Search

Background the hallmark of the neurobehavioural phenotype of Williams-Beuren syndrome (WBS) is increased sociability and relatively preserved language skills, often described as opposite to autism spectrum disorders (ASD). However, the prevalence of ASD in WBS is 6-10 times higher than in the general population. We have investigated the genetic factors that could contribute to the ASD phenotype in individuals with WBS. Methods We studied four males and four females with WBS and a confirmed diagnosis of ASD by the autism Diagnostic interview-revised. We performed a detailed molecular characterisation of the deletion and searched for genomic variants using exome sequencing. Results a de novo deletion of 1.55 Mb (6 cases) or 1.83 Mb (2 cases) at 7q11.23 was detected, being in 7/8 patients of paternal origin. no common breakpoint, deletion mechanism or size was found. two cases were hemizygous for the rare t allele at rs12539160 in MLXIPL, previously associated with ASD. inherited rare variants in ASD-related or functionally constrained genes and a de novo nonsense mutation in the UBR5 gene were identified in six cases, with higher burden in females compared with males (p=0.016). Conclusions the increased susceptibility to ASD in patients with WBS might be due to additive effects of the common WBS deletion, inherited and de novo rare sequence variants in ASD-related genes elsewhere in the genome, with higher burden of deleterious mutations required for females, and possible hypomorphic variants in the hemizygous allele or cis-acting mechanisms on imprinting. [ABSTRACT FROM AUTHOR]

Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement 'hotspot' loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained. Objective To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype. Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls. Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10-6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10-12, OR 7.45, 95% CI 4.20-13.5). Outside hotspots, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10-3,OR 2.85, 95% CI 1.62-4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls. Conclusions Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE. [ABSTRACT FROM AUTHOR]

Background The pseudoautosomal short stature homeobox-containing (SHOX) gene encodes a homeodomain transcription factor involved in cell-cycle and growth regulation. SHOX/SHOX enhancers deletions cause short stature and skeletal abnormalities in a female-dominant fashion; duplications appear to be rare. Neurodevelopmental disorders (NDDs), such as autism spectrum disorders (ASDs), are complex disorders with high heritability and skewed sex ratio; several rare (<1% frequency) CNVs have been implicated in risk. Methods We analysed data from a discovery series of 90 adult ASD cases, who underwent clinical genetic testing by array-comparative genomic hybridisation (CGH). Twenty-seven individuals harboured CNV abnormalities, including two unrelated females with microduplications affecting SHOX. To determine the prevalence of SHOX duplications and delineate their associated phenotypic spectrum, we subsequently examined array-CGH data from a follow-up sample of 26 574 patients, including 18 857 with NDD (3541 with ASD). Results We found a significant enrichment of SHOX microduplications in the NDD cases (p=0.00036; OR 2.21) and, particularly, in those with ASD (p=9.18×10-7; OR 3.63) compared with 12 594 population-based controls. SHOX duplications affecting the upstream or downstream enhancers were enriched only in females with NDD (p=0.0043; OR 2.69/ p=0.00020; OR 7.20), but not in males (p=0.404; OR 1.38/p=0.096; OR 2.21). Conclusions Microduplications at the SHOX locus are a low penetrance risk factor for ASD/NDD, with increased risk in both sexes. However, a concomitant duplication of SHOX enhancers may be required to trigger a NDD in females. Since specific SHOX isoforms are exclusively expressed in the developing foetal brain, this may reflect the pathogenic effect of altered SHOX protein dosage on neurodevelopment. [ABSTRACT FROM AUTHOR]

Objective We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. Methods We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. Results We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 30 and 50 exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. Conclusions SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers. [ABSTRACT FROM AUTHOR]

In humans, most of the genetic variation is rare and often population-specific. Whereas the role of rare genetic variants in familial monogenic diseases is firmly established, we are only now starting to explore the contribution of this class of genetic variation to human common diseases and other complex traits. Such largescale experiments are possible due to the development of next-generation DNA sequencing. Early findings suggested that rare and low-frequency coding variation might have a large effect on human phenotypes (eg, PCSK9 missense variants on low-density lipoproteincholesterol and coronary heart diseases). This observation sparked excitement in prognostic and diagnostic medicine, as well as in genetics-driven strategies to develop new drugs. In this review, I describe results and present initial conclusions regarding some of the recent rare and low-frequency variant discoveries. We can already assume that most phenotype-associated rare and low-frequency variants have modest-to-weak phenotypical effect. Thus, we will need large cohorts to identify them, as for common variants in genome-wide association studies. As we expand the list of associated rare and low-frequency variants, we can also better recognise the current limitations: we need to develop better statistical methods to optimally test association with rare variants, including non-coding variation, and to account for potential confounders such as population stratification. [ABSTRACT FROM AUTHOR]

