Association analysis of chromosome 1 migraine candidate genes

Background  

Migraine with aura (MA) is a subtype of typical migraine. Migraine with aura (MA) also encompasses a rare severe subtype Familial Hemiplegic Migraine (FHM) with several known genetic loci. The type 2 FHM (FHM-2) susceptibility locus maps to chromosome 1q23 and mutations in the ATP1A2 gene at this site have recently been implicated. We have previously provided evidence of linkage of typical migraine (predominantly MA) to microsatellite markers on chromosome 1, in the 1q31 and 1q23 regions. In this study, we have undertaken a large genomic investigation involving candidate genes that lie within the chromosome 1q23 and 1q31 regions using an association analysis approach.     

Sequence analysis of 21 genes located in the Kartagener syndrome linkage region on chromosome 15q

Primary ciliary dyskinesia (PCD) is a rare genetic disorder, which shows extensive genetic heterogeneity and is mostly inherited in an autosomal recessive fashion. There are four genes with a proven pathogenetic role in PCD. DNAH5 and DNAI1 are involved in 28 and 10% of PCD cases, respectively, while two other genes, DNAH11 and TXNDC3, have been identified as causal in one PCD family each. We have previously identified a 3.5 cM (2.82 Mb) region on chromosome 15q linked to Kartagener syndrome (KS), a subtype of PCD characterized by the randomization of body organ positioning. We have now refined the KS candidate region to a 1.8 Mb segment containing 18 known genes. The coding regions of these genes and three neighboring genes were subjected to sequence analysis in seven KS probands, and we were able to identify 60 single nucleotide sequence variants, 35 of which resided in mRNA coding sequences. However, none of the variations alone could explain the occurrence of the disease in these patients.     

Exome sequencing reveals NAA15 and PUF60 as candidate genes associated with intellectual disability

Intellectual Disability (ID) is a clinically heterogeneous condition that affects 2–3% of population worldwide. In recent years, exome sequencing has been a successful strategy for studies of genetic causes of ID, providing a growing list of both candidate and validated ID genes. In this study, exome sequencing was performed on 28 ID patients in 27 patient‐parent trios with the aim to identify de novo variants (DNVs) in known and novel ID associated genes. We report the identification of 25 DNVs out of which five were classified as pathogenic or likely pathogenic. Among these, a two base pair deletion was identified in the PUF60 gene, which is one of three genes in the critical region of the 8q24.3 microdeletion syndrome (Verheij syndrome). Our result adds to the growing evidence that PUF60 is responsible for the majority of the symptoms reported for carriers of a microdeletion across this region. We also report variants in several genes previously not associated with ID, including a de novo missense variant in NAA15. We highlight NAA15 as a novel candidate ID gene based on the vital role of NAA15 in the generation and differentiation of neurons in neonatal brain, the fact that the gene is highly intolerant to loss of function and coding variation, and previously reported DNVs in neurodevelopmental disorders.     

Two translocations of chromosome 15q associated with dyslexia

Developmental dyslexia is characterised by difficulties in learning to read. As reading is a complex cognitive process, multiple genes are expected to contribute to the pathogenesis of dyslexia. The genetics of dyslexia has been a target of molecular studies during recent years, but so far no genes have been identified. However, a locus for dyslexia on chromosome 15q21 (DYX1) has been established in previous linkage studies. We have identified two families with balanced translocations involving the 15q21-q22 region. In one family, the translocation segregates with specific dyslexia in three family members. In the other family, the translocation is associated with dyslexia in one family member. We have performed fluorescence in situ hybridisation (FISH) studies to refine the position of the putative dyslexia locus further. Our results indicate that both translocation breakpoints on 15q map within an interval of approximately 6-8 Mb between markers D15S143 and D15S1029, further supporting the presence of a locus for specific dyslexia on 15q21.


