Search for genetic modifiers of IRF6 and genotype-phenotype correlations in Van der Woude and popliteal pterygium syndromes.

Van der Woude syndrome is the most common form of syndromic orofacial clefting, accounting for 1-2% of all patients with cleft lip and/or cleft palate. Van der Woude and popliteal pterygium syndromes are caused by mutations in IRF6, but phenotypic variability within and among families with either syndrome suggests that other genetic factors contribute to the phenotypes. The aim of this study was to identify common variants acting as genetic modifiers of IRF6 as well as genotype-phenotype correlations based on mutation type and location. We identified an association between mutations in the DNA-binding domain of IRF6 and limb defects (including pterygia). Although we did not detect formally significant associations with the genes tested, borderline associations suggest several genes that could modify the VWS phenotype, including FOXE1, TGFB3, and TFAP2A. Some of these genes are hypothesized to be part of the IRF6 gene regulatory network and may suggest additional genes for future study when larger sample sizes are also available. We also show that families with the Van de Woude phenotype but in whom no mutations have been identified have a lower frequency of cleft lip, suggesting there may be locus and/or mutation class differences in Van de Woude syndrome.

Mutations in BMP4 are associated with subepithelial, microform, and overt cleft lip.

Cleft lip with or without cleft palate (CL/P) is a complex trait with evidence that the clinical spectrum includes both microform and subepithelial lip defects. We identified missense and nonsense mutations in the BMP4 gene in 1 of 30 cases of microform clefts, 2 of 87 cases with subepithelial defects in the orbicularis oris muscle (OOM), 5 of 968 cases of overt CL/P, and 0 of 529 controls. These results provide confirmation that microforms and subepithelial OOM defects are part of the spectrum of CL/P and should be considered during clinical evaluation of families with clefts. Furthermore, we suggest a role for BMP4 in wound healing.

FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate.

Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

Active choice but not too active: public perspectives on biobank consent models.

PURPOSE: Despite important recent work, US public attitudes toward specific biobank consent models are not well understood. Public opinion data can help shape efforts to develop ethically sound and publicly trusted mechanisms for informing and consenting prospective biobank donors. The purpose of this study was to explore public perspectives toward a range of consent models currently being used or considered for use among comprehensive US biobanks. METHODS: The study used an exploratory mixed-methods design, using focus groups and telephone surveys. Eligible participants were English-speaking residents in the catchment area of a comprehensive biobank being developed at the University of Iowa. RESULTS: Forty-eight participants in seven focus groups and 751 survey participants were recruited. Biobanks were unfamiliar to almost all study participants but were seen as valuable resources. Most focus group (63%) and survey (67%) participants preferred a prospective opt-in over an opt-out consent approach. Broad, research-unspecific consent was preferred over categorical and study-specific consent models for purposes of approving future research use. CONCLUSION: Many individuals may want to make an active and informed choice at the point of being approached for biobank participation but are prepared to consent broadly to future research use and to forego additional choices as a result.

A case of 3q29 microdeletion syndrome involving oral cleft inherited from a nonaffected mosaic parent: molecular analysis and ethical implications.

OBJECTIVE: The objective of this study was to use array comparative genomic hybridization to detect causal microdeletions in samples of subjects with cleft lip and palate. SUBJECTS: We analyzed DNA samples from a male patient and his parents seen during surgical screening for an Operation Smile medical mission in the Philippines. METHOD: We used Affymetrix® Genome-Wide Human SNP Array 6.0 followed by sequencing and quantitative polymerase chain reaction using SYBR Green I dye. RESULTS: We report the second case of 3q29 microdeletion syndrome including cleft lip with or without cleft palate and the first case of this microdeletion syndrome inherited from a phenotypically normal mosaic parent. CONCLUSIONS: Our findings confirm the usefulness of a comparative genomic hybridization to detect causal microdeletions and indicate that parental somatic mosaicism should be considered in healthy parents for genetic counseling of the families. We discuss important ethical implications of sharing health impact results from research studies with the participant families.

Wound complications after cleft repair in children with Van der Woude syndrome.

Van der Woude syndrome (VWS; OMIM 119300) is an autosomal-dominant condition associated with clefts of the lip and/or palate and lower lip pits and is caused by mutations in interferon regulatory factor 6 (IRF6). The standard of practice for children born with cleft lip/palate is surgical repair, which requires proper wound healing. We tested the hypothesis that children with VWS are more likely to have wound complications after cleft repair than children with nonsyndromic cleft lip/palate (NSCLP). Furthermore, we hypothesized that children with VWS have more surgical procedures. A retrospective, case-controlled study was performed. Seventeen children with VWS and 68 matched controls with NSCLP were scored for the presence of wound complications after cleft repair, for the severity of complications, and for number of surgeries from age 0 to 10. Of the 17 children with VWS, 8 had wound complications. Of 68 controls, 13 had wound complications (P = 0.02). Of 8 wound complications in the VWS group, 6 were major, whereas of 13 complications in the control group, 9 were major (P = 0.04). Most wound complications were fistulae and occurred in isolated cleft palate and bilateral cleft lip. The mean number of surgeries in the VWS group was 3.0 compared with 2.8 in the control group (P = 0.67). Our studies suggest that children with VWS have an increased risk for wound complications after cleft repair compared with children with NSCLP. Furthermore, these data support a role for IRF6 in wound healing.

Public perspectives on biospecimen procurement: what biorepositories should consider.

PURPOSE: Human biospecimens are central to biobanking efforts, yet how members of the public think about biobank procurement strategies is not well understood. This study aimed to explore public perspectives toward the procurement of residual clinical material versus "direct" procurement strategies such as the drawing of blood. METHODS: Members of the public residing in and beyond the biobank catchment area of the University of Iowa Hospitals and Clinics were randomly selected to participate in focus groups and a telephone survey. RESULTS: The majority of survey participants (75%, n=559) found both residual and direct procurement strategies equally workable. Small proportions preferred either residual (15%; n=117) or direct (5%; n=40) procurement. Focus group participants (n=48) could identify benefits to both procurement strategies, but raised concerns about possible donor inconvenience/discomfort and reduced biospecimen accrual in the case of direct procurement. Residual procurement raised concerns about lower-quality samples being procured without full donor awareness. CONCLUSION: Biobanks should consider that members of the public in their research programs may be willing to make specimen donations regardless of whether a residual or direct procurement strategy is employed. Limiting patient discomfort and inconvenience may make direct procurement strategies more acceptable to some members of the public. Ensuring donor awareness through effective informed consent may allay public concerns about the indirectness of donating clinical biospecimens.