Evidence for an attentional component in saccadic inhibition of return

After presentation of a peripheral cue, facilitation at the cued location is followed by inhibition of return (IOR). It has been recently proposed that IOR may originate at different processing stages for manual and ocular responses, with manual IOR resulting from inhibited attentional orienting, and ocular IOR resulting form inhibited motor preparation. Contrary to this interpretation, we found an effect of target contrast on saccadic IOR. The effect of contrast decreased with increasing reaction times (RTs) for saccades, but not for manual key-press responses. This may have masked the effect of contrast on IOR with saccades in previous studies (Hunt and Kingstone in J Exp Psychol Hum Percept Perform 29:1068–1074, 2003) because only mean RTs were considered. We also found that background luminance strongly influenced the effects of gap and target contrast on IOR.

Toriello-Carey syndrome: Evidence for X-linked inheritance

Toriello-Carey syndrome is characterized by agenesis of the corpus callosum, telecanthus, short palpebral fissures, Robin sequence, abnormal ears, cardiac anomalies, and hypotonia. We describe two patients with Toriello-Carey syndrome and call attention to an unbalanced sex ratio. The first patient, a male, was born at term by Cesarean section and manifests micrognathia, cleft soft palate, hypoplastic right ear, anotia on the left side, cerebellar vermis hypoplasia, hydrocephalus, agenesis of the corpus callosum, and hypoplastic left heart. He died 2 days after birth. The second patient is the male sib of a patient reported previously [Am J Med Genet 42: 374–376; 1992]. He had large fontanelles, telecanthus, a short nose, small and malformed ears, micrognathia, a large ventricular septal defect, and pulmonary stenosis. At age 8 months he has growth retardation and developmental delay. A sister is unaffected. Review documented eight other patients with Toriello-Carey syndrome, six of whom were male. The two female patients are less severely affected and are still alive. Of the other male patients, all are deceased except one who is still alive at age 5 years; he has severe growth retardation (-3 SD), mental retardation (DQ44), severe speech delay, and characteristic anomalies. The predominance of affected males and the milder phenotype in the female patients suggests an X-linked gene or sex influenced gene. © 1996 Wiley-Liss, Inc.     

Cascade genetic screening for familial hypercholesterolemia

Familial hypercholesterolemia (FH) is caused by a mutation in the low-density lipoprotein receptor gene and is characterized by hypercholesterolemia, xanthomas, and premature coronary heart disease. Heterozygotes typically have values for total serum cholesterol in the range of 7-15 mmol/l and efficient lipid-lowering drug therapy is available. However, only approximately 20% of patients are diagnosed and less than 10% are being adequately treated. The most cost-effective strategy to diagnose patients with FH is to screen close relatives of patients already diagnosed with FH. This is referred to as cascade genetic screening. This review focuses on organization of a cascade genetic screening program for FH as well as cost-efficiency assessments, health benefits, possible adverse effects, and the screening of children. The author concludes that cascade genetic screening for FH leads to health benefits and is cost-effective without causing psychological or social damage. Accordingly, national cascade genetic screening programs for FH should be part of ordinary health care.     

Evidence for a major gene in familial anencephaly

A 21-year-old white woman sought counseling after the birth of two consecutive anencephalic male fetuses with complete rachischisis and discordant renal dysplasia. The presence of parental consanguinity prompted reconsideration of recessive inheritance. The segregation ratio from 23 additional consanguineous cases was compared with that observed in 294 presumably nonconsanguineous families previously reported. Using classical segregation analysis, the segregation ratios in the non-sporadic cases were consistent with a major autosomal recessive locus in both populations.     

