Clinical and molecular characteristics of FMR1 microdeletion in patient with fragile X syndrome and review of the literature.

BACKGROUND: Fragile X syndrome (FXS) is mainly caused by FMR1 CGG repeat expansions. Other types of mutations, particularly deletions, are also responsible for FXS phenotypes, however these mutations are often missed by routine clinical testing. MATERIALS AND METHODS: Molecular diagnosis in cases of suspected FXS was a combination of PCR and Southern blot. Measurement of the FMRP protein level was useful for detecting potentially deleterious impact. RESULTS: PCR analysis and Southern blot revealed a case with premutation and suspected deletion alleles. Sanger sequencing showed that the deletion involved 313 bp upstream of repeats and some parts of CGG repeat tract, leaving transcription start site. FMRP was detected in 5.5 % of blood lymphocytes. CONCLUSION: According to our review of case reports, most patients carrying microdeletion and full mutation had typical features of FXS. To our knowledge, our case is the first to describe mosaicism of a premutation and microdeletion in the FMR1 gene. The patient was probably protected from the effects of the deletion by mosaicism with premutation allele, leading to milder phenotype. It is thus important to consider appropriate techniques for detecting FMR1 variants other than repeat expansions which cannot be detected by routine FXS diagnosis.

Case report: Molecular analysis of a 47,XY,+21/46,XX chimera using SNP microarray and review of literature.

Chimerism is a very rare genetic finding in human. Most reported cases have a chi 46,XX/46,XY karyotype. Only three non-twin cases carrying both trisomy 21 and a normal karyotype have been reported, including two cases with a chi 47,XY,+21/46,XX karyotype and a case with a chi 47,XX,+21/46,XY karyotype. Herein we describe an additional case with a chi 47,XY,+21/46,XX karyotype. For the case, a physical examination at the age of 1 year revealed ambiguous genitalia with no features of Down syndrome or other malformations. Growth and developmental milestones were within normal ranges. We performed short tandem repeat (STR) and single nucleotide polymorphism (SNP) microarray analyses to attempt to identify the mechanism underlying the chimerism in this patient and the origin of the extra chromosome 21. Cytogenetic analyses of the patient's peripheral blood revealed approximately 17% of a 47,XY,+21 lineage by G-banding karyotype analysis, 13%-17% by FISH analyses of uncultured peripheral blood, and 10%-15% by SNP microarray analysis. Four years later, the percentage of trisomy 21 cells had decreased to approximately 6%. SNP microarray and STR analyses revealed a single maternal and double paternal genetic contribution to the patient for the majority of the markers, including the chromosome 21 markers. The extra chromosome 21 was paternally derived and meiosis I nondisjunction likely occurred during spermatogenesis. The mechanisms underlying chimera in our case was likely fertilization two spermatozoa, one with an ovum and the other with the second polar body.

Association between 19-bp Insertion/Deletion Polymorphism of Dopamine ß-Hydroxylase and Autism Spectrum Disorder in Thai Patients.

Background and Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder the cause of which is not fully known. Genetic factors are believed to play a major role in the etiology of ASD. However, genetic factors have been identified in only some cases, and other causes remain to be identified. This study aimed to identify potential associations between ASD and the 19-bp insertion/deletion polymorphism in the dopamine beta-hydroxylase (DBH) gene which plays a crucial role in the metabolism of neurotransmitters. Materials and Methods: The 19-bp insertion/deletion polymorphism upstream of the DBH gene was analyzed for associations in 177 ASD patients and 250 healthy controls. Family-based analysis was performed in family trios of each patient using the transmission disequilibrium test to investigate the potential contributions of this DBH polymorphism to ASD. Results: The frequency of the 19-bp insertion allele was significantly higher in the patient group compared to the controls (0.624 vs. 0.556, respectively; p = 0.046). The frequency of the insertion/insertion genotype was also higher in the patient group (0.378 vs. 0.288, respectively) but without statistical significance (p = 0.110). The family-based analysis showed an association between patient families and the insertion allele when only families of male participants were analyzed (73 vs. 48 events; OR 1.521; 95% CI 1.057-2.189; p = 0.023). Conclusions: This population-based analysis found an association between the 19-bp insertion allele of the DBH gene and ASD. No association at the genotype level was found. The family-based analysis found an association between the insertion allele and ASD when the analysis was performed on male participants only, suggesting a linkage between the DBH locus and ASD.

Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

No Evidence of Abnormal Expression of Beta-Catenin and Bcl-2 Proteins in Pilomatricoma as One Clinical Feature of Tetrasomy 9p Syndrome.

BACKGROUND: Little is currently known about the genetics of pilomatricoma. A number of studies have reported some evidence that this disease may have a genetic association with mutations of CTNNB1 gene or expression of the beta-catenin protein. In this study, we reviewed literatures involving 30 patients with various genetic syndromes that have been linked to pilomatricoma and found that somatic mutations of the CTNNB1 gene were reported in 67% of patients. Pilomatricoma has been reported in patients with chromosome 9 rearrangements, including 4 patients with tetrasomy 9p syndrome and one patient with partial trisomy 9. In addition to beta-catenin, the expression of bcl2 was observed in pilomatricoma. OBJECTIVES: To report an additional case of tetrasomy 9p syndrome with concurrent pilomatricoma and to examine whether abnormal protein expressions of the CTNNB1 and/or BCL2 genes were present. METHODS: Cytogenetic analysis was carried out on peripheral blood, biopsied skin, and pilomatricoma tissue obtained from a patient with tetrasomy 9p syndrome. Immunohistochemical staining was performed on the pilomatricoma tissue, using beta-catenin and bcl2 monoclonal antibodies. RESULTS: SNP microarray revealed nonmosaic gain of the short arm of chromosome 9. A nonmosaic isodicentric chromosome 9 was identified in the peripheral blood but this rearranged chromosome was detected in only 8.3% of the skin fibroblasts. Chromosomal abnormalities were not detected in the pilomatricoma nor expression of beta-catenin or bcl2 proteins in our patient. CONCLUSION: Pilomatricoma could be a new clinical feature associated with tetrasomy 9p syndrome; however, we found no evidence of tetrasomy 9p or abnormal beta-catenin or bcl2 proteins of the CTNNB1 and BCL2 genes in our pilomatricoma patient.

Case Report: An Atypical Angelman Syndrome Case With Obesity and Fulfilled Autism Spectrum Disorder Identified by Microarray.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are etiologically heterogeneous. Chromosomal microarray is now recommended as the first-tier clinical diagnostic test for ASD. We performed chromosomal microarray in 16 Thai patients with ASD using an Illumina HumanCytoSNP-12 v2.1 array and found one case with uniparental disomy (UPD) of chromosome 15. Methylation-specific PCR showed abnormal methylation of the maternal SNRPN allele. Haplotype analysis revealed that the patient had received both chromosomes 15 from his father. These results were consistent with Angelman syndrome. However, his clinical features had no clinical significance for classic Angelman syndrome. He had first presented at the pediatric clinic with no speech, poor social interaction skills and repetitive behaviors consistent with ASD based on the DSM-IV criteria at 2 years of age and later confirmed by ADOS at 5 years of age. He was strikingly overweight but had no dysmorphic facies, seizures nor ataxia and was diagnosed as non-syndromic ASD, a diagnosis which was believed until at 10 years of age, his DNA was included for analysis in this current cohort study. Our findings suggest that ASD patients with unknown etiology should be considered for methylation-specific PCR testing for Angelman syndrome where chromosomal microarray is not available. In the study, we also review the clinical features of Angelman syndrome caused by UPD and the frequency of ASD in individuals with Angelman syndrome.

Significant associations between 5-hydroxytryptaminetransporter-linked promoter region polymorphisms of the serotonin transporter (solute carrier family 6 member 4) gene and Thai patients with autism spectrum disorder.

Autism spectrum disorder (ASD) is a form of pervasive developmental disorder manifested by impairment in social interactions and repetitive behaviors. Although genetic contribution is strongly suspected in autism, the specific genetic factors remain unidentified. Hyperserotoninemia has been reported in some autistic patients, and several studies have demonstrated an association between 5-hydroxytryptamine-transporter-linked promoter region (5-HTTLPR) polymorphisms and rs25531 single nucleotide polymorphism in the serotonin transporter gene (solute carrier family 6 member 4; SLC6A4) and ASD, indicating a possible involvement of the serotonin system in the etiology of ASD.To explore this situation further, a case-control association study of 5-HTTLPR and rs25531 polymorphisms on Thai ASD patients was conducted. A total of 188 ASD cases fulfilling the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria (156 males and 32 females) and a total of 250 normal controls were recruited from the same ethnic backgrounds. 5-HTTLPR polymorphisms (Long, L; Short, S) and rs25531 (A/G) single nucleotide polymorphism were genotyped and compared between the patients and normal controls using chi-square statistics.The L/L genotype was more common in patients than in the controls (13.8% vs 5.2%, P = .006), and the LA haplotype was found in patients more than the controls (16.9% vs 12.2%, P = .048). When male patients were analyzed alone (156 individuals), the associations were also statistically significant with P = .017 for L/L genotype, and P = .019 for LA haplotype distribution.Our findings support previous reports suggesting an association between the 5-HTTLPR and rs25531 polymorphisms of SLC6A4 and patients with ASD.

