Whole genome sequencing of orofacial cleft trios from the Gabriella Miller Kids First Pediatric Research Consortium identifies a new locus on chromosome 21.

Orofacial clefts (OFCs) are among the most prevalent craniofacial birth defects worldwide and create a significant public health burden. The majority of OFCs are non-syndromic, and the genetic etiology of non-syndromic OFCs is only partially determined. Here, we analyze whole genome sequence (WGS) data for association with risk of OFCs in European and Colombian families selected from a multicenter family-based OFC study. This is the first large-scale WGS study of OFC in parent-offspring trios, and a part of the Gabriella Miller Kids First Pediatric Research Program created for the study of childhood cancers and structural birth defects. WGS provides deeper and more specific genetic data than using imputation on present-day single nucleotide polymorphic (SNP) marker panels. Genotypes of case-parent trios at single nucleotide variants (SNV) and short insertions and deletions (indels) spanning the entire genome were called from their sequences using human GRCh38 genome assembly, and analyzed for association using the transmission disequilibrium test. Among genome-wide significant associations, we identified a new locus on chromosome 21 in Colombian families, not previously observed in other larger OFC samples of Latin American ancestry. This locus is situated within a region known to be expressed during craniofacial development. Based on deeper investigation of this locus, we concluded that it contributed risk for OFCs exclusively in the Colombians. This study reinforces the ancestry differences seen in the genetic etiology of OFCs, and underscores the need for larger samples when studying for OFCs and other birth defects in populations with diverse ancestry.

Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in Down syndrome births

Abstract Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin −1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.

Combined association of Presenilin-1 and Apolipoprotein E polymorphisms with maternal meiosis II error in Down syndrome births.

Alzheimer's disease and Down syndrome often exhibit close association and predictively share common genetic risk-factors. Presenilin-1 (PSEN-1) and Apolipoprotein E (APOE) genes are associated with early and late onset of Alzheimer's disease, respectively. Presenilin -1 is involved in faithful chromosomal segregation. A higher frequency of the APOE ε4 allele has been reported among young mothers giving birth to Down syndrome children. In this study, 170 Down syndrome patients, grouped according to maternal meiotic stage of nondisjunction and maternal age at conception, and their parents were genotyped for PSEN-1 intron-8 and APOE polymorphisms. The control group consisted of 186 mothers of karyotypically normal children. The frequencies of the PSEN-1 T allele and TT genotype, in the presence of the APOE ε4 allele, were significantly higher among young mothers (< 35 years) with meiosis II nondisjunction than in young control mothers (96.43% vs. 65.91% P = 0.0002 and 92.86% vs. 45.45% P < 0.0001 respectively) but not among mothers with meiosis I nondisjunction. We infer that the co-occurrence of the PSEN-1 T allele and the APOE ε4 allele associatively increases the risk of meiotic segregation error II among young women.

Replication of a genome-wide association study of birth weight in preterm neonates.

OBJECTIVE: To examine associations between rs9883204 in ADCY5 and rs900400 near LEKR1 and CCNL1 with birth weight in a preterm population. Both markers were associated with birth weight in a term population in a recent genome-wide association study of Freathy et al. STUDY DESIGN: A meta-analysis of mother and infant samples was performed for associations of rs900400 and rs9883204 with birth weight in 393 families from the US, 265 families from Argentina, and 735 mother-infant pairs from Denmark. Z-scores adjusted for infant sex and gestational age were generated for each population separately and regressed on allele counts. Association evidence was combined across sites by inverse-variance weighted meta-analysis. RESULTS: Each additional C allele of rs900400 (LEKR1/CCNL1) in infants was marginally associated with a 0.069 SD lower birth weight (95% CI, -0.159 to 0.022; P = .068). This result was slightly more pronounced after adjusting for smoking (P = .036). No significant associations were identified with rs9883204 or in maternal samples. CONCLUSIONS: These results indicate the potential importance of this marker on birth weight regardless of gestational age.

Age of onset in hereditary lymphedema.

OBJECTIVE: To characterize age of onset patterns and penetrance in hereditary lymphedema, including differences caused by sex and genetic heterogeneity. STUDY DESIGN: Kaplan-Meier analysis of three family cohorts with autosomal dominant lymphedema: (1) five families with unique mutations in FLT4, (2) 16 families with unique mutations in FOXC2, and (3) 77 families with no mutations yet identified in any gene (the heterogeneous group). RESULTS: Age of onset was typically congenital among FLT4 mutation families and pubertal among FOXC2 mutation families, with similar male and female penetrance in both groups. Age of onset was highly variable in the families with no identified mutation, with substantially higher penetrance among female patients than male patients. In addition, male patients and female patients in the heterogeneous group had very different overall age of onset profiles. CONCLUSIONS: The two genes identified to date that cause hereditary lymphedema have equal male and female effects, but each displays a different pattern of onset age and penetrance. The heterogeneous group represents a genetically heterogeneous population and has phenotypic overlaps with the FLT4 and FOXC2 mutation families.