A specific RAD51 haplotype increases breast cancer risk in Jewish non-Ashkenazi high-risk women

While the precise genes involved in determining familial breast cancer risk in addition to BRCA1/2 are mostly unknown, one strong candidate is RAD51. Jewish non-Ashkenazi women at high-risk for breast/ovarian cancer and ethnically matched controls were genotyped using four single nucleotide polymorphisms spanning the RAD51 genomic region, and the resulting haplotypes were constructed using the GERBIL algorithm. A total of 314 individuals were genotyped: 184 non-Ashkenazi high-risk women (119 with breast cancer), and 130 unaffected, average-risk ethnically matched controls. Using GEBRIL, three frequent haplotypes were constructed. One of the haplotypes (TGTA -coined haplotype 3) was present in 7.3% (19/260 haplotypes) of controls (n = 130) and in 16.8% (40/238 haplotypes) of high-risk breast cancer patients (n = 119, P = 0.001). A specific RAD51 haplotype is more prevalent among non-Ashkenazi Jewish high-risk women than in average-risk population

Latitudinal clines of the human vitamin D receptor and skin color genes

The well-documented latitudinal clines of genes affecting human skin color presumably arise from the need for protection from intense ultraviolet radiation (UVR) vs. the need to use UVR for vitamin D synthesis. Sampling 751 subjects from a broad range of latitudes and skin colors, we investigated possible multilocus correlated adaptation of skin color genes with the vitamin D receptor gene (VDR), using a vector correlation metric and network method called BlocBuster. We discovered two multilocus networks involving VDR promoter and skin color genes that display strong latitudinal clines as multilocus networks, even though many of their single gene components do not. Considered one by one, the VDR components of these networks show diverse patterns: no cline, a weak declining latitudinal cline outside of Africa, and a strong in- vs. out-of-Africa frequency pattern. We confirmed these results with independent data from HapMap. Standard linkage disequilibrium analyses did not detect these networks. We applied BlocBuster across the entire genome, showing that our networks are significant outliers for interchromosomal disequilibrium that overlap with environmental variation relevant to the genes\u27 functions. These results suggest that these multilocus correlations most likely arose from a combination of parallel selective responses to a common environmental variable and coadaptation, given the known Mendelian epistasis among VDR and the skin color genes

EPG5-related Vici syndrome: a paradigm of neurodevelopmental disorders with defective autophagy

Vici syndrome is a progressive neurodevelopmental multisystem disorder due to recessive mutations in the key autophagy gene EPG5. We report genetic, clinical, neuroradiological, and neuropathological features of 50 children from 30 families, as well as the neuronal phenotype of EPG5 knock-down in Drosophila melanogaster. We identified 39 different EPG5 mutations, most of them truncating and predicted to result in reduced EPG5 protein. Most mutations were private, but three recurrent mutations (p.Met2242Cysfs*5, p.Arg417*, and p.Gln336Arg) indicated possible founder effects. Presentation was mainly neonatal, with marked hypotonia and feeding difficulties. In addition to the five principal features (callosal agenesis, cataracts, hypopigmentation, cardiomyopathy, and immune dysfunction), we identified three equally consistent features (profound developmental delay, progressive microcephaly, and failure to thrive). The manifestation of all eight of these features has a specificity of 97%, and a sensitivity of 89% for the presence of an EPG5 mutation and will allow informed decisions about genetic testing. Clinical progression was relentless and many children died in infancy. Survival analysis demonstrated a median survival time of 24 months (95% confidence interval 0–49 months), with only a 10th of patients surviving to 5 years of age. Survival outcomes were significantly better in patients with compound heterozygous mutations (P = 0.046), as well as in patients with the recurrent p.Gln336Arg mutation. Acquired microcephaly and regression of skills in long-term survivors suggests a neurodegenerative component superimposed on the principal neurodevelopmental defect. Two-thirds of patients had a severe seizure disorder, placing EPG5 within the rapidly expanding group of genes associated with early-onset epileptic encephalopathies. Consistent neuroradiological features comprised structural abnormalities, in particular callosal agenesis and pontine hypoplasia, delayed myelination and, less frequently, thalamic signal intensity changes evolving over time. Typical muscle biopsy features included fibre size variability, central/internal nuclei, abnormal glycogen storage, presence of autophagic vacuoles and secondary mitochondrial abnormalities. Nerve biopsy performed in one case revealed subtotal absence of myelinated axons. Post-mortem examinations in three patients confirmed neurodevelopmental and neurodegenerative features and multisystem involvement. Finally, downregulation of epg5 (CG14299) in Drosophila resulted in autophagic abnormalities and progressive neurodegeneration. We conclude that EPG5-related Vici syndrome defines a novel group of neurodevelopmental disorders that should be considered in patients with suggestive features in whom mitochondrial, glycogen, or lysosomal storage disorders have been excluded. Neurological progression over time indicates an intriguing link between neurodevelopment and neurodegeneration, also supported by neurodegenerative features in epg5-deficient Drosophila, and recent implication of other autophagy regulators in late-onset neurodegenerative disease

