationships between fracture risk and commonly used AEDs in Rett syndrome, a genetic disorder associated with intellectual and physical disability. Study design - Cases (n=233) were sourced from the population-based Australian Rett Syndrome Database and longitudinal data were used. The Cox proportional hazard model was used to analyse relationships between fracture and prescribed AEDs, mobility, epilepsy diagnosis and genotype. Results - After controlling for mobility, epilepsy diagnosis and genotype, use of valproate increased the risk of fracture threefold after at least 1 year (HR 3.56; 95% CI 1.85 to 6.82) and after 2 or more years (HR 3.02; 95% CI 1.90 to 4.80). There was a lesser increased risk (HR 1.99; 95% CI 0.99 to 4.02) with lamotrigine in the first year of use but not for subsequent years of use. Carbamazepine slightly decreased the risk (HR 0.60; 95% CI 0.35 to 1.02) after 2 or more years of use. Conclusions - The effect of valproate on bone health should be considered when managing epilepsy in Rett syndrome. Multiple mechanisms could be contributing to this effect.

Background: There is a growing expectation that cell-based therapies will prove effective for a wide range of conditions including lung diseases such as cystic fibrosis. The promise of these therapies will depend largely on effective delivery and engraftment. In this study, in the setting of human lung transplantation, we sought to determine whether exogenous epithelial cells are able to engraft the transplanted organ and if cells of a similar phenotype could be detected in peripheral blood. Methods: Cells obtained from bronchial brushings and peripheral blood were analyzed via dual fluorescent in situ hybridization/fluorescent immunohistochemistry (FISH/IHC), short tandem repeat polymerase chain reaction (STR-PCR) and flow cytometry. Results: In 2 of 3 gender-mismatched patients we observed limited (5.9% to 6.8% by STR-PCR and 3.5% to 4% by FISH/IHC) engraftment of the bronchial epithelium by exogenous epithelial cells. Engrafting cells were CD34- CD15- CD68- c-Kit-, but expressed CXCR4 on the cell surface. Cells with a similar phenotype were also identified in peripheral blood. In 8 patients, at 2 to 66 months post-transplant, 0.57 ± 0.17% of CD14- peripheral blood mononuclear cells were of epithelial lineage. Almost all were CD45+ and most expressed CXCR4 on the cell membrane. Cells of epithelial lineage were also identified in peripheral blood in healthy individuals but in much lower numbers (0.08 ± 0.01%, p < 0.05). Conclusions: Cells of epithelial lineage are detectable in peripheral blood and are able to engraft the bronchial epithelium in humans. Cell numbers are increased in lung transplantation. Crown Copyright © 2009.

MECP2, a relatively small gene located in the human X chromosome, was initially described with three exons transcribing RNA from which the protein MeCP2 was translated. It is now known to have four exons from which two isoforms are translated; however, there is also evidence of additional functional genomic structures within MECP2, including exons potentially transcribing non-coding RNAs. Accompanying the recognition of a higher level of intricacy within MECP2 has been a recent surge of knowledge about the structure and function of human genes more generally, to the extent that the definition of a gene is being revisited. It is timely now to review the published and novel functional elements within MECP2, which is proving to have a complexity far greater than was previously thought.

Background: Rett syndrome is a neurodevelopmental disorder mainly affecting females. It is principally caused by mutations in the MECP2 gene. Seizures occur in about 80% of subjects but there has been little research into the factors contributing to their frequency. Aims: To investigate seizure frequency in Rett syndrome and its relationship with other factors, including genetic characteristics and the use of anti-epileptic drugs. Methods: Information on daily seizure occurrence and health service utilization and monthly anti-epileptic drug use was provided on 162 Rett syndrome cases for a calendar year. Age at onset of seizures, developmental history and other clinical and genetic characteristics were obtained from a contemporaneously completed questionnaire and from the Australian Rett Syndrome Database. Negative binomial regression was used to investigate factors associated with seizure rates. Results: Seizure rates were highest in the 7-12 year age group. They were lower in those with p.R294X, p.R255X mutations and C terminal mutations. Those who had early developmental problems and poorer mobility had higher seizure rates as did those with greater clinical severity and poorer functional ability. Many different combinations of medications were being used with carbamazepine, sodium valproate and lamotrigine either singly or in combination with another being the most common. Conclusions: Seizure frequency in Rett syndrome is age-dependent, more common in those with more severe early developmental problems and influenced by mutation type.

Objective: To audit the clinical indications for HFE gene mutation testing in a consecutive series of requests.Design: Retrospective audit of reasons prompting 187 HFE test requests received between June 2003 and June 2005, by examination of the request form, hospital notes (when available) and, when required, information from the referring doctor.Setting: A tertiary care public teaching hospital laboratory, Perth, Western Australia.Main outcome measures: Reasons prompting requests for HFE genotype testing and compliance with accepted clinical indications (biochemical evidence of iron overload on repeated samples, or a first-degree relative with either haemochromatosis or a C282Y mutation).Results: Insufficient clinical details in requests prevented the inclusion of interpretive comments in HFE genotype reports in 70 of 187 cases (37%). Re-evaluation after collation of the missing details for all but seven requests revealed that 103 of the 180 auditable requests (57%) had been prompted for reasons other than biochemical evidence of iron accumulation or family history.Conclusions: A substantial proportion of HFE genotype test requests are made for inappropriate reasons. Clinical practice could be improved by educating doctors on the practical utility of this genetic test and by laboratories taking steps to secure the clinical information needed to include appropriate interpretive comments in their reports.

Rett syndrome (RTT) is a severe neurodevelopmental disorder mainly affecting female patients and caused by mutationsin the methyl-CpG binding protein 2 (MECP2) gene. Major features include loss of acquired skills, such as speech andpurposeful hand use, and the development of characteristic repetitive hand stereotypies, after relatively normal earlydevelopment. Other features include deceleration of head growth, impaired locomotion, autonomic dysfunction (manifestparticularly by respiratory abnormalities), scoliosis, and epilepsy. Epilepsy, which occurs in 50% to 94% of cases, and may be medically refractory, is among the most challenging of the comorbidities for those affected and their families. However, little is known about the predictors of seizures, including the relation, if any, to the underlying gene defect.This study explores possible genetic and other risk factors for seizure onset in RTT by using an Australian population-based longitudinal data set.

Among cases in the Australian Rett Syndrome Database, the nonsense mutation p.R270X is one of the most commonly occurring single pathogenic MECP2 mutations. In two recent published reports of the MECP2 mutational spectrum the p.R270X appeared to be under represented. We hypothesised that increased mortality arising from this mutation may underlie this apparent discrepancy. We investigated our hypothesis in two independent study groups from Australia and the UK with prospective data collections (total n=524). Only females with Rett syndrome and an identified MECP2 mutation were included. Significant differences in survival were detected among Rett syndrome cases grouped for the eight most frequent mutations (log-rank v2 (7)=15.71, P=0.03). Moreover, survival among cases with p.R270X, when compared with survival among cases with all the other mutations was reduced (log-rank v2 (2)=6.94, P=0.01). Our observation of a reduced survival associated with the p.R270X mutation offers an explanation for the under representation of p.R270X in older subjects with Rett syndrome.