Molecular pathogenesis and heterogeneity in type 3 VWD families in U.S. Zimmerman program.

BACKGROUND: Type 3 von Willebrand Disease (VWD) is a rare and severe form of VWD characterized by the absence of von Willebrand factor (VWF). OBJECTIVES: As part of the Zimmerman Program, we sought to explore the molecular pathogenesis, correlate bleeding phenotype and severity, and determine the inheritance pattern found in type 3 VWD families. PATIENTS/METHODS: 62 index cases with a pre-existing diagnosis of type 3 VWD were analyzed. Central testing included FVIII, VWF:Ag, VWF:RCo, and VWFpp. Bleeding symptoms were quantified using the ISTH bleeding score. Genetic analysis included VWF sequencing, comparative genomic hybridization and predictive computational programs. RESULTS: 75% of subjects (46) had central testing confirming type 3, while 25% were re-classified as type 1-Severe or type 1C. Candidate VWF variants were found in all subjects with 93% of expected alleles identified. The majority were null alleles including frameshift, nonsense, splice site, and large deletions, while 13% were missense variants. Additional studies on 119 family members, including 69 obligate carriers, revealed a wide range of heterogeneity in VWF levels and bleeding scores, even amongst those with the same variant. Co-dominant inheritance was present in 51% of families and recessive in 21%, however 28% were ambiguous. CONCLUSION: This report represents a large cohort of VWD families in the U.S. with extensive phenotypic and genotypic data. While co-dominant inheritance was seen in approximately 50% of families, this study highlights the complexity of VWF genetics due to the heterogeneity found in both VWF levels and bleeding tendencies amongst families with type 3 VWD.

The Influence of Paternal Separation, Paternal History of Alcohol Use Disorder Risk, and Early Substance Use on Offspring Educational Attainment by Young Adulthood.

OBJECTIVE: This study aimed to determine the associations among paternal alcohol problems, separation, and educational attainment in European American and African American offspring and whether offspring early alcohol/tobacco/marijuana use influenced these associations. METHOD: Families with offspring ages 13-19 years at intake were selected from state birth records and screened by telephone to determine high-risk or low-risk status (with/without paternal heavy drinking). Families of men with two or more driving-under-the-influence offenses were added as a very-high-risk group. Data from 340 African American and 288 European American offspring who were not enrolled in school at their last interview were analyzed. Educational attainment was modeled as less than high school, high school only (reference category), and some college or higher. Separation was defined as offspring report of not having lived continuously in the same household with their biological father from birth to age 14. Analyses were stratified by race. RESULTS: In European Americans, neither family risk status nor early alcohol/tobacco/marijuana use was associated with educational outcomes. However, paternal separation significantly elevated the likelihood of not completing high school in all models (relative risk ratios [RRRs] = 6.0-8.1, p <.001). For African American offspring, likelihoods of high school noncompletion were elevated marginally for paternal separation in only one model, but significantly for early marijuana use (RRRs = 2.8-3.2, p < .05). Very-high-risk status significantly reduced the likelihood of post-high school education in an adjusted model (RRR = 0.4, p < .05). CONCLUSIONS: High school noncompletion was significantly associated with paternal separation in European Americans and with early marijuana use in African American offspring. In addition, very-high-risk status reduced the likelihood of post-high school education in African American offspring only, suggesting that research with ethnically diverse samples yields important differences when examining outcomes of both separation and substance use on offspring education.

Genetic and environmental contributions to variation in baboon cranial morphology.

The development, function, and integration of morphological characteristics are all hypothesized to influence the utility of traits for phylogenetic reconstruction by affecting the way in which morphological characteristics evolve. We use a baboon model to test the hypotheses about phenotypic and quantitative genetic variation of traits in the cranium that bear on a phenotype's propensity to evolve. We test the hypotheses that: 1) individual traits in different functionally and developmentally defined regions of the cranium are differentially environmentally, genetically, and phenotypically variable; 2) genetic covariance with other traits constrains traits in one region of the cranium more than those in others; 3) and regions of the cranium subject to different levels of mechanical strain differ in the magnitude of variation in individual traits. We find that the levels of environmental and genetic variation in individual traits are randomly distributed across regions of the cranium rather than being structured by developmental origin or degree of exposure to strain. Individual traits in the cranial vault tend to be more constrained by covariance with other traits than those in other regions. Traits in regions subject to high degrees of strain during mastication are not any more variable at any level than other traits. If these results are generalizable to other populations, they indicate that there is no reason to suppose that individual traits from any one part of the cranium are intrinsically less useful for reconstructing patterns of evolution than those from any other part.