Novel Compound Heterozygous Mutations in the TRAPPC9 Gene in Two Siblings With Autism and Intellectual Disability.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with many contributing risk genes and loci. To date, several intellectual disability (ID) susceptibility genes have frequently been identified in ASD. Here, whole exome sequencing was carried out on a proband with ASD and identified compound heterozygous mutations of the TRAPPC9, which plays a role in the neuronal NF-κB signaling pathway. These mutations consisted of a novel frameshift mutation (c.2415_2416insC, p.His806Profs∗9) and a rare splice site mutation (c.3349+1G>A) that were segregated from an unaffected father and unaffected mother, respectively. These two heterozygous mutations were also identified in the patient's older brother with ID. Quantitative RT-PCR revealed a significant reduction of TRAPPC9 transcript in two siblings. This study first describes compound heterozygous mutations of the TRAPPC9 gene in two siblings with ASD and ID, which is notable as only homozygous mutations or compound heterozygous for copy number variations and rare variant in this gene have been reported to date and associated with autosomal recessive intellectual disability. The two siblings carrying compound heterozygous TRAPPC9 mutations presented with ID, developmental delay, microcephaly and brain abnormalities similarly to the clinical features found in almost cases with homozygous TRAPPC9 mutation in previous studies. Together this study provides evidence that clinical manifestations of TRAPPC9 mutations as seen in our patients with ID and autism may be broader than previous case reports have indicated.

Whole-Exome Sequencing Identifies One De Novo Variant in the FGD6 Gene in a Thai Family with Autism Spectrum Disorder.

Autism spectrum disorder (ASD) has a strong genetic basis, although the genetics of autism is complex and it is unclear. Genetic testing such as microarray or sequencing was widely used to identify autism markers, but they are unsuccessful in several cases. The objective of this study is to identify causative variants of autism in two Thai families by using whole-exome sequencing technique. Whole-exome sequencing was performed with autism-affected children from two unrelated families. Each sample was sequenced on SOLiD 5500xl Genetic Analyzer system followed by combined bioinformatics pipeline including annotation and filtering process to identify candidate variants. Candidate variants were validated, and the segregation study with other family members was performed using Sanger sequencing. This study identified a possible causative variant for ASD, c.2951G>A, in the FGD6 gene. We demonstrated the potential for ASD genetic variants associated with ASD using whole-exome sequencing and a bioinformatics filtering procedure. These techniques could be useful in identifying possible causative ASD variants, especially in cases in which variants cannot be identified by other techniques.

Significant Changes in Plasma Alpha-Synuclein and Beta-Synuclein Levels in Male Children with Autism Spectrum Disorder.

Alpha-synuclein (α-synuclein) and beta-synuclein (ß-synuclein) are presynaptic proteins playing important roles in neuronal plasticity and synaptic vesicle regulation. To evaluate the association of these two proteins and autism spectrum disorder (ASD), we investigated the plasma α-synuclein and ß-synuclein levels in 39 male children with ASD (2 subgroups: 25 autism and 14 pervasive developmental disorder-not otherwise specified (PDD-NOS)) comparing with 29 sex- and age-matched controls by using enzyme-linked immunosorbent assay (ELISA). We first determined the levels of these two proteins in the ASD subgroups and found that there were no significant differences in both plasma α-synuclein and ß-synuclein levels in the autism and PDD-NOS groups. Thus, we could combine the 2 subgroups into one ASD group. Interestingly, the mean plasma α-synuclein level was significantly lower (P < 0.001) in the ASD children (10.82 ± 6.46 ng/mL) than in the controls (29.47 ± 18.62 ng/mL), while the mean plasma ß-synuclein level in the ASD children (1344.19 ± 160.26 ng/mL) was significantly higher (P < 0.05) than in the controls (1219.16 ± 177.10 ng/mL). This is the first study examining the associations between α-synuclein and ß-synuclein and male ASD patients. We found that alterations in the plasma α-synuclein and ß-synuclein levels might be implicated in the association between synaptic abnormalities and ASD pathogenesis.

