Search

We performed a genetic investigation into the case of an inherited Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Our patients were an adolescent and her mother, both with MRKH syndrome. The delivery of a biological offspring was achieved via a gestational carrier. Karyotype and exome sequencing were used to complete a three-generation genetic analysis of the family. Both the mother and her daughter harbored a deletion of 4 Mb at the locus of 2q37, a syndrome rarely described in association with MRKH. No pathogenic single-nucleotide variant relevant to the phenotype was found. The deletion was not inherited from either parent of the mother. In addition, some physical findings suggesting 2q37 deletion syndrome were found in our patients. We conclude that when combined with the use of a gestational carrier or uterine transplantation, the identification of a genetic cause for MRKH may enable the application of preimplantation genetic testing on embryos, thus potentially averting the transmission of the genetic anomaly to subsequent generations. [ABSTRACT FROM AUTHOR]

Ample data on recessive disorders among Ashkenazi Jews has been gathered and published through the years. The opportunity to integrate molecular records analyzed in actual affected individuals with data derived from population-documented frequencies enables to compare these figures. We reviewed assumed pathogenic variants reported among patients in the Israeli medical genetic database (IMGD) with a carrier frequency of 1% or more among Ashkenazi Jews in gnomAD. Among the 60 assumed pathogenic variants recorded in IMGD, 15 (25%) had either a disease incidence considerably lower than expected by the calculated carrier frequency (12 variants), or the variant was not characterized in Ashkenazi Jewish patients (three variants). Possible explanations for the rarity or absence of affected individuals despite high carrier frequency include embryonic lethality, clinical variability, and incomplete and age-related penetrance, in addition to the existence of additional assumed pathogenic variants on the founder haplotype, hypomorphic variants or digenic inheritance. The discrepancy in actual versus expected number of patients calls for caution upon designing and choosing targeted genes and recessive mutations for carrier screening. [ABSTRACT FROM AUTHOR]

Mutations in MCM9, which encodes DNA helicase, were recently shown to cause a clinical phenotype of primary ovarian failure and chromosomal instability. MCM9 plays an essential role in homologous recombination-mediated double-strand break repair. We describe a multiplex family with early colorectal carcinoma and mixed polyposis associated with primary hypergonadotropic hypogonadism. A combination of whole genome homozygosity mapping as well as exome sequencing and targeted gene sequencing identified a homozygous c.672_673delGGinsC mutation that predicts a truncated protein, p.Glu225Lysfs*4. Our data expand the phenotypic spectrum of MCM9 mutations and suggest a link between MCM9 and inherited predisposition to mixed polyposis and early-onset colorectal cancer. [ABSTRACT FROM AUTHOR]

Purpose: To explore the association between birth weight in offspring, a marker of the intrauterine environment, and mortality in their mothers, taking into account maternal pre-pregnancy characteristics, including maternal body mass index (BMI), smoking, and socioeconomic status. Distinguishing the effects of offspring''s birth weight and pre-pregnancy characteristics on maternal outcome may provide clues regarding mechanisms underlying the association between birth weight and maternal mortality. Methods: We studied long-term total mortality (average follow-up period, 29.1 years) in a population-based cohort of 13,185 mothers, aged 15 to 48 years at their offspring''s birth, who delivered in West Jerusalem during 1974 through 1976. Results: Univariate and multivariate Cox-proportional hazard models used to estimate the hazard of overall mortality among mothers indicated a nonlinear relationship with birth weight of offspring when introduced into the models as a continuous variable, and a linear positive association with maternal pre-pregnancy BMI. Inclusion of maternal BMI and other pre-pregnancy characteristics in the model did not alter the association between offspring''s birth weight and mothers’ all-cause mortality. When birth weight was introduced as a categorical variable, higher mortality was observed among mothers who gave birth to babies with birth weight less than 2500 g (hazard ratio [HR] = 1.90; 95% confidence interval [95%CI], 1.23–2.94) as compared to mothers whose offspring had birth weight between 3000 and 3499 g. The HR for mothers who gave birth to babies with birth weight 4000 g or more was 1.30 (95%CI, 0.88–1.91). Conclusions: Independent of pre-pregnancy maternal BMI and other characteristics, birth weight of offspring was associated with mortality in their mothers, suggesting that intrauterine metabolic events reflected by birth weight and not explained by maternal obesity, smoking, and socioeconomic status have remote consequences for maternal health. These findings underline the need to explore specific genetic and/or environmental mechanisms that account for these associations. [Copyright &y& Elsevier]

Abstract: Background: Cholesterol metabolism is mediated, in part, by the sterol-regulatory element binding proteins (SREBPs) that are activated by a SREBP cleavage-activating protein (SCAP). We examined whether coding variations in the interacting domains of both genes, are related to early-onset MI risk in a population-based case-control study from western Washington State. Methods: Cases were 257 women, aged 18–59 years, and 320 men, aged 18–49 years, with first acute non-fatal MI; controls were 353 women and 311 men, similar in age, identified from the community who had no history of clinical CHD or stroke. Genotyping of the SREBF-2 G1784C polymorphism (SREBP-2-595A/G isoforms), and the SCAP A2386G polymorphism (SCAP-796I/V isoforms), were performed. Results: After adjustment for age and race, the SREBP-2-595A isoform was associated with increased MI risk among men (OR=1.63, 95% CI=1.26–2.12). In contrast, there was little evidence for an association among women in a multiplicative model. However, compared to SREBP-2-595G homozygotes, homozygote women for the SREBP-2-595A isoform were at nearly two-fold increased risk (OR=1.95, 95% CI=1.07–3.54). Overall, SCAP genotypes were neither associated with MI in men nor in women. However, in men, SCAP genotypes were found to modify the association between SREBF-2 and MI (p-value for interaction=0.01). Conclusion: The SREBP-2-595A isoform was associated with an increased risk of early-onset MI in U.S. men. The SCAP polymorphism appeared to modify the associations of SREBF-2 genotype with MI risk among men. These novel findings require confirmation in other populations. [Copyright &y& Elsevier]

Abstract: Objective: To examine whether genetic polymorphisms in the cholesteryl-ester transfer protein (CETP) and the P-glycoprotein drug transporter (MDR1), are associated with variable lipid response to fluvastatin. Methods: Lipid levels were determined in a compliance-monitored clinical study at baseline and following 20 weeks of treatment with 40mg dose of fluvastatin in 76 FH patients. CETP and MDR1 SNP genotyping was performed and linear regression was used to examine the associations between common SNPs and haplotypes and lipid response. Results: Treatment with 40mg of fluvastatin resulted in mean low density lipoprotein cholesterol (LDL-C) reduction of 21.5%; mean triglyceride (TG) reduction of 8.3%; and a mean high-density lipoprotein cholesterol (HDL-C) increase of 13.4%. Five tagging SNPs in both genes were used to reconstruct five and six haplotypes accounting for 71.4% and 90.2% of the observed haplotypes in the CETP and MDR1 genes, respectively. CETP-H13 and MDR1-h4 were associated with an increase in LDL-C response. CETP-H5 was significantly associated with decreased TG and HDL-C response, whereas MDR1-h10 was associated with decreased TG response. A multivariate regression model indicated an independent additive effect of CETP-H5 and MDR1-h10 on the level of TG response. Conclusions: CETP and MDR1 have independent effects on lipid changes following fluvastatin treatment. The results of this study may lead to an improved understanding of the genetic determinants of lipids response to treatment. [Copyright &y& Elsevier]

: ObjectivesThe goal of this study was to analyze the genetic disorder of a family with cardiomyopathy, skin disorder, and woolly hair.: BackgroundArrhythmogenic right ventricular dysplasia (ARVD) is a heart muscle disorder causing arrhythmia and sudden cardiac death. We report a patient with familial autosomal recessive ARVD, woolly hair, and a pemphigous-like skin disorder with a new mutation in the desmoplakin gene.: MethodsGenomic deoxyribonucleic acid was extracted from the patient’s blood and 12 first- and second-degree family members, and was amplified by polymerase chain reaction. Linkage analysis with polymorphic microsatellites was performed for 11 genes that code for structural desmosomal proteins. The genetic locus of the disease in this family was mapped to the chromosomal region 6p24 that contains the desmoplakin gene. Exons of the desmoplakin gene were analyzed by single-strand conformational polymorphism and direct sequencing. Confirmation of the mutation was carried out by restriction enzyme analysis.: ResultsWe identified in the patient a homozygous missense mutation in exon 24 of the desmoplakin gene, leading to a Gly2375Arg substitution in the C-terminal of the protein where the binding site to intermediate filaments is located. Eight of 12 family members without hair or skin abnormalities were heterozygous for this mutation. The remaining 4, as well as 90 unrelated healthy control individuals of the same ethnic origin, were homozygous for the normal allele.: ConclusionsWe have described a new mutation in the desmoplakin gene that causes familial ARVD. These findings suggest that desmosomal proteins play an important role in the integrity and function of the myocardium. Dysfunction of these proteins can lead to the development of cardiomyopathies and arrhythmias. [Copyright &y& Elsevier]