Keywords: dyslexia; reading disability; chromosome 15; translocation     

具有家族史鼻咽癌4p15.1-4q12区等位基因杂合性丢失分析

目的确定有家族史鼻咽癌患者4p15．1-4q12区域等位基因杂合性丢失（loss of heterozygosity，LOH）的分布和频率，为进一步缩小该区域内易感基因的范围提供新的线索和依据。方法收集具有家族史的鼻咽癌患者石蜡包埋的活检组织标本，采用显微切割的方法在肿瘤组织石蜡切片上分离肿瘤细胞和正常淋巴细胞，选定7个定位于4p15．1-4q12区域内的高密度微卫星位点，多重PCR扩增和丙烯酰胺凝胶电泳后，Genescan软件对各位点LOH进行分析。结果25例具家族史鼻咽癌患者中，23例在4p15．1-4q12区至少存在一个微卫星位点的LOH（92％）。其中D4S2382位点LOH的频率最高，达到56％；D4S350和D4S1547位点LOH频率均约为50％。最小共同缺失区位于位点D4S350和D4S1547之间。结论鼻咽癌4p15．1—4q12区域内的易感基因可能位于微卫星位点D4S350和D4S1547附近。     

Meta-analysis for linkage to asthma and atopy in the chromosome 5q31-33 candidate region

Asthma is a common, complex human disease. Gene discovery inasthma has been complicated by substantial etiological heterogeneity,the possibility of genes of small effect and the concomitantrequirement for large sample sizes. Linkage to asthma phenotypeshas been investigated most intensively in the 5q chromosomalregion, although results have been inconsistent across studiesand all studies have had modest sample sizes. One potentialsolution to these issues is to combine data from multiple studiesin a retrospective meta-analysis by pooling either summary statisticsor raw data. The International Consortium on Asthma Genetics combined data from 11 data sets (n = 6277 subjects) to investigateevidence for linkage of 35 markers spanning the cytokine clusteron chromosome 5q31–33 to ‘asthma’ dichotomyand total serum immunoglobulin E (IgE) levels. Chromosome 5qmarkers typed in different centers were integrated into a consensusmap to facilitate effective data pooling. Multipoint linkageanalyses using a new Haseman–Elston method were performedwith all data sets pooled together, and also separately withthe resulting linkage statistics pooled by meta-analytic methods.Our results did not provide any evidence significant at the5% level that loci conferring susceptibility to asthma or atopyare present in the 5q31–33 region; however, there wassome weak evidence (empirical P = 0.077) of linkage toasthma affection. This study suggests that loci in 5q31–33have at most a modest effect on susceptibility to asthma ortotal serum IgE levels, may not be detectable or present inall human populations and are difficult to detect even usingcombined linkage evidence from 2400–2600 full siblingpairs. ⁺ To whom correspondence should be addressed. Tel: +1 617 5250872; Fax: +1 617 525 0958; Email: reljp@channing.harvard.edu.     

Confirmation that the velo-cardio-facial syndrome is associated with haplo-insufficiency of genes at chromosome 22q11

The velo-carido-facial syndrome (VCFS) and DiGeorge sequence (DGS) have many similar phenotypic characteristics, suggesting that in some cases they share a common cause. DGS is known to be associated with monosomy for a region of chromosome 22q11, and DNA probes have been shown to detect these deletions even in patients with apparently normal chromosomes. Twelve patients with VCFS were examined and monsomy for a region of 22q11 was found in all patients. The DNA probes used in this study could not distinguish the VCFS locus and the DGS locus, indicating that the genes involved in these haplo-insufficiencies are closely linked, and may be identical. The phenotypic variation of expression in VCFS and DGS may indicate that patients without the full spectrum of VCFS abnormalities but with some manifestations of the disorder may also have 22q11 deletions. © 1993 Wiley-Liss, Inc.     

Duplication of chromosome 15 in the region 15q11-13 in a patient with developmental delay and ataxia with similarities to Angelman syndrome.

Duplications of the proximal long arm of chromosome 15 have been seen in the Prader-Willi syndrome (PWS), and in subjects without the Prader-Willi phenotype but with other clinical features including short stature, diabetes, anal and jejunal atresia, and acanthosis nigricans. The non-PWS subjects all had different phenotypes despite the identical findings on cytogenetic analysis. A normal phenotype has also been observed in patients with similar duplications. We report a further patient with a duplication of 15q11-13 which was detected cytogenetically and confirmed on molecular genetic analysis. She has developmental delay, particularly concerning the acquisition of speech, and an ataxic gait. These are interesting clinical features in view of the association of Angelman syndrome with abnormalities of 15q11-13.     