Chromosomal microarray analysis in a cohort of underrepresented population identifies SERINC2 as a novel candidate gene for autism spectrum disorder.

Chromosomal microarray (CMA) is now recognized as the first-tier genetic test for detection of copy number variations (CNVs) in patients with autism spectrum disorder (ASD). The aims of this study were to identify known and novel ASD associated-CNVs and to evaluate the diagnostic yield of CMA in Thai patients with ASD. The Infinium CytoSNP-850K BeadChip was used to detect CNVs in 114 Thai patients comprised of 68 retrospective ASD patients (group 1) with the use of CMA as a second line test and 46 prospective ASD and developmental delay patients (group 2) with the use of CMA as the first-tier test. We identified 7 (6.1%) pathogenic CNVs and 22 (19.3%) variants of uncertain clinical significance (VOUS). A total of 29 patients with pathogenic CNVs and VOUS were found in 22% (15/68) and 30.4% (14/46) of the patients in groups 1 and 2, respectively. The difference in detected CNV frequencies between the 2 groups was not statistically significant (Chi square = 1.02, df = 1, P = 0.31). In addition, we propose one novel ASD candidate gene, SERINC2, which warrants further investigation. Our findings provide supportive evidence that CMA studies using population-specific reference databases in underrepresented populations are useful for identification of novel candidate genes.

Common Clinical Characteristics and Rare Medical Problems of Fragile X Syndrome in Thai Patients and Review of the Literature.

Background. Clinical characteristics of fragile X syndrome (FXS) have been well documented in Caucasians, whereas in Asians they have rarely been described. Those that have been conducted used small cohorts that utilized DNA for diagnosis and larger cohorts that utilized cytogenetics for diagnosis. This study is to describe clinical characteristics of FXS in a large cohort of Thai patients diagnosed by standard molecular methods. Methods. Seventy-seven index cases and 46 affected relatives diagnosed with FXS were recruited into the study. To determine frequencies of common characteristics of FXS in prepubertal boys, we reviewed 56 unrelated cases aged between 18 and 146 months. To list rare medical problems, we reviewed 75 cases aged between 8 months to 71 years old, including 53 index cases and 22 affected relatives. In addition, we selected 16 clinical studies from various ethnicities for comparison with our findings. Results. In prepubertal boys with FXS, attention deficit and/or hyperactivity, prominent ears, macroorchidism, and elongated face were observed in 96%, 80%, 53%, and 48% of patients, respectively, whereas recognizable X-linked inheritance presented in 11% of patients. IQ scores ranged between 30 and 64 (mean ± SD = 43 ± 9, n = 25). We observed clinical findings that rarely or have never been reported, for example, medulloblastoma and tetralogy of Fallot. Conclusion. Attention deficit and/or hyperactivity and prominent ear are the most common behavioral and physical features in prepubertal boys with FXS, respectively. There are differences in frequencies of clinical characteristics observed between ethnicities; however, it is difficult to draw a solid conclusion due to different recruitment criteria and sample sizes within each study.

HLA-B*15:21 and carbamazepine-induced Stevens-Johnson syndrome: pooled-data and in silico analysis.

HLA-B*15:02 screening before carbamazepine (CBZ) prescription in Asian populations is the recommended practice to prevent CBZ-induced Stevens-Johnson syndrome (CBZ-SJS). However, a number of patients have developed CBZ-SJS even having no HLA-B*15:02. Herein, we present the case of a Thai patient who had a negative HLA-B*15:02 screening result but later developed CBZ-SJS. Further HLA typing revealed HLA-B*15:21/B*13:01. HLA-B*15:21 is a member of the HLA-B75 serotype and is commonly found in Southeast Asian populations. Based on this case, we hypothesised that if all HLA-B*15:02 carriers were prevented from CBZ prescription, another common HLA-B75 serotype marker would show its association with CBZ-SJS. To test this hypothesis, we pooled data from previous association studies in Asian populations, excluded all cases with HLA-B*15:02, and analysed the association significance of HLA-B75 serotype markers. A significant association was found between CBZ-SJS and HLA-B*15:21 and HLA-B*15:11. We also applied an in silico analysis and found that all HLA-B75 serotype molecules shared similar capability in binding the CBZ molecule. In summary, this report provides the first evidence of a positive association between HLA-B*15:21 and CBZ-SJS and the first in silico analysis of CBZ binding sites and details of the molecular behaviour of HLA-B75 molecule to explain its molecular action.

