Correction: Exome Sequencing in an Admixed Isolated Population IndicatesNFXL1 Variants Confer a Risk for Specific Language Impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model

The HABP2 G534E variant is an unlikely cause of familial non-medullary thyroid cancer.

ContextA recent study reported the non-synonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial non-medullary thyroid cancer (NMTC).ObjectiveThe objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multi-center population based study of NMTC cases from the British Isles.Design and settingA case-control analysis of rs7080536 genotypes was performed using 2,105 TCUKIN cases and 5,172 UK controls.ParticipantsCases comprised 2,105 NMTC cases. Patients sub-groups with papillary (N=1,056), follicular (N=691) and Hurthle cell (N=86) TC cases were studied separately. Controls comprised 5,172 individuals from the 1958 Birth Cohort (58C) and the National Blood Donor Service (NBS) study. The controls had previously been genotyped using genome-wide SNP arrays by the Wellcome Trust Case Control Consortium study.OutcomeMeasures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression.ResultsThe frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (OR=0.896, 95% CI: 0.746-1.071, P=0.233). We also failed to detect an association between HABP2 G534E and cases with papillary (1056 cases, G534E frequency= 3.5%, OR=0.74, P=0.017), follicular (691 cases, G534E frequency= 4.7%, OR=1.00, P=1.000) or Hurthle cell (86 cases, G534E frequency= 6.3%, OR=1.40, P=0.279) histology.ConclusionsWe found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC and additional data are required before using this variant in NMTC risk assessment

The HABP2 G534E variant is an unlikely cause of familial non-medullary thyroid cancer

ContextA recent study reported the non-synonymous G534E (rs7080536, allele A) variant in the HABP2 gene as causal in familial non-medullary thyroid cancer (NMTC).ObjectiveThe objective of this study was to evaluate the causality of HABP2 G534E in the TCUKIN study, a multi-center population based study of NMTC cases from the British Isles.Design and settingA case-control analysis of rs7080536 genotypes was performed using 2,105 TCUKIN cases and 5,172 UK controls.ParticipantsCases comprised 2,105 NMTC cases. Patients sub-groups with papillary (N=1,056), follicular (N=691) and Hurthle cell (N=86) TC cases were studied separately. Controls comprised 5,172 individuals from the 1958 Birth Cohort (58C) and the National Blood Donor Service (NBS) study. The controls had previously been genotyped using genome-wide SNP arrays by the Wellcome Trust Case Control Consortium study.OutcomeMeasures: Association between HABP2 G534E (rs7080536A) and NMTC risk was evaluated using logistic regression.ResultsThe frequency of HABP2 G534E was 4.2% in cases and 4.6% in controls. We did not detect an association between this variant and NMTC risk (OR=0.896, 95% CI: 0.746-1.071, P=0.233). We also failed to detect an association between HABP2 G534E and cases with papillary (1056 cases, G534E frequency= 3.5%, OR=0.74, P=0.017), follicular (691 cases, G534E frequency= 4.7%, OR=1.00, P=1.000) or Hurthle cell (86 cases, G534E frequency= 6.3%, OR=1.40, P=0.279) histology.ConclusionsWe found that HABP2 G534E is a low-to-moderate frequency variant in the British Isles and failed to detect an association with NMTC risk, independent of histological type. Hence, our study does not implicate HABP2 G534E or a correlated polymorphism in familial NMTC and additional data are required before using this variant in NMTC risk assessment

Exome Sequencing in an Admixed Isolated Population Indicates NFXL1 Variants Confer a Risk for Specific Language Impairment

Children affected by Specific Language Impairment (SLI) fail to acquire age appropriate language skills despite adequate intelligence and opportunity. SLI is highly heritable, but the understanding of underlying genetic mechanisms has proved challenging. In this study, we use molecular genetic techniques to investigate an admixed isolated founder population from the Robinson Crusoe Island (Chile), who are affected by a high incidence of SLI, increasing the power to discover contributory genetic factors. We utilize exome sequencing in selected individuals from this population to identify eight coding variants that are of putative significance. We then apply association analyses across the wider population to highlight a single rare coding variant (rs144169475, Minor Allele Frequency of 4.1% in admixed South American populations) in the NFXL1 gene that confers a nonsynonymous change (N150K) and is significantly associated with language impairment in the Robinson Crusoe population (p = 2.04 × 10–4, 8 variants tested). Subsequent sequencing of NFXL1 in 117 UK SLI cases identified four individuals with heterozygous variants predicted to be of functional consequence. We conclude that coding variants within NFXL1 confer an increased risk of SLI within a complex genetic model

Germline Mutations in PALB2, BRCA1, and RAD51C, Which Regulate DNA Recombination Repair, in Patients With Gastric Cancer

