Female‐restricted syndromic intellectual disability in a patient from Thailand

Female‐restricted syndromic intellectual disability (ID) is a neurodevelopmental disorder with developmental delay (DD)/ID, facial dysmorphism, and diverse congenital anomalies comprising heart defects, anal anomalies, choanal atresia, postaxial polydactyly, scoliosis, and brain abnormalities. Loss‐of‐function mutations in the USP9X gene inherited as X‐linked dominance were identified as its etiology in females of different ethnic groups. Here, we report a 15‐year‐old Thai girl harboring a novel de novo heterozygous one‐base pair deletion (c.3508delG, p.Val1170TrpfsX9) in exon 23 of USP9X. Her profound DD, dysmorphic face including attached earlobes, short stature, and congenital malformations including s‐shaped thoracolumbar scoliosis, hip dislocation, and generalized brain atrophy shared common characteristics of X‐linked syndromic ID. We have observed severely malformed oro‐dental organs and a choledochal cyst, which have never been reported. Our study presents the first patient from Thailand expanding the phenotypic and mutational spectra of the syndrome.     

Distinct craniofacial‐skeletal‐dermatological dysplasia in a patient with W290C mutation in FGFR2

Mutations in the fibroblast growth factor receptor genes (FGFR) have been known to be associated with many craniosynostosis syndromes with overlapping phenotypes. We studied a 15‐year‐old Thai boy with an unspecified craniosynostosis syndrome characterized by multiple suture craniosynostoses, a persistent anterior fontanel, corneal scleralization, choanal stenosis, atresia of the auditory meatus, broad thumbs and great toes, severe scoliosis, acanthosis nigricans, hydrocephalus, and mental retardation. Radiography revealed bony ankyloses of vertebral bodies of T9–12, humero‐radio‐ulnar joints, intercarpal joints, distal interphalangeal joints of fifth fingers, fibulo‐tibial joints, intertarsal joints, and distal interphalangeal joints of the first toes. The patient was a heterozygous for a 870G → T change resulting in a W290C amino acid substitution in the extracellular domain of the fibroblast growth factor receptor 2 gene (FGFR2). This mutation has previously been reported in a patient with severe Pfeiffer syndrome type 2 that is distinct from the craniosynostosis in our patient. These findings emphasize locus, allelic, and phenotypic heterogeneity of craniofacial‐skeletal‐dermatological syndrome due to FGFR2 mutations. © 2002 Wiley‐Liss, Inc.     

TIGIT Monoallelic Nonsense Variant in Patient with Severe COVID-19 Infection,Thailand

A heterozygous nonsense variant in the TIGIT gene was identified in a patient in Thailand who had severe COVID-19, resulting in lower TIGIT expression in T cells. The patient’s T cells produced higher levels of cytokines upon stimulation. This mutation causes less-controlled immune responses, which might contribute to COVID-19 severity.     

FGFR2 mutations among Thai children with Crouzon and Apert syndromes

Crouzon and Apert syndromes have been reported to be associated with mutations in Fibroblast Growth Factor Receptor 2 (FGFR2) gene in various ethnic groups, but never in Southeast Asian subjects. Therefore, the authors conducted a study to characterize 11 Thai patients: four with Crouzon syndrome and seven with Apert syndrome. All cases are sporadic. Mean paternal and maternal ages were 38.7 and 28.6 years, respectively. Molecularly, all patients were found to have mutations in the FGFR2 gene. Three mutations (C278F, S347C, S351C) were detected in all Crouzon patients with two having S351C. The seven patients with Apert syndrome have either S252W or P253R mutation. The authors' findings that sporadic cases were associated with advanced paternal age and that they all had mutations in FGFR2 are consistent with previous reports. This is another observation supporting the causative role of FGFR2 mutations in Crouzon and Apert syndromes.     