Exome Sequencing Identifies Compound Heterozygous Mutations in SCN5A Associated with Congenital Complete Heart Block in the Thai Population.

Background. Congenital heart block is characterized by blockage of electrical impulses from the atrioventricular node (AV node) to the ventricles. This blockage can be caused by ion channel impairment that is the result of genetic variation. This study aimed to investigate the possible causative variants in a Thai family with complete heart block by using whole exome sequencing. Methods. Genomic DNA was collected from a family consisting of five family members in three generations in which one of three children in generation III had complete heart block. Whole exome sequencing was performed on one complete heart block affected child and one unaffected sibling. Bioinformatics was used to identify annotated and filtered variants. Candidate variants were validated and the segregation analysis of other family members was performed. Results. This study identified compound heterozygous variants, c.101G>A and c.3832G>A, in the SCN5A gene and c.28730C>T in the TTN gene. Conclusions. Compound heterozygous variants in the SCN5A gene were found in the complete heart block affected child but these two variants were found only in the this affected sibling and were not found in other unaffected family members. Hence, these variants in the SCN5A gene were the most possible disease-causing variants in this family.

Screening for Subtelomeric Rearrangements in Thai Patients with Intellectual Disabilities Using FISH and Review of Literature on Subtelomeric FISH in 15,591 Cases with Intellectual Disabilities.

We utilized fluorescence in situ hybridization (FISH) to screen for subtelomeric rearrangements in 82 Thai patients with unexplained intellectual disability (ID) and detected subtelomeric rearrangements in 5 patients. Here, we reported on a patient with der(20)t(X;20)(p22.3;q13.3) and a patient with der(3)t(X;3)(p22.3;p26.3). These rearrangements have never been described elsewhere. We also reported on a patient with der(10)t(7;10)(p22.3;q26.3), of which the same rearrangement had been reported in one literature. Well-recognized syndromes were detected in two separated patients, including 4p deletion syndrome and 1p36 deletion syndrome. All patients with subtelomeric rearrangements had both ID and multiple congenital anomalies (MCA) and/or dysmorphic features (DF), except the one with der(20)t(X;20), who had ID alone. By using FISH, the detection rate of subtelomeric rearrangements in patients with both ID and MCA/DF was 8.5%, compared to 2.9% of patients with only ID. Literature review found 28 studies on the detection of subtelomeric rearrangements by FISH in patients with ID. Combining data from these studies and our study, 15,591 patients were examined and 473 patients with subtelomeric rearrangements were determined. The frequency of subtelomeric rearrangements detected by FISH in patients with ID was 3%. Terminal deletions were found in 47.7%, while unbalanced derivative chromosomes were found in 47.9% of the rearrangements.

Maternal Age-Specific Rates for Trisomy 21 and Common Autosomal Trisomies in Fetuses from a Single Diagnostic Center in Thailand.

To provide maternal age-specific rates for trisomy 21 (T21) and common autosomal trisomies (including trisomies 21, 18 and 13) in fetuses. We retrospectively reviewed prenatal cytogenetic results obtained between 1990 and 2009 in Songklanagarind Hospital, a university teaching hospital, in southern Thailand. Maternal age-specific rates of T21 and common autosomal trisomies were established using different regression models, from which only the fittest models were used for the study. A total of 17,819 records were included in the statistical analysis. The fittest models for predicting rates of T21 and common autosomal trisomies were regression models with 2 parameters (Age and Age2). The rate of T21 ranged between 2.67 per 1,000 fetuses at the age of 34 and 71.06 per 1,000 at the age of 48. The rate of common autosomal trisomies ranged between 4.54 per 1,000 and 99.65 per 1,000 at the same ages. This report provides the first maternal age-specific rates for T21 and common autosomal trisomies fetuses in a Southeast Asian population and the largest case number of fetuses have ever been reported in Asians.

Whole-exome sequencing identifies a novel heterozygous missense variant of the EN2 gene in two unrelated patients with autism spectrum disorder.

