ASSOCIATION BETWEEN MATERNAL BODY MASS INDEX AND WEIGHT GAIN WITH LOW BIRTH WEIGHT IN EASTERN THAILAND.

We conducted a retrospective study to determine the association between maternal body mass index and pregnancy weight gain with low birth weight newborns (LBWN) at Phrapokklao Hospital in eastern Thailand. We evaluated the files of 2,012 women who delivered at the hospital. Data obtained from the charts were parity, maternal age, body mass index (BMI), prepregnancy weight, weight gained during pregnancy, gestational age, hematocrit level, referral status, place of residence, fetal presentation, completion of antenatal care visits and maternal HIV infection. Sixty-five point two percent of subjects were aged 20-34 years old. Fifty-seven percent of subjects had a normal BMI and 13.2% were anemic. Thirty- seven point five percent, 32.9% and 29.6% gained too little, the correct amount and too much weight during pregnancy, respectively. Primiparity, too little weight gain and gestational age less than 37 weeks at delivery were all significantly associated with LBWN. Preterm babies were 25 times more likely to have a low birth weight than term infants (adjusted OR = 24.995; 95% CI: 16.824-37.133, p < 0.001). When maternal weight gain of any BMI group was inadequate, the subject had a 3.4 times greater risk (adjusted OR = 3.357; 95% CI: 22.114-5.332, p < 0.001) of having a LBWN. Primiparous women had a 1.7 times (adjusted OR=1.720; 95% CI: 1.182-2.503, p-0.005) greater risk of having a LBWN. The results from this study may be useful to plan maternal health programs for eastern Thailand.

Mutations in the guanine nucleotide exchange factor gene IQSEC2 cause nonsyndromic intellectual disability.

The first family identified as having a nonsyndromic intellectual disability was mapped in 1988. Here we show that a mutation of IQSEC2, encoding a guanine nucleotide exchange factor for the ADP-ribosylation factor family of small GTPases, caused this disorder. In addition to MRX1, IQSEC2 mutations were identified in three other families with X-linked intellectual disability. This discovery was made possible by systematic and unbiased X chromosome exome resequencing.

A distinctive gene expression fingerprint in mentally retarded male patients reflects disease-causing defects in the histone demethylase KDM5C.

BACKGROUND: Mental retardation is a genetically heterogeneous disorder, as more than 90 genes for this disorder has been found on the X chromosome alone. In addition the majority of patients are non-syndromic in that they do not present with clinically recognisable features. This makes it difficult to determine the molecular cause of this disorder on the basis of the phenotype alone. Mutations in KDM5C (previously named SMCX or JARID1C), a gene that encodes a transcriptional regulator with histone demethylase activity specific for dimethylated and trimethylated H3K4, are a comparatively frequent cause of non-syndromic X-linked mental retardation (NS-XLMR). Specific transcriptional targets of KDM5C, however, are still unknown and the effects of KDM5C deficiency on gene expression have not yet been investigated. RESULTS: By whole-mount in situ hybridisation we showed that the mouse homologue of KDM5C is expressed in multiple tissues during mouse development.We present the results of gene expression profiling performed on lymphoblastoid cell lines as well as blood from patients with mutations in KDM5C. Using whole genome expression arrays and quantitative reverse transcriptase polymerase chain reaction (QRT-PCR) experiments, we identified several genes, including CMKOR1, KDM5B and KIAA0469 that were consistently deregulated in both tissues. CONCLUSIONS: Our findings shed light on the pathological mechanisms underlying mental retardation and have implications for future diagnostics of this heterogeneous disorder.

Identification and characterization of two novel JARID1C mutations: suggestion of an emerging genotype-phenotype correlation.

Mental retardation (MR) is characterized by cognitive impairment with an IQ <70. Many of the major causes are genetically determined and the approximately 30% male excess suggests that mutations in genes carried on the X chromosome are disproportionably represented. One such gene, jumonji AT-rich interactive domain 1C (JARID1C) on Xp11.2, has been identified in families with X-linked MR (XLMR), with 18 different mutations reported to date. As part of a systematic resequencing of 720 genes in 208 XLMR families of the International Genetic of Learning Disability (IGOLD) consortium, two novel nucleotide changes in the JARID1C coding region were identified, with the nucleotide changes segregating with the disease phenotype in the two families. The first mutation is a single-nucleotide insertion in exon 21 (c.3258_3259insC p.K1087fs(*)43) causing a frameshift and resulting in a premature termination codon (PTC). Such PTC-containing mRNAs are generally degraded by nonsense-mediated mRNA decay (NMD) surveillance, but our results show that this is not the case with this mutation. The other change is a single-nucleotide substitution in exon 12 (c.1160C>A) in a published family with nonsyndromic MR, MRX13. This change occurs in a highly conserved amino acid, with proline (P) being substituted by threonine (T) (p.P554T). [corrected] Functional analysis shows that this amino-acid substitution compromises both tri- and didemethylase activity of the JARID1C protein. We conclude that the two novel changes impair JARID1C protein function and are disease-causing mutations in these families.