In vitro Correction of a Novel Splicing Alteration in the BTK Gene by Using Antisense Morpholino Oligonucleotides

A novel sequence variant, c.240+109C>A, in the Bruton’s tyrosine kinase (BTK) gene was identified in a patient with X-linked agammaglobulinemia. This alteration resulted in an incorporation of 106 nucleotides of BTK intron 3 into its mRNA. Administration of the 25-mer antisense morpholino oligonucleotide analog in the patient’s cultured peripheral blood mononuclear cells was able to restore correctly spliced BTK mRNA, a potential treatment for X-linked agammaglobulinemia.     

GABRG1 and GABRA2 variation associated with alcohol dependence in African Americans

Background: GABRG1 and GABRA2, genes that encode the γ1 and α2 subunits, respectively, of the GABA‐A receptor, are located in a cluster on chromosome 4p. Association of alcohol dependence (AD) with markers located at the 3′ region of GABRA2 has been replicated in several studies, but recent studies suggested the possibility that the signal may be attributable to the adjacent gene, GABRG1, located 90 kb distant in the 3′ direction. Owing to strong linkage disequilibrium (LD) in European Americans (EAs), the origin, or origins, of the association signal is very difficult to discern, but our previous population‐based study suggested that decreased LD across the GABRG1–GABRA2 region in African Americans (AAs) may be useful for fine mapping and resolution of the association signal in that population. Methods: To examine these associations in greater detail, we genotyped 13 single nucleotide polymorphisms (SNPs) spanning GABRG1 and GABRA2 in 380 AAs with AD and in 253 AA controls. Results: Although there was no association between any individual SNP and AD, a highly significant difference was shown between AD subjects and controls in the frequency of a 3‐SNP GABRA2 haplotype (global p = 0.00029). A similar level of significance was obtained in 6‐SNP haplotypes that combined tagging SNPs from both genes (global p = 0.00994). High statistical significance was also shown with a 6‐SNP haplotype (T‐G‐C‐G‐T‐A), p = 0.0033. The T‐G‐C‐G‐T‐A haplotype contains the most significant GABRA2 3‐SNP haplotype (p = 0.00019), G‐T‐A. Conclusions: These findings reflect the interrelationship between these 2 genes and the likelihood that risk loci exist in each of them. Study of an AA population allowed evaluation of these associations at higher genomic resolution than is possible in a EA population, owing to the much lower LD across these loci in AAs.     

Association between polymorphisms in catechol‐O‐methyltransferase (COMT) and cocaine‐induced paranoia in European‐American and African‐American populations

Catechol‐O‐methyltransferase (genetic locus, COMT) is a major enzyme involved in catecholamine metabolism and has been associated with numerous psychiatric phenotypes. We studied COMT SNPs and haplotypes in cocaine‐induced paranoia (CIP) in African‐American (AA) and European‐American (EA) populations. We genotyped 17 SNPs across the COMT locus in 319 AA pedigrees (848 individuals) and 302 EA pedigrees (707 individuals). Family‐controlled association analyses were conducted using FBAT. We found SNP rs737865 to be nominally significantly associated in the AA family population (P = 0.05). In EAs, the best‐known marker, rs4680 (Val158Met), was nominally significant in additive models (P = 0.03). SNP rs174696 also showed nominal significance in additive models (P = 0.02). We considered the three SNPs (rs737866–rs4680–rs174696) together in haplotype analysis in both family populations, using HBAT. The A–A–T haplotype was significantly associated with CIP in EAs (Z = 2.845; P = 0.0044, global P = 0.020). We then studied COMT SNPs in an additional 738 AA and 404 EA unrelated cocaine dependent individuals with and without paranoia. The A–A–T haplotype was significantly associated to CIP in the AA unrelated population (P = 0.0015). Two haplotypes, A–G–C and A–A–C, were significant in the EA unrelated population (P = 0.001 and 0.0003). We also identified rs4680 and three other SNPs, rs933271, rs5993883, and rs740603, as potentially functional variants, as predicted by a signature of positive selection in unrelated EAs and AAs. Based on our robust family‐controlled and unrelated‐affected analyses, we conclude that COMT is associated with CIP, possibly as a result of its role in the metabolism of dopamine and norepinephrine. © 2011 Wiley‐Liss, Inc.