Converging evidence for an association of ATP2B2 allelic variants with autism in male subjects.

BACKGROUND: Autism is a severe developmental disorder, with strong genetic underpinnings. Previous genome-wide scans unveiled a linkage region spanning 3.5 Mb, located on human chromosome 3p25. This region encompasses the ATP2B2 gene, encoding the plasma membrane calcium-transporting ATPase 2 (PMCA2), which extrudes calcium (Ca2+) from the cytosol into the extracellular space. Multiple lines of evidence support excessive intracellular Ca2+ signaling in autism spectrum disorder (ASD), making ATP2B2 an attractive candidate gene. METHODS: We performed a family-based association study in an exploratory sample of 277 autism genetic resource exchange families and in a replication sample including 406 families primarily recruited in Italy. RESULTS: Several markers were significantly associated with ASD in the exploratory sample, and the same risk alleles at single nucleotide polymorphisms rs3774180, rs2278556, and rs241509 were found associated with ASD in the replication sample after correction for multiple testing. In both samples, the association was present in male subjects only. Markers associated with autism are all comprised within a single block of strong linkage disequilibrium spanning several exons, and the "risk" allele seems to follow a recessive mode of transmission. CONCLUSIONS: These results provide converging evidence for an association between ATP2B2 gene variants and autism in male subjects, spurring interest into the identification of functional variants, most likely involved in the homeostasis of Ca2+ signaling. Additional support comes from a recent genome-wide association study by the Autism Genome Project, which highlights the same linkage disequilibrium region of the gene.

Family-based association study of ITGB3 in autism spectrum disorder and its endophenotypes.

The integrin-ß 3 gene (ITGB3), located on human chromosome 17q21.3, was previously identified as a quantitative trait locus (QTL) for 5-HT blood levels and has been implicated as a candidate gene for autism spectrum disorder (ASD). We performed a family-based association study in 281 simplex and 12 multiplex Caucasian families. ITGB3 haplotypes are significantly associated with autism (HBAT, global P=0.038). Haplotype H3 is largely over-transmitted to the affected offspring and doubles the risk of an ASD diagnosis (HBAT P=0.005; odds ratio (OR)=2.000), at the expense of haplotype H1, which is under-transmitted (HBAT P=0.018; OR=0.725). These two common haplotypes differ only at rs12603582 located in intron 11, which reaches a P-value of 0.072 in single-marker FBAT analyses. Interestingly, rs12603582 is strongly associated with pre-term delivery in our ASD patients (P=0.008). On the other hand, it is SNP rs2317385, located at the 5' end of the gene, that significantly affects 5-HT blood levels (Mann-Whitney U-test, P=0.001; multiple regression analysis, P=0.010). No gene-gene interaction between ITGB3 and SLC6A4 has been detected. In conclusion, we identify a significant association between a common ITGB3 haplotype and ASD. Distinct markers, located toward the 5' and 3' ends of the gene, seemingly modulate 5-HT blood levels and autism liability, respectively. Our results also raise interest into ITGB3 influences on feto-maternal immune interactions in autism.

Mosaic trisomy 16 in a fetus: the complex relationship between phenotype and genetic mechanisms.

OBJECTIVES: This study was undertaken to discuss the workup of trisomy 16 pregnancies. STUDY DESIGN: This case study reports the prenatal detection and postnatal confirmation of mosaic trisomy 16, associated with uniparental disomy (UPD) 16, in a 34-year-old woman who showed elevated maternal serum alpha-fetoprotein and beta-HCG at a gestational age (GA) of 15.5 weeks. RESULTS: Amniotic fluid (AF) karyotyping at different GAs revealed various levels of trisomy 16 mosaicism (0 to level III). UPD studies at 21 weeks of gestation revealed maternal heterodisomy 16. Serial fetal ultrasonography showed fetal abnormalities: intrauterine growth restriction (IUGR), dilated digestive tract, and gallbladder agenesis. Postmortem examination confirmed the prenatal findings and revealed additional anomalies, such as hypoplastic cerebellum with abnormal gyration of the vermis. CONCLUSIONS: Workup following prenatal detection of trisomy 16 mosaicism in chorionic villi must include AF karyotyping and serial ultrasound examination of the fetus in order to approach postnatal developmental prognosis.

GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.

OBJECTIVES: To analyze the clinical features of hearing impairment and to search for correlations with the genotype in patients with DFNB1. DESIGN: Case series. SETTING: Collaborative study in referral centers, institutional practice. Patients A total of 256 hearing-impaired patients selected on the basis of the presence of biallelic mutations in GJB2 or the association of 1 GJB2 mutation with the GJB6 deletion (GJB6-D13S1830)del. MAIN OUTCOME MEASURES: The prevalence of GJB2 mutations and the GJB6 deletion and audiometric phenotypes related to the most frequent genotypes. RESULTS: Twenty-nine different GJB2 mutations were identified. Allelic frequency of 35delG was 69%, and the other common mutations, 313del14, E47X, Q57X, and L90P, accounted for 2.6% to 2.9% of the variants. Concerning GJB6, (GJB6-D13S1830)del accounted for 5% of all mutated alleles and was observed in 25 of 93 compound heterozygous patients. Three novel GJB2 mutations, 355del9, V95M, and 573delCA, were identified. Hearing impairment was frequently less severe in compound heterozygotes 35delG/L90P and 35delG/N206S than in 35delG homozygotes. Moderate or mild hearing impairment was more frequent in patients with 1 or 2 noninactivating mutations than in patients with 2 inactivating mutations. Of 93 patients, hearing loss was stable in 73, progressive in 21, and fluctuant in 2. Progressive hearing loss was more frequent in patients with 1 or 2 noninactivating mutations than in those with 2 inactivating mutations. In 49 families, hearing loss was compared between siblings with similar genotypes, and variability in terms of severity was found in 18 families (37%). CONCLUSION: Genotype may affect deafness severity, but environmental and other genetic factors may also modulate the severity and evolution of GJB2-GJB6 deafness.

Large deletion of the GJB6 gene in deaf patients heterozygous for the GJB2 gene mutation: genotypic and phenotypic analysis.

Recent investigations identified a large deletion of the GJB6 gene in trans to a mutation of GJB2 in deaf patients. We looked for GJB2 mutations and GJB6 deletions in 255 French patients presenting with a phenotype compatible with DFNB1. 32% of the patients had biallelic GJB2 mutations and 6% were a heterozygous for a GJB2 mutation and a GJB6 deletion. Biallelic GJB2 mutations and combined GJB2/GJB6 anomalies were more frequent in profoundly deaf children. Based on these results, we are now assessing GJB6 deletion status in cases of prelingual hearing loss.