Cellular imaging demonstrates genetic mosaicism in heterozygous carriers of an X-linked ciliopathy gene

X-linked retinitis pigmentosa (XLRP) is the least common genetic type of retinitis pigmentosa; however, it has extremely devastating consequences to patients'' activities of daily living. RPGR and RP2 genes expressed in the photoreceptor sensory cilia are predominantly implicated in XLRP; however, the interpretation of genetic mutations and their correlation with clinical phenotypes remain unknown, and the role of these genes in photoreceptor cilia function is not completely elucidated. Therefore, we evaluated structural characteristics in five female obligate carriers of XLRP by using state-of-the-art non-invasive imaging methods, including adaptive optics (AO) scanning laser ophthalmoscopy (SLO). In all five carriers examined, qualitative and quantitative analyses by AO SLO imaging revealed a mosaic pattern of cone disruption, even in the absence of visual symptoms, normal visual acuity and normal macular thickness, on optical coherence tomography and mildly subnormal full-field cone electroretinographic findings. As the technique is sensitive to the level of a single cone, the ability to visualize the cone cells in vivo should be especially useful in other retinal diseases. In addition, further investigation of XLRP carriers may yield insight into how cone structures change over time and ultimately enable understanding of the role of RPGR and RP2 in cone cell survival.     

Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome.

A previously unreported family in which seven members in two generations have Beckwith-Wiedemann syndrome (BWS) is documented. Paternal imprinting of the gene responsible for BWS is involved as the mechanism responsible for the aberrant inheritance pattern in this kindred. A review of published reports showed 27 previously published pedigrees with two or more affected subjects with BWS. Paternal imprinting would explain the non-mendelian inheritance of BWS in all but four kindreds. The latter families are examined in more detail and in only one example is the evidence against imprinting totally unexplained.     

Communication and technology in genetic counseling for familial cancer

When a cancer predisposing germline mutation is detected in an index case, the presence of the underlying syndrome is confirmed and the potential for predictive testing of at‐risk relatives is established. However, the reporting of a positive family history does not routinely lead to communication of information about risk to close, much less distant relatives. This review summarizes information technology utilized to address penetration or ‘reach’ of knowledge of risk within extended families, including the use of telephone and video counseling to reach distant patients, and anticipate novel internet‐based processes for communication between investigators and relatives.     

Evidence for a new late positive ERP component in an attended novelty oddball task

In attended novelty oddball tasks, rare nontarget stimuli can elicit two late positive ERP components: P3a and P300. In passive oddball tasks, P300 is not elicited by these stimuli. In passive tasks, however, P3a is accompanied by another positive component, termed eP3a, which may have evaded detection in attended oddball tasks because of its spatiotemporal overlap with P300. To address this, temporal‐spatial principal components analysis was used to quantify ERPs recorded in attended three‐tone and novelty oddball tasks. As expected, novel stimuli elicited both P3a and P300. The analysis also identified a third component, evident in novelty ERPs as an inflection on the leading edge of P3a. This component has the same antecedent conditions as P3a, but is earlier and more centrally distributed. Its spatiotemporal characteristics suggest that it may be the eP3a component recently described in passive oddball tasks.     

HLA genetic determinants in familial MS

Fourteen multiplex MS families, 9 single-case MS families and 11 normal families from the Grampian region of North-East Scotland were studied. The prevalence rate of MS for individuals in multiplex families was calculated at 809/100,000; 4.5 times the prevalence rate for the general population in this region. The distribution of shared haplotypes in 12 affected and 19 unaffected sib-pair comparisons did not differ significantly from that expected by chance. Furthermore there was no evidence that homozygosity of a particular HLA gene was required for increased susceptibility to the disease. HLA-B7, C4A3, C4B1, BfS, HLA-DR2, HLA-DQw1 was the commonest haplotype accounting for 18.9% and 24.2% of parental haplotypes from multiplex and single-case families, respectively, compared with 2.3% of parental haplotypes from control families (p less than 0.05 and p less than 0.01, respectively). No significant differences were observed in the frequencies of complement gene polymorphisms (Factor B and C4). The data suggests that a MS susceptibility gene exists, in the HLA complex, and is in closest linkage disequilibrium with the HLA-D region; although other factors, environmental and/or independent genetic loci, may have an important influence.     

