Intrafamilial segregation analysis of the p.E148Q MEFV allele in familial Mediterranean fever

BACKGROUND: Familial Mediterranean fever (FMF) is the most frequent of the recurrent inherited fevers. This autosomal recessive disorder is characterised by periodic episodes of fever and serositis that commonly affect the people of Arab, Armenian, Sephardic Jewish and Turkish origin. Most of the described MEFV gene anomalies responsible for the disease are missense mutations. In the absence of any functional test, epidemiological studies or pedigree analyses are the only means of proving the deleterious character of these sequence variations. Evidence was provided by our recent study using a population‐based approach, that the p.E148Q allele is probably a benign polymorphism and not a disease‐causing mutation. Its implication in FMF remains, however, controversial. OBJECTIVE: To evaluate the segregation of the p.E148Q MEFV allele with FMF disease by using pedigree analysis. PARTICIPANTS: 21 patients and 48 unaffected relatives belonging to 18 independent families with FMF. RESULTS: Segregation analysis of the p.E148Q allele was compatible with a Mendelian autosomal recessive transmission of the disease phenