Heritability of immune function in the caterpillar Spodoptera littoralis

Phenoloxidase (PO) is believed to be a key mediator of immune function in insects and has been implicated both in non-self recognition and in resistance to a variety of parasites and pathogens, including baculoviruses and parasitoids. Using larvae of the Egyptian cotton leafworm, Spodoptera littoralis, we found that despite its apparent importance, haemolymph PO activity varied markedly between individuals, even amongst insects reared under apparently identical conditions. Sib-analysis methods were used to determine whether individuals varied genetically in their PO activity, and hence in one aspect of immune function. The heritability estimate of haemolymph PO activity was high (h 2 = 0.690 +/- 0.069), and PO activity in the haemolymph was strongly correlated with PO activity in both the cuticle and midgut; the sites of entry for most parasites and pathogens. Haemolymph PO activity was also strongly correlated with the degree to which a synthetic parasite (a small piece of nylon monofilament) was encapsulated and melanized (r = 0.622 +/- 0.142), suggesting that the encapsulation response is also heritable. The mechanism maintaining this genetic variation has yet to be elucidated.

Delineation of a recognisable phenotype of interstitial deletion 3 (q22.3q25.1) in a case with previously unreported truncus arteriosus

Interstitial deletions of chromosome 3q22.3e25.1 are very rare with only five previous reports of deletions in this region [1,2,4,7,9]. We describe a case of a female infant with a de novo deletion. Dysmorphic features and congenital heart disease led to a clinical genetics assessment on day 1 of life. Chromosomal analysis showed an interstitial deletion with a female karyotype 46,XX,del (3)(q23q25.1) dn. Subsequent array CGH demonstrated the breakpoints as 3q22.3q25.1. This is the first documented association with a truncus arteriosus. We identify an emerging clinical phenotype of microphthalmia, microcephaly, congenital heart disease, slow feeding, skeletal abnormalities, with an abnormal facies and developmental delay. Array CGH demonstrated that the FOXL2 gene responsible for BPES was not deleted in this patient. (C) 2010 Elsevier Masson SAS. All rights reserved.

Tumor Risks and Genotype-Phenotype-Proteotype Analysis in 358 Patients With Germline Mutations in SDHB and SDHD

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n = 295) and SDHD (n = 63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma, risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma. Hum Mutat 31:41-51, 2010. (C) 2009 Wiley-Liss, Inc.

Risk reducing mastectomy: outcomes in 10 European centres

Background: Increasingly women at high risk of breast cancer are opting for risk reducing surgery. The aim of this study was to assess the effectiveness of this approach in women at high risk in both carriers and non-carriers of BRCA1/2.

Exonic STK11 deletions are not a rare cause of Peutz-Jeghers syndrome

Background: Peutz-Jeghers syndrome (PJS) is a rare, autosomal dominant cancer predisposition syndrome characterised by oro-facial pigmentation and hamartomatous polyposis of the gastrointestinal tract. A causal germline mutation in STK11 can be identified in 30% to 80% of PJS patients.

Genetic professionals' reports of nondisclosure of genetic risk information within families

Patients attending genetic clinics are often the main gatekeepers of information for other family members. There has been much debate about the circumstances under which professionals may have an obligation, or may be permitted, to pass on personal genetic information about their clients but without their consent to other family members. We report findings from the first prospective study investigating the frequency with which genetics professionals become concerned about the failure of clients to pass on such information to their relatives. In all, 12 UK and two Australian regional genetic services reported such cases over 12 months, including details of actions taken by professionals in response to the clients' failure to disclose information. A total of 65 cases of nondisclosure were reported, representing

Evidence for a modifier of onset age in Huntington disease linked to the HD gene in 4p16

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. A recent genome scan for genetic modifiers of age at onset of motor symptoms (AO) in HD suggests that one modifier may reside in the region close to the HD gene itself. We used data from 535 HD participants of the New England Huntington cohort and the HD MAPS cohort to assess whether AO was influenced by any of the three markers in the 4p16 region: MSX1 (Drosophila homeo box homologue 1, formerly known as homeo box 7, HOX7), Delta2642 (within the HD coding sequence), and BJ56 (D4S127). Suggestive evidence for an association was seen between MSX1 alleles and AO, after adjustment for normal CAG repeat, expanded repeat, and their product term (model P value 0.079). Of the variance of AO that was not accounted for by HD and normal CAG repeats, 0.8% could be attributed to the MSX1 genotype. Individuals with MSX1 genotype 3/3 tended to have younger AO. No association was found between Delta2642 (P=0.44) and BJ56 (P=0.73) and AO. This study supports previous studies suggesting that there may be a significant genetic modifier for AO in HD in the 4p16 region. Furthermore, the modifier may be present on both HD and normal chromosomes bearing the 3 allele of the MSX1 marker.