Evidence for an extended interacting surface between beta-amyloid and serum amyloid P component

Studying the interaction between serum amyloid P component (SAP) and beta-amyloid (Abeta) a new Abeta binding site was identified on the SAP near the known binding site at the two bound calcium ions. SAP stabilizes deposits in neurodegenerative diseases, which is manifested via Abeta-binding. Because the inhibition of this interaction is a potential therapeutic target in neurodegeneration, the structural basis of SAP-Abeta binding was studied. The chymotryptic digestion of SAP resulted in a 18,223Da product identified by mass spectrometry. This cleavage was inhibited by Abeta revealing that this cleaving site between Tyr-140 and Gly-141 is involved in the interaction between SAP and Abeta These results suggest that the Abeta-binding site on SAP is larger than it was recently assumed.     

Identifying genetic risk variants for coronary heart disease in familial hypercholesterolemia: an extreme genetics approach

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), a disorder characterized by coronary heart disease (CHD) at young age. We aimed to apply an extreme sampling method to enhance the statistical power to identify novel genetic risk variants for CHD in individuals with FH. We selected cases and controls with an extreme contrast in CHD risk from 17 000 FH patients from the Netherlands, whose functional LDLR mutation was unequivocally established. The genome-wide association (GWA) study was performed on 249 very young FH cases with CHD and 217 old FH controls without CHD (above 65 years for males and 70 years of age for females) using the Illumina HumanHap550K chip. In the next stage, two independent samples (one from the Netherlands and one from Italy, Norway, Spain, and the United Kingdom) of FH patients were used as replication samples. In the initial GWA analysis, we identified 29 independent single nucleotide polymorphisms (SNPs) with suggestive associations with premature CHD (P<1 × 10⁻⁴). We examined the association of these SNPs with CHD risk in the replication samples. After Bonferroni correction, none of the SNPs either replicated or reached genome-wide significance after combining the discovery and replication samples. Therefore, we conclude that the genetics of CHD risk in FH is complex and even applying an ‘extreme genetics'' approach we did not identify new genetic risk variants. Most likely, this method is not as effective in leveraging effect size as anticipated, and may, therefore, not lead to significant gains in statistical power.     

Maternal component in the familial aggregation of hypertension

To assess maternal versus paternal contributions to the familial aggregation of hypertension, we examined family history data from 344 hypertensive probands (69 African American, 153 US Caucasian, 122 Greek Caucasian) ascertained without respect to parental hypertension status. The proportion of hypertensive mothers (81.7, 65.0 and 84.8% for African Americans, US Caucasians and Greek Caucasians, respectively) of these probands was significantly greater than the proportion of hypertensive fathers (50.0, 44.9 and 48.3%, respectively) in all three ethnic groups. The lifetime risk of hypertension was significantly greater for mothers compared with fathers of these hypertensive probands (p<0.001). Examination of the proband's siblings indicated that maternal history of hypertension was associated with greater lifetime risk for hypertension than paternal history (p<0.01). In conclusion, we observe a consistent maternal component in the inheritance of hypertension. Although we cannot separate a maternal genetic from epigenetic or environmental effect, our findings suggest that genetic research should include studies of the mitochondrial as well as nuclear genome. Furthermore, when assessing a patient's risk for hypertension, particular attention should be paid to the maternal family history.     

DNA-based X-enriched sperm separation as an adjunct to preimplantation genetic testing for the prevention of X-linked disease

We report the world's first clinical pregnancy resulting fromDNA-based enrichment for X-bearing human spermatozoa, for preventionof X-linked hydrocephalus. Sperm separation was followed byembryo biopsy and nested multiplex polymerase chain reaction(PCR) for gender determination. Enriched populations of X-bearingspermatozoa ranging from 80 to 89% pure as determined by fluorescencein-srtu hybridization (FISH) resulted in in-vitro fertilization(IVF) rates indistinguishable from normal IVF procedures (65%).In two separate biopsy procedures, 7/9 and 15/16 of the resultingembryos were determined to be female by multiplex PCR. Embryotransfer resulted in a karyotypically normal female fetus. Thistechnique should be widely applicable to gender selection forthe prevention of genetic disorders. flow cytometry/fluorescence in-situ hybridization/gender selection/hereditary diseases/spermatozoa