Hormone Therapy and the Risk of Breast Cancer in BRCA1 Mutation Carriers

Background: Hormone therapy (HT) is commonly given to women to alleviate the climacteric symptoms associated with menopause. There is concern that this treatment may increase the risk of breast cancer. The potential association of HT and breast cancer risk is of particular interest to women who carry a mutation in BRCA1 because they face a high lifetime risk of breast cancer and because many of these women take HT after undergoing prophylactic surgical oophorectomy at a young age. Methods: We conducted a matched case-control study of 472 postmenopausal women with a BRCA1 mutation to examine whether or not the use of HT is associated with subsequent risk of breast cancer. Breast cancer case patients and control subjects were matched with respect to age, age at menopause, and type of menopause (surgical or natural). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated with conditional logistic regression. Statistical tests were two-sided. Results: In this group of BRCA1 mutation carriers, the adjusted OR for breast cancer associated with ever use of HT compared with never use was 0.58 (95% CI = 0.35 to 0.96; P =. 03). In analyses by type of HT, an inverse association with breast cancer risk was observed with use of estrogen only (OR = 0.51, 95% CI = 0.27 to 0.98; P =. 04); the association with use of estrogen plus progesterone was not statistically significant (OR = 0.66, 95% CI = 0.34 to 1.27; P =. 21). Conclusion: Among postmenopausal women with a BRCA1 mutation, HT use was not associated with increased risk of breast cancer; indeed, in this population, it was associated with a decreased risk

Vascular Behcet and Mutations in Thrombogenic Genes: Methylene Tetrahydrofolate Reductase, Factor V, and Prothrombin

Vasculitis, thrombophlebitis, arterial aneurysms, and occlusions occur in about 25% of patients with Behcet's disease (BD). The common inherited gene defects, factor V (FV) 1691A (Leiden), methylene tetrahydrofolate reductase (MTHFR) 677T, and prothrombin 20210A, are known risk factors for thrombosis. The aim of the study was to evaluate the contribution of these mutations to thrombosis in Israeli patients with BD. Fifty-four patients with BD (n = 54; 27 men and 27 women) underwent clinical and genetic evaluation. Most patients (n = 43; 79.6%) were of Arab descent (31 sporadic and 12 familial cases from 4 families), and 11 patients (20.4%) were of Jewish descent (all sporadic cases). The FV Leiden mutation was identified in five patients (9.2%), and eight patients were MTHFR 677TT homozygotes (14.8%). None had the 20210A mutant prothrombin allele. No statistical differences between carriers and noncarriers with regards to demographic and disease manifestations were calculated. Arabs were diagnosed earlier than Jewish patients (25.8 +/- 11.6 compared with 37.2 +/- 10.7, p = 0.01, respectively), but Jewish patients had, respectively, more events of deep vein thrombosis (DVT) compared with Arabs (3 of 11, 27.3% and 3 of 43, 7%, p = 0.09). Thrombotic events in our patients with BD were not associated with variations in thrombophilic genes

Essential Tremor Prevalence is Low in the Druze Population in Northern Israel

Background: Essential tremor (ET) and Parkinson's disease (PD) are probably the most common movement disorders. As ethnic differences have been reported in ET, we designed the present study to evaluate the prevalence of ET and that of Parkinson's disease (PD) in the Druze villages of northern Israel. Methods: A two-phase, door-to-door survey was undertaken. Residents aged &ge;51 years who agreed to participate and answered &ldquo;yes&rdquo; to tremor or PD-related screening questions and 3% of subjects who screened negative were evaluated. Diagnostic criteria for ET were similar to those used in Sicilian and Spanish studies. PD was diagnosed according to Gelb's criteria. Results: The target population consisted of 9,086, the study cohort of 3,980 residents. Tremor was observed in 36 subjects. In 27, the tremor fully met the criteria for ET. The prevalence of ET (age &ge;65) was 1.49% (95% CI 0.91&ndash;2.07%). PD was diagnosed in 23 subjects. The prevalence of PD (age &ge;65) was 1.13 (95% CI 0.62&ndash;1.64%). Leucine-rich repeat protein kinase 2 (G2019S mutation) was evaluated in subjects diagnosed with tremor PD and those screened for assessment of the validity of the questionnaire. None carried the mutation. Discussion: The prevalence of ET in the Druze population is low and similar to the prevalence of PD.</div

Myeloid dysplasia in familial 3-methylglutaconic aciduria

A kindred is reported with four members affected with neurodegenerative disorder and 3-methylglutaconic aciduria. Two siblings developed thrombocytopenia heralding a myelodysplastic syndrome; in one patient it evolved into acute myeloid leukemia with monosomy 7 in the marrow. The hematologic complications have hitherto not been previously reported in other cases of 3-methylglutaconic aciduria and are thus thought to represent a new disease entity. This family adds additional evidence to the genetic heterogeneity of Mendelian disorders in which the primary mutation may have a mutator effect that could give origin to myelodysplastic syndrome and acute myeloid leukemia through acquired chromosomal change