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Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA (microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C→T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR 4 ) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus 3 . Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2-associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCDmutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.We had previously localized MAA2 to a 10-Mb candidate region of Xp 3 . To identify the gene, we narrowed this region by excluding regions deleted in males with Xp deletions but without microphthalmia. Coriell cell line GM07947 is from a male with Duchenne muscular dystrophy, chronic granulomatous disease, McLeod phenotype and retinitis pigmentosa without microphthalmia 5 . Sequence-tagged site (STS) mapping confirmed previous data and oriented it to current genome maps. The deletion extended from DMD (telomeric) to between RPGR and OTC (centromeric; Fig. 1). The Coriell cell line GM10283 excluded two genes telomeric to DMD. This narrowed the critical region to ∼5 Mb, including 12 identified genes not known to be mutated in humans. One of these, DDX3, has an active Y homolog, and we therefore considered it unlikely to underlie a disorder with X-linked recessive inheritance. We sequenced the remaining 11 genes in members of the family in which MAA2 was originally identified. Ten of these genes showed no alterations, but we identified a missense change (nt 254C→T) in BCOR 4 that co-segregated with the disease phenotype (lod score of 2.46, above the threshold of 2.0 for X linkage 3 ). The corresponding residue of human BCOR, Pro85, is conserved in mouse, rat, chicken and pufferfish (Fig. 2), and we did not detect the nt 254C→T mutation among >450 control chromosomes. X-inactivation studies of peripheral blood leukocytes in two carriers of the mutation showed no ske...

Genomic research is transforming our understanding of the role of genes in health and disease. These advances, and their application to common diseases that affect large segments of the general population, suggest that researchers and practitioners in public health genomics will increasingly be called upon to translate genomic information to individuals with varying levels of health literacy and numeracy. This paper discusses the current state of research regarding public understanding of genetics and genomics, the influence of health literacy and numeracy on genetic communication, and behavioral responses to genetic and genomic information. The existing research suggests that members of the general public have some familiarity with genetic and genomic terms but have gaps in understanding of underlying concepts. Findings from the limited research base to date indicate that health literacy affects understanding of print and oral communications about genetic and genomic information. Numeracy is also likely to be an important predictor of being able to understand and apply this information, although little research has been conducted in this area to date. In addition, although some research has examined behavior change in response to the receipt of information about genetic risk for familial disorders and genomic susceptibility to common, complex diseases, the effects of health literacy and numeracy on these responses have not been examined. Potential areas in which additional research is needed are identified and practical suggestions for presenting numeric risk information are outlined. Public health genomics researchers and practitioners are uniquely positioned to engage in research that explores how different audiences react to and use genomic risk information.

Holoprosencephaly (HPE) is the most common malformation of the human forebrain, and may be due to cytogenetic anomalies, teratogens, occur in the context of a syndrome, or be due to mutations in single genes associated with non-syndromic HPE. Mutations in ZIC2, a transcription factor located on chromosome 13q32, are the second-most common cause of non-syndromic, non-chromosomal HPE. Blood samples from over 1000 individuals with HPE-spectrum disorders and their relatives were analyzed for sequence variations in ZIC2. We examined clinical details and included all other known previously published and unpublished cases of mutations in ZIC2 through a literature search and collaboration with other centers. We find mutations in ZIC2 in 8% of probands with HPE, and describe 153 individuals from 116 unrelated kindreds, including 137 patients with molecularly-determined mutations in ZIC2 and 16 patients with deletions of the ZIC2 locus. Unlike HPE due to mutations in other genes, the vast majority of cases are sporadic and the proportional distribution of HPE types differs significantly from previously published analyses of non-chromosomal non-syndromic HPE. Furthermore, we describe a novel facial phenotype in patients with mutations in ZIC2 which includes bitemporal narrowing, upsplanting palpebral fissures, a short nose with anteverted nares, and a broad and well-demarcated philtrum, and large ears. This phenotype is distinct from the standard facial dysmorphisms associated with non-chromosomal, non-syndromic HPE. Our findings show that HPE due to mutations in ZIC2 is distinct from that due to mutations in other genes. This may shed light on the mechanisms that contribute to the formation of the face and the forebrain and may help direct genetic counseling and diagnostic strategies.