Up to 10% of cases of gastric cancer are familial, but so far, only mutations in CDH1 have been associated with gastric cancer risk. To identify genetic variants that affect risk for gastric cancer, we collected blood samples from 28 patients with hereditary diffuse gastric cancer (HDGC) not associated with mutations in CDH1 and performed whole-exome sequence analysis. We then analyzed sequences of candidate genes in 333 independent HDGC and non-HDGC cases. We identified 11 cases with mutations in PALB2, BRCA1, or RAD51C genes, which regulate homologous DNA recombination. We found these mutations in 2 of 31 patients with HDGC (6.5%) and 9 of 331 patients with sporadic gastric cancer (2.8%). Most of these mutations had been previously associated with other types of tumors and partially co-segregated with gastric cancer in our study. Tumors that developed in patients with these mutations had a mutation signature associated with somatic homologous recombination deficiency. Our findings indicate that defects in homologous recombination increase risk for gastric cancer

Genome-wide association study of breast cancer in Latinas identifies novel protective variants on 6q25

The genetic contributions to breast cancer development among Latinas are not well understood. Here we carry out a genome-wide association study of breast cancer in Latinas and identify a genome-wide significant risk variant, located 50 of the Estrogen Receptor 1 gene (ESR1; 6q25 region). The minor allele for this variant is strongly protective (rs140068132: odds ratio (OR) 0.60, 95% confidence interval (CI) 0.53–0.67, P = 9 x 10^-18), originates from Indigenous Americans and is uncorrelated with previously reported risk variants at 6q25. The association is stronger for oestrogen receptor-negative disease (OR 0.34, 95% CI 0.21–0.54) than oestrogen receptor-positive disease (OR 0.63, 95% CI 0.49–0.80; P heterogeneity = 0.01) and is also associated with mammographic breast density, a strong risk factor for breast cancer (P = 0.001). rs140068132 is located within several transcription factor-binding sites and electrophoretic mobility shift assays with MCF-7 nuclear protein demonstrate differential binding of the G/A alleles at this locus. These results highlight the importance of conducting research in diverse populations

<i>NFXL1</i> coding variants observed in 117 UK (SLIC) probands affected by SLI.

<p>1 – Variant allele freq (VAF) in 117 UK SLIC probands is estimated by Syzygy using the proportion of reads that have the variant</p><p>2 – Median read depth for given base across all pools</p><p>3 - Variant allele frequency (VAF) in 1000 genomes super-populations (Integrated phase I data, accessed March 2014). ALL – all 1000 genomes populations combined (No. alleles ∼ 2184), AFR – African populations (YRI, LWK, GWD, MSL, ESN, ASW & ACB, No. chromosomes = 492), AMR – Ad mixed Americans (MXL, PUR, CLM, PEL, No. chromosomes = 362),ASN – East Asian (CHB, JPT, CHS, CDX & KHV, No. chromosomes = 572), EUR-European (TSI, FIN, GBR, IBS, no. chromosomes = 758).</p><p>4 – Exome Sequencing Project (ESP) variant allele frequency (VAF). EA – European Americans (no. chromosomes = 8600), AA – African Americans (no. chromosomes = 4268).</p><p>5 – Combined variant allele frequency across European controls from 1000 genomes and EVS (no. chromosomes = 9358)</p><p>6 – Allele frequency in SLI probands after confirmatory Sanger sequencing (no. chromosomes = 234)</p><p>7 – Amino acid change conferred by given sequence variant in protein NP_694540.3. If the change occurs within a conserved motif, this is noted.</p><p>8 – Fisher’s exact test for differences in allele frequencies between EVS European Americans and SLIC probands. ns = non-significant P<0.05</p><p>NT = not tested</p><p>Ns = not significant</p><p><i>NFXL1</i> coding variants observed in 117 UK (SLIC) probands affected by SLI.</p

Coding variants observed in SLIC probands and their families.

<p>Pedigrees are shown for nuclear families of SLIC individuals carrying three coding variations in <i>NFXL1</i>. Individuals carrying the variants are identified with a black circle. Sequencing traces of each variant is shown. SLIC probands are colored in red and other family members with SLI (defined as expressive and/or receptive language skills >1.5SD below that expected for their age) are colored in orange. In pedigree 3 (rs151113647), the youngest sibling (colored in yellow) did not meet the criteria for SLI but had expressive and receptive language scores ∼1SD below that expected for his age. Individuals with no shading have typical language ability. DNA was not available for individuals colored in grey.</p

Association of novel nonsynonymous or canonical splice-site variants in 111 individuals from the Robinson Crusoe validation cohort.

<p>1 – The number of individuals with SLI genotyped / the number of individuals with typical language ability genotyped.</p><p>2 – Frequency of discovered variant in all genotyped Islanders</p><p>3 – Frequency of discovered variant in genotyped Islanders with SLI</p><p>4 – Frequency of discovered variant in genotyped Islanders with typical language ability</p><p>Note that all Islanders (both cases and controls) were related</p><p>*- this variant was not validated with Sanger sequencing and represents a false positive finding from the exome sequencing</p><p>Association of novel nonsynonymous or canonical splice-site variants in 111 individuals from the Robinson Crusoe validation cohort.</p