Background Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. Aim To identify CNVs associated with osteoporotic bone fracture risk. Method We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. Results A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p=8.69×10-5). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p=0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. [ABSTRACT FROM AUTHOR]

Background The contribution of copy-number variation (CNV) to disease has been highlighted with the widespread adoption of array-based comparative genomic hybridisation (aCGH) and microarray technology. Contiguous gene deletions involving ANKRD11 in 16q24.3 are associated with autism spectrum disorder (ASD) and intellectual disability (ID), while 16q24.1 deletions affecting FOXF1 are associated with congenital renal malformations, alveolar capillary dysplasia, and various other abnormalities. The disease associations of deletions in the intervening region, 16q24.2, have only been defined to a limited extent. Aim To determine whether deletions affecting 16q24.2 are correlated with congenital anomalies. Methods 35 individuals, each having a deletion in 16q24.2, were characterised clinically and by aCGH and/ or SNP-genotyping microarray. Results Several of the 35 16q24.2 deletions identified here closely abut or overlap the coding regions of FOXF1 and ANKRD11, two genes that have been previously associated with the disease. 25 patients were reported to have ASD/ID, and three were found to have bilateral hydronephrosis. 14 of the deletions associated with ASD/ ID overlap the coding regions of FBXO31 and MAP1LC3B. These same genes and two others, C16orf95 and ZCCHC14, are also included in the area of minimal overlap of the three deletions associated with hydronephrosis. Conclusions Our data highlight 16q24.2 as a region of interest for ASD, ID and congenital renal malformations. These conditions are associated, albeit without complete penetrance, with deletions affecting C16orf95, ZCCHC14, MAP1LC3B and FBXO31. The function of each gene in development and disease warrants further investigation. [ABSTRACT FROM AUTHOR]

Background Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited. Objective Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing. Results Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with nonprogressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial nonsyndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation. Conclusion The authors have evidence that loss-offunction of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue including Stephen Scherer on the pericentromeric euchromatic variant on chromosome 9, Daryl Scott on the causes of isolated or syndromic diaphragmatic hernia and Johns Hopkins on parental origin and mechanism of mosaic trisomy.

Background Recurrent microdeletions and microduplications of ~555 kb at 16p11.2 confer susceptibility to autism spectrum disorder (ASD) in up to 1% of ASD patients. No physical or behavioural features have been identified that distinguish these individuals as having a distinct ASD subtype, but clinical data are limited. Methods We report five autistic probands identified by microarray analysis with copy number variation (CNV) of 16p11.2 (three deletions, two duplications). Each patient was assessed for ASD and dysmorphic features. We also describe a deletion positive 26-month-old female who has developmental delay (DD) and autistic features. Results Proband 1 (female with ASD, de novo deletion) is not dysmorphic. Proband 2 (male with autism, de novo deletion) and proband 3 and his brother (males with autism, inherited deletions) are dysmorphic, but the two probands do not resemble one another. The mother of proband 3 has mild mental retardation (MR), minor dysmorphism and meets the criteria for ASD. Proband 4 (dysmorphic autistic male, de novo duplication) had a congenital diaphragmatic hernia. Proband 5 (non-dysmorphic ASD female with a duplication) has two apparently healthy duplication positive relatives. Probands 1 and 2 have deletion negative siblings with ASD and Asperger syndrome, respectively. Proband 6 (a female with DD and an inherited duplication) is dysmorphic, but has oligohydramnios sequence. Conclusions The phenotypic spectrum associated with CNV at 16p11.2 includes ASD, MR/DD and/or possibly other primary psychiatric disorders. Compared with the microduplications, the reciprocal microdeletions are more likely to be penetrant and to be associated with non-specific major or minor dysmorphism. There are deletion positive ASD probands with a less severe phenotype than deletion negative ASD siblings underscoring the significant phenotypic heterogeneity. [ABSTRACT FROM AUTHOR]