To identify the underlying genetic cause of autism spectrum disorder (ASD), we performed whole-exome sequencing in 10 unrelated Thai patients with ASD. We identified a novel heterozygous missense variant (c.425C>G, p.Pro142Arg) in the Engrailed 2 (EN2) gene in two patients. The G variant has never been reported in public databases and was absent in 100 Thai patients with ASD and 435 Thai controls. A case-control study showed that the G allele of c.425C>G was significantly associated with ASD (Fisher's exact test, P=0.0359). In addition, the new variant was predicted to be possibly damaging to the EN2 protein by the PolyPhen-2 and FATHMM bioinformatic programs. Our findings suggest that the arginine variant of the EN2 protein may play an important role in the pathology of ASD. Therefore, EN2 protein functional studies should be carried out to determine whether the novel variant has an effect on protein expression.

Comparison of a New In-House and Three Published HLA-B*15:02 Screening Methods for Prevention of Carbamazepine-Induced Severe Drug Reactions.

Currently, there are three published HLA-B*15:02 screening methods for prevention of carbamazepine-induced severe drug reactions in Asian populations. To analyze available HLA-B*15:02 screening methods, we compared four screening methods, including a multiplex PCR method, a nested PCR method, a LAMP method and our new in-house PCR-dot blot hybridization method. These methods were reviewed regarding their sensitivity, specificity, false positivity and technical considerations. Possible false positive (FP) alleles and genotypes were checked regarding the primers and probes designs, using the IMGT/HLA database. Expected FP rates in Asian populations were predicted using the Allele Frequencies Net Database. All methods had a sensitivity of more than 99.9%, although giving FP results to certain very rare alleles and genotypes. The multiplex PCR method was the only test that gave FP results to certain genotypes of HLA-B*15:13, the allele which is prevalent in Southeast Asian populations. In conclusion, the nested PCR, LAMP and our in-house methods could be applied in various Asian populations, but the multiplex PCR, or any test with FP to HLA-B*15:13, should be applied with caution in the Southeast Asian populations.

Unique AGG Interruption in the CGG Repeats of the FMR1 Gene Exclusively Found in Asians Linked to a Specific SNP Haplotype.

Fragile X syndrome (FXS) is the most common inherited intellectual disability. It is caused by the occurrence of more than 200 pure CGG repeats in the FMR1 gene. Normal individuals have 6-54 CGG repeats with two or more stabilizing AGG interruptions occurring once every 9- or 10-CGG-repeat blocks in various populations. However, the unique (CGG)6AGG pattern, designated as 6A, has been exclusively reported in Asians. To examine the genetic background of AGG interruptions in the CGG repeats of the FMR1 gene, we studied 8 SNPs near the CGG repeats in 176 unrelated Thai males with 19-56 CGG repeats. Of these 176 samples, we identified AGG interruption patterns from 95 samples using direct DNA sequencing. We found that the common CGG repeat groups (29, 30, and 36) were associated with 3 common haplotypes, GCGGATAA (Hap A), TTCATCGC (Hap C), and GCCGTTAA (Hap B), respectively. The configurations of 9A9A9, 10A9A9, and 9A9A6A9 were commonly found in chromosomes with 29, 30, and 36 CGG repeats, respectively. Almost all chromosomes with Hap B (22/23) carried at least one 6A pattern, suggesting that the 6A pattern is linked to Hap B and may have originally occurred in the ancestors of Asian populations.

Association of ABO Blood Group Phenotype and Allele Frequency with Chikungunya Fever.

Background. The objective of this study was to investigate the association of the ABO blood group phenotype and allele frequency with CHIK fever. Methods. A rural community survey in Southern Thailand was conducted in August and September 2010. A total of 506 villagers were enrolled. Cases were defined as individuals having anti-CHIK IgG by hemagglutination ≥1 : 10. Results. There were 314 cases (62.1%) with CHIK seropositivity. Females were less likely to have positive anti-CHIK IgG with odds ratio (OR) (95% CI) of 0.63 (0.43, 0.93). All samples tested were Rh positive. Distribution of CHIK seropositivity versus seronegativity (P value) in A, B, AB, and O blood groups was 80 versus 46 (0.003), 80 versus 48 (0.005), 24 versus 20 (0.55), and 130 versus 78 (<0.001), respectively. However, chi-square test between ABO and CHIK infection showed no statistical significance (P = 0.76). Comparison of the ABO blood group allele frequency between CHIK seropositivity and seronegativity was not statistically significant. Conclusion. This finding demonstrated no association of the ABO blood group phenotypes and allele frequencies with CHIK infection.