Evidence for an ependymoma tumour suppressor gene in chromosome region 22pter–22q11.2

Ependymomas are glial tumours of the brain and spinal cord. The most frequent genetic change in sporadic ependymoma is monosomy 22, suggesting the presence of an ependymoma tumour suppressor gene on that chromosome. Clustering of ependymomas has been reported to occur in some families. From an earlier study in a family in which four cousins developed an ependymoma, we concluded that an ependymoma-susceptibility gene, which is not the NF2 gene in 22q12, might be located on chromosome 22. To localize that gene, we performed a segregation analysis with chromosome 22 markers in this family. This analysis revealed that the susceptibility gene may be located proximal to marker D22S941 in 22pter–22q11.2. Comparative genomic hybridization showed that monosomy 22 was the sole detectable genetic aberration in the tumour of one of the patients. Loss of heterozygosity studies in that tumour revealed that, in accordance to Knudson’s two-hit theory of tumorigenesis, the lost chromosome 22 originated from the parent presumed to have contributed the wild-type allele of the susceptibility gene. Thus, our segregation and tumour studies collectively indicate that an ependymoma tumour suppressor gene may be present in region 22pter–22q11.2. © 1999 Cancer Research Campaig

Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism

The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well

Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy

Association Testing Of Copy Number Variants in Schizophrenia and Autism Spectrum Disorders

Background: Autism spectrum disorders and schizophrenia have been associated with an overlapping set of copynumber variant loci, but the nature and degree of overlap in copy number variants (deletions compared toduplications) between these two disorders remains unclear.Methods: We systematically evaluated three lines of evidence: (1) the statistical bases for associations of autismspectrum disorders and schizophrenia with a set of the primary CNVs thus far investigated, from previous studies;(2) data from case series studies on the occurrence of these CNVs in autism spectrum disorders, especially amongchildren, and (3) data on the extent to which the CNVs were associated with intellectual disability anddevelopmental, speech, or language delays. We also conducted new analyses of existing data on these CNVs inautism by pooling data from seven case control studies.Results: Four of the CNVs considered, dup 1q21.1, dup 15q11-q13, del 16p11.2, and dup 22q11.21, showed clearstatistical evidence as autism risk factors, whereas eight CNVs, del 1q21.1, del 3q29, del 15q11.2, del 15q13.3, dup16p11.2, dup 16p13.1, del 17p12, and del 22q11.21, were strongly statistically supported as risk factors forschizophrenia. Three of the CNVs, dup 1q21.1, dup 16p11.2, and dup 16p13.1, exhibited statistical support as riskfactors for both autism and schizophrenia, although for each of these CNVs statistical significance was nominal fortests involving one of the two disorders. For the CNVs that were statistically associated with schizophrenia but werenot statistically associated with autism, a notable number of children with the CNVs have been diagnosed withautism or ASD; children with these CNVs also demonstrate a high incidence of intellectual disability anddevelopmental, speech, or language delays.Conclusions: These findings suggest that although CNV loci notably overlap between autism and schizophrenia,the degree of strongly statistically supported overlap in specific CNVs at these loci remains limited. These analysesalso suggest that relatively severe premorbidity to CNV-associated schizophrenia in children may sometimes bediagnosed as autism spectrum disorder

Biallelic PRMT7 pathogenic variants are associated with a recognizable syndromic neurodevelopmental disorder with short stature, obesity, and craniofacial and digital abnormalities.

PURPOSE: Protein arginine methyltransferase 7 (PRMT7) is a member of a family of enzymes that catalyzes the methylation of arginine residues on several protein substrates. Biallelic pathogenic PRMT7 variants have previously been associated with a syndromic neurodevelopmental disorder characterized by short stature, brachydactyly, intellectual developmental disability, and seizures. To our knowledge, no comprehensive study describes the detailed clinical characteristics of this syndrome. Thus, we aim to delineate the phenotypic spectrum of PRMT7-related disorder. METHODS: We assembled a cohort of 51 affected individuals from 39 different families, gathering clinical information from 36 newly described affected individuals and reviewing data of 15 individuals from the literature. RESULTS: The main clinical characteristics of the PRMT7-related syndrome are short stature, mild to severe developmental delay/intellectual disability, hypotonia, brachydactyly, and distinct facial morphology, including bifrontal narrowing, prominent supraorbital ridges, sparse eyebrows, short nose with full/broad nasal tip, thin upper lip, full and everted lower lip, and a prominent or squared-off jaw. Additional variable findings include seizures, obesity, nonspecific magnetic resonance imaging abnormalities, eye abnormalities (i.e., strabismus or nystagmus), and hearing loss. CONCLUSION: This study further delineates and expands the molecular, phenotypic spectrum and natural history of PRMT7-related syndrome characterized by a neurodevelopmental disorder with skeletal, growth, and endocrine abnormalities