Linkage analysis of a candidate region in Scandinavian sib pairs with multiple sclerosis reveals linkage to chromosome 17q

To date, four genome screens have been completed in the demyelinating autoimmune disease multiple sclerosis (MS). Although these screens failed to identify any loci with major effects on susceptibility, several novel regions of potential linkage were suggested, including the long arm of chromosome 17. In order to further pursue this promising region we have investigated six highly polymorphic microsatellite markers in 115 Scandinavian families with MS affected sib pairs. Multipoint linkage analysis revealed a peak maximum likelihood score (MLS) of 0.9 in the region of marker D17S787. Stratifying the results on the basis of HLA-DR2 status showed that the linkage was not limited to families segregating for the HLA-DR2 allele as has previously been suggested. In conclusion, our results further support the proposal that a multiple sclerosis susceptibility locus is contained on chromosome 17q.     

Narrowing the deleted region associated with the 15q21 syndrome

Interstitial deletions of chromosome 15q, not involving the PWS/AS region, are uncommon and poorly characterized. Few cases defined at the cytogenetic level have been reported with 15q21 deletions and characteristic facial dysmorphisms are present in all them. We report on the molecular characterization by array-CGH of a new patient with a 15q21 deletion and on the redefinition of a second patient previously studied with multicolor banding. The two deletions resulted to be similar and involve about 12 and 8 Mb, respectively. Our study might promote to delineate a better genotype-phenotype correlation associated with 15q21 deletions.     

Mutation screening and association analysis of six candidate genes for autism on chromosome 7q

Genetic studies have provided evidence for an autism susceptibility locus (AUTS1) on chromosome 7q. Screening for mutations in six genes mapping to 7q, CUTL1, SRPK2, SYPL, LAMB1, NRCAM and PTPRZ1 in 48 unrelated individuals with autism led to the identification of several new coding variants in the genes CUTL1, LAMB1 and PTPRZ1. Analysis of genetic variants provided evidence for association with autism for one of the new missense changes identified in LAMB1; this effect was stronger in a subgroup of affected male sibling pair families, implying a possible specific sex-related effect for this variant. Association was also detected for several polymorphisms in the promoter and untranslated region of NRCAM, suggesting that alterations in expression of this gene may be linked to autism susceptibility.     

Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting via the GABAA receptors. The GABAA receptors are comprised of several different homologous subunits, forming a group of receptors that are both structurally and functionally diverse. Three of the GABAA receptor subunit genes (GABRB3, GABRA5 and GABRG3) form a cluster on chromosome 15q11-q13, in a region that has been genetically associated with autistic disorder (AutD). Based on these data, we examined 16 single nucleotide polymorphisms (SNPs) located within GABRB3, GABRA5 and GABRG3 for linkage disequilibrium (LD) in 226 AutD families (AutD patients and parents). Genotyping was performed using either OLA (oligonucleotide ligation assay), or SSCP (single strand conformation polymorphism) followed by DNA sequencing. We tested for LD using the Pedigree Disequilibrium Test (PDT). PDT results gave significant evidence that AutD is associated with two SNPs located within the GABRG3 gene (exon5_539T/C, p=0.02 and intron5_687T/C, p=0.03), suggesting that the GABRG3 gene or a gene nearby contributes to genetic risk in AutD.     

Gene-based single nucleotide polymorphisms and linkage disequilibrium patterns of 29 asthma candidate genes in the chromosome 5q31-33 region in Koreans

BACKGROUND AND METHODS: Numerous genetic studies have mapped asthma susceptibility genes to a region on chromosome 5q31-33 in several populations. This region contains a cluster of cytokines and other immune-related genes important in immune response. In the present study, to determine the genetic variations and patterns of linkage disequilibrium (LD), we resequenced all the exons and promoter regions of the 29 asthma candidate genes in the chromosome 5q31-33 region. RESULTS: We identified a total of 314 genetic variants, including 289 single nucleotide polymorphisms (SNPs), 22 insertion/deletion polymorphisms and 3 microsatellites. Standardized variance data for allele frequency revealed substantial differences in SNP allele frequencies among different ethnic groups. Interestingly, significant ethnic differences were observed mainly in intron SNPs. LD block analysis using 174 common SNPs with a frequency of >10% disclosed strong LD within most candidate genes. No significant LD was observed across genes, except for one LD block (CD14-IK block). Gene-based haplotype analyses showed that 1-5 haplotype-tagging SNPs may be used to define the six or fewer common haplotypes with a frequency of >5%, regardless of the number of SNPs. CONCLUSION: Overall, our results provide useful information for the identification of immune-mediated disease genes in the chromosome 5q31-33 region, as well as valuable evidence for gene-based haplotype analysis in disease association studies.