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Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

Abstract Craniosynostosis (CS) is a major birth defect resulting from premature fusion of cranial sutures. Nonsyndromic CS occurs more frequently than syndromic CS, with sagittal nonsyndromic craniosynostosis (sNCS) presenting as the most common CS phenotype. Previous genome-wide association and targeted sequencing analyses of sNCS have identified multiple associated loci, with the strongest association on chromosome 20. Herein, we report the first whole-genome sequencing study of sNCS using 63 proband-parent trios. Sequencing data for these trios were analyzed using the transmission disequilibrium test (TDT) and rare variant TDT (rvTDT) to identify high-risk rare gene variants. Sequencing data were also examined for copy number variants (CNVs) and de novo variants. TDT analysis identified a highly significant locus at 20p12.3, localized to the intergenic region between BMP2 and the noncoding RNA gene LINC01428. Three variants (rs6054763, rs6054764, rs932517) were identified as potential causal variants due to their probability of being transcription factor binding sites, deleterious combined annotation dependent depletion scores, and high minor allele enrichment in probands. Morphometric analysis of cranial vault shape in an unaffected cohort validated the effect of these three single nucleotide variants (SNVs) on dolichocephaly. No genome-wide significant rare variants, de novo loci, or CNVs were identified. Future efforts to identify risk variants for sNCS should include sequencing of larger and more diverse population samples and increased omics analyses, such as RNA-seq and ATAC-seq.

This family‐based study was conducted in a group of Iranians with Type 1 diabetes (T1D) to investigate the transmission from parents of risk and non‐risk HLA alleles and haplotypes, and to estimate the genetic risk score for this disease within this population. A total of 240 T1D subjects including 111 parent–child trios (111 children with T1D, 133 siblings, and 222 parents) and 330 ethnically matched healthy individuals were recruited. High‐resolution HLA typing for DRB1/DQB1 loci was performed for all study subjects (n = 925) using polymerase chain reaction–sequence‐specific oligonucleotide probe method. The highest predisposing effect on developing T1D was conferred by the following haplotypes both in all subjects and in probands compared to controls: DRB1*04:05–DQB1*03:02 (Pc = 2.97e‐06 and Pc = 6.04e‐10, respectively), DRB1*04:02–DQB1*03:02 (Pc = 5.94e‐17 and Pc = 3.86e‐09, respectively), and DRB1*03:01–DQB1*02:01 (Pc = 8.26e‐29 and Pc = 6.56e‐16, respectively). Conversely, the major protective haplotypes included DRB1*13:01–DQB1*06:03 (Pc = 6.99e‐08), DRB1*15:01–DQB1*06:02 (Pc = 2.97e‐06) in the cases versus controls. Also, DRB1*03:01–DQB1*02:01/DRB1*04:02|05–DQB1*03:02 and DRB1*03:01–DQB1*02:01/DRB1*03:01–DQB1*02:01 diplotypes conferred the highest predisposing effect in the cases (Pc = 8.65e‐17 and Pc = 6.26e‐08, respectively) and in probands (Pc = 5.4e‐15 and Pc = 0.001, respectively) compared to controls. Transmission disequilibrium test showed that the highest risk was conferred by DRB1*04:02–DQB1*03:02 (Pc = 3.26e‐05) and DRB1*03:01–DQB1*02:01 (Pc = 1.78e‐12) haplotypes and the highest protection by DRB1*14:01–DQB1*05:03 (Pc = 8.66e‐05), DRB1*15:01–DQB1*06:02 (Pc = 0.002), and DRB1*11:01–DQB1*03:01 (Pc = 0.0003) haplotypes. Based on logistic regression analysis, carriage of risk haplotypes increased the risk of T1D development 24.5 times in the Iranian population (p = 5.61e‐13). Also, receiver operating characteristic curve analysis revealed a high predictive power of those risk haplotypes in discrimination of susceptible from healthy individuals (area under curve: 0.88, p = 5.5e‐32). Our study highlights the potential utility of genetic risk assessment based on HLA diplotypes for predicting T1D risk in individuals, particularly among family members of affected children in our population. [ABSTRACT FROM AUTHOR]

Objectives: This study investigated the associations of PVRL1 gene variants with non-syndromic cleft lip with or without cleft palate (NSCL/P) by evaluating transmission distortion and parent-of-origin (POO) effects in multiple ethnic populations., Methods: We conducted allelic and genotypic transmission disequilibrium tests (TDT) on 10 single-nucleotide variants (SNVs) in PVRL1 using data from 142 Korean families with an affected child. POO effects were analyzed using the POO likelihood ratio test, comparing transmission rates of maternally and paternally inherited alleles. To assess generalizability and ethnic heterogeneity, we compared results from Korean families with data from the Center for Craniofacial and Dental Genetics, which included 2,226 individuals from 497 European and 245 Asian trios., Results: TDT analysis identified significant over-transmission of the rs7940667 (G361V) C allele in Korean families (p=0.007), a finding replicated in both Asian (p=6.5×10-7) and European families (p=1.6×10-10). Eight SNVs showed strong TDT evidence in larger Asian and European datasets after multiple comparison corrections (p<0.0073). Of these, 4 SNVs (rs7940667, rs7103685, rs7129848, and rs4409845) showed particularly robust association (p<5×10-8). POO analysis revealed significant maternal over-transmission of the rs10790330-A allele in Korean families (p=0.044). This finding was replicated in European families (p=9.0×10-4). Additionally, 3 other SNVs, rs7129848 (p=0.001) and the linked SNVs rs3935406 and rs10892434 (p=0.025), exhibited maternal over-transmission in the validation datasets., Conclusions: Our findings provide robust evidence supporting the associations of PVRL1 variants with NSCL/P susceptibility. Further research is necessary to explore the potential clinical applications of these findings.