Genetic counseling and testing for HNPCC significantly influences the use of colonic endoscopy and adherence to recommendations for colon cancer screening.

Although BRCA1/2 testing has increasingly entered clinical practice, much is to be learned about the most effective ways to provide counseling to persons potentially interested in receiving test results. The purpose of this study was to identify factors affecting genetic testing decisions in a cohort of hereditary breast and ovarian cancer (HBOC) families presented with the choice to undergo testing. Relatives in these families are known to carry BRCA1 or BRCA2 mutations. Sociodemographics, personality traits, and family functioning were self-assessed using validated psychometric instruments at baseline. Among 172 individuals who participated in pretest education and counseling, 135 (78%) chose to undergo genetic testing and 37 (22%) chose not to be tested. Individuals who chose to undergo genetic testing were more likely to be older (> or =40 years), to have lower levels of optimism, and to report higher levels of cohesiveness in their families. A better understanding of factors that influence interest in predictive testing may help to inform the counseling that occurs prior to genetic testing.

Background Holoprosencephaly (HPE) is the most common structural malformation of the human forebrain. There are several important HPE mutational target genes, including the transcription factor SIX3, which encodes an early regulator of Shh, Wnt, Bmp and Nodal signalling expressed in the developing forebrain and eyes of all vertebrates. Objective To characterise genetic and clinical findings in patients with SIX3 mutations. Methods Patients with HPE and their family members were tested for mutations in HPE-associated genes and the genetic and clinical findings, including those for additional cases found in the literature, were analysed. The results were correlated with a mutation-specific functional assay in zebrafish. Results In a cohort of patients (n = 800) with HPE, SIX3 mutations were found in 4.7% of probands and additional cases were found through testing of relatives. In total, 138 cases of HPE were identified, 59 of whom had not previously been clinically presented. Mutations in SIX3 result in more severe HPE than in other cases of non-chromosomal, non-syndromic HPE. An over-representation of severe HPE was found in patients whose mutations confer greater loss of function, as measured by the functional zebrafish assay. The gender ratio in this combined set of patients was 1.5:1 (F:M) and maternal inheritance was almost twice as common as paternal. About 14% of SIX3 mutations in probands occur de novo. There is a wide intrafamilial clinical range of features and classical penetrance is estimated to be at least 62%. Conclusions Our data suggest that SIX3 mutations result in relatively severe HPE and that there is a genotype–phenotype correlation, as shown by functional studies using animal models.

Muenke syndrome is an autosomal dominant disorder characterized by coronal suture craniosynostosis, hearing loss, developmental delay, carpal and tarsal fusions, and the presence of the Pro250Arg mutation in the FGFR3 gene. Reduced penetrance and variable expressivity contribute to the wide spectrum of clinical findings in Muenke syndrome. To better define the clinical features of this syndrome, we initiated a study of the natural history of Muenke syndrome. To date, we have conducted a standardized evaluation of nine patients with a confirmed Pro250Arg mutation in FGFR3. We reviewed audiograms from an additional 13 patients with Muenke syndrome. A majority of the patients (95%) demonstrated a mild-to-moderate, low frequency sensorineural hearing loss. This pattern of hearing loss was not previously recognized as characteristic of Muenke syndrome. We also report on feeding and swallowing difficulties in children with Muenke syndrome. Combining 312 reported cases of Muenke syndrome with data from the nine NIH patients, we found that females with the Pro250Arg mutation were significantly more likely to be reported with craniosynostosis than males (P < 0.01). Based on our findings, we propose that the clinical management should include audiometric and developmental assessment in addition to standard clinical care and appropriate genetic counseling.