Mutation screening of the Aristaless-related homeobox (ARX) gene in Thai pediatric patients with delayed development: first report from Thailand.

Mutations in the Aristaless-related homeobox gene, ARX, have been a cause of X-linked mental retardation (XLMR) and are responsible for a vast phenotypic spectrum including syndromic and non-syndromic forms of mental retardation. Since the gene was initially identified, it has been generally screened in several patients with XLMR. This study is the first report of ARX mutational screening in Thai pediatric patients with delayed development. Two hundred and fifty-one patients participated in this study. Two hundred and three of the 251 patients were initially referred for molecular diagnosis of the Fragile XA syndrome and had negative test results. The remaining 48 patients were specifically recruited for the ARX mutational analysis and had previously reported phenotypes of the ARX mutations. Screening for the c.428_451 dup mutation was performed in all samples. Screening for other point mutations in all coding exons was performed in all 48 patients recruited for the ARX mutational analysis and in 29 patients initially referred for diagnosis of the Fragile XA syndrome who had two or more affected males in the family suggesting an X-linked inheritance pattern. Two patients were found to have the c.428_451 dup mutation. Considering genotype-phenotype correlation, we suggest screening of the most common mutation, the c.428_451 dup mutation by PCR, in patients with infantile spasm syndrome, Partington syndrome and non-syndromic X-linked mental retardation. Screening in patients who have negative Fragile XA test results should be considered when no other known causes of mental retardation are identified especially in families with suggestive X-linked inheritance pattern.

De novo subtelomeric deletion of 15q associated with satellite translocation in a child with developmental delay and severe growth retardation.

We report on a case of satellited 15q with subtelomeric deletion in a girl with delayed development and severe growth retardation. The patient also has a triangular face, downturned angles of the mouth, micrognathia, and minor limb malformations including mild talipes equinovarus, genu recurvatum, and increased dorsiflexion of both limbs. Cytogenetic analysis using standard GTG banding showed a female karyotype with a satellited-like structure at the distal long arm of one chromosome 15. Silver staining of the nucleolar organizing region (AgNOR) confirmed the presence of a satellite DNA translocation at the lesion. Analysis using fluorescent in situ hybridization (FISH) detected a subtelomeric deletion of the terminal 15q. Additional molecular analysis using microsatellite markers along the long arm of chromosome 15 defined a maximally deleted region at approximately 4.7 Mb. Haploinsufficiency of the IGF1R gene expression is thought to be the cause of growth delay in all 15q terminal deletion including our patient.

Prenatal diagnosis of complete trisomy 9: a case report and review of the literature.

Complete trisomy 9 is a very rare chromosome aneuploidy, associated with specific patterns of multisystem dysmorphism and a wide spectrum of congenital anomalies. We present a case of complete trisomy 9 with prenatal sonographic findings in the second trimester. The combination of sonography and karyotyping from cordocentesis enabled us to establish the prenatal diagnosis. An additional clinical feature of this syndrome that has not been reported previously is an aortopulmonary communication. A review of the literature specifically dealing with prenatal sonographic findings with complete trisomy 9 is also presented.

Genomewide analysis of gene expression associated with Tcof1 in mouse neuroblastoma.

Mutations in the Treacher Collins syndrome gene, TCOF1, cause a disorder of craniofacial development. We manipulated the levels of Tcof1 and its protein treacle in a murine neuroblastoma cell line to identify downstream changes in gene expression using a microarray platform. We identified a set of genes that have similar expression with Tcof1 as well as a set of genes that are negatively correlated with Tcof1 expression. We also showed that the level of Tcof1 and treacle expression is downregulated during differentiation of neuroblastoma cells into neuronal cells. Inhibition of Tcof1 expression by siRNA induced morphological changes in neuroblastoma cells that mimic differentiation. Thus, expression of Tcof1 and treacle synthesis play an important role in the proliferation of neuroblastoma cells and we have identified genes that may be important in this pathway.