An Irish three-generation family of Cornelia de Lange syndrome displaying autosomal dominant inheritance

The existence of familial de Lange syndrome has been documented in sibs and in parent-child families, but the inheritance pattern continues to be the cause of much debate. We describe a classically affected neonate with de Lange syndrome, an affected mother and probably affected maternal grandmother. These cases show evidence for a dominantly inherited syndrome with a de Lange phenotype.

Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease

Huntington disease (HD) is a neurodegenerative disorder caused by the abnormal expansion of CAG repeats in the HD gene on chromosome 4p16.3. Past studies have shown that the size of expanded CAG repeat is inversely associated with age at onset (AO) of HD. It is not known whether the normal Huntington allele size influences the relation between the expanded repeat and AO of HD. Data collected from two independent cohorts were used to test the hypothesis that the unexpanded CAG repeat interacts with the expanded CAG repeat to influence AO of HD. In the New England Huntington Disease Center Without Walls (NEHD) cohort of 221 HD affected persons and in the HD-MAPS cohort of 533 HD affected persons, we found evidence supporting an interaction between the expanded and unexpanded CAG repeat sizes which influences AO of HD (P = 0.08 and 0.07, respectively). The association was statistically significant when both cohorts were combined (P=0.012). The estimated heritability of the AO residual was 0.56 after adjustment for normal and expanded repeats and their interaction. An analysis of tertiles of repeats sizes revealed that the effect of the normal allele is seen among persons with large HD repeat sizes (47-83). These findings suggest that an increase in the size of the normal repeat may mitigate the expression of the disease among HD affected persons with large expanded CAG repeats. (C) 2003 Wiley-Liss, Inc.

Resequencing of the CCL5 and CCR5 genes and investigation of variants for association with diabetic nephropathy

Chemokine (C-C motif) ligand 5 (CCL5) and chemokine (C-C motif) receptor 5 are implicated in the pathogenesis of diabetic nephropathy (DN). We hypothesize that variants in these genes may be associated with DN. The CCL5 and chemokine receptor type 5 (CCR5) genes were resequenced, variants identified (n=58), allele frequencies determined in 46 individuals (92 chromosomes) and efficient haplotype tag single-nucleotide polymorphisms (htSNPs) selected to effectively evaluate the common variation in these genes. One reportedly functional gene variant and eight htSNPs were genotyped in a case-control association study involving Caucasian individuals with type 1 diabetes (267 cases with DN and 442 non-nephropathic diabetic controls). Genotyping was performed using MassARRAY iPLEX, TaqMan, gel electrophoresis and direct capillary sequencing. After correction for multiple testing, there were no statistically significant associations between variants in the CCL5 and CCR5 genes and DN. Journal of Human Genetics (2010) 55, 248-251; doi:10.1038/jhg.2010.15; published online 5 March 2010

Association of Genetic Variants at 3q22 with Nephropathy in Patients with Type 1 Diabetes Mellitus

Diabetic nephropathy (DN) is the primary cause of morbidity and mortality in patients with type 1 diabetes mellitus (T1DM) and affects about 30% of these patients. We have previously localized a DN locus on chromosome 3q with suggestive linkage in Finnish individuals. Linkage to this region has also been reported earlier by several other groups. To fine map this locus, we conducted a multistage case-control association study in T1DM patients, comprising 1822 cases with nephropathy and 1874 T1DM patients free of nephropathy, from Finland, Iceland, and the British Isles. At the screening stage, we genotyped 3072 tag SNPs, spanning a 28 Mb region, in 234 patients and 215 controls from Finland. SNPs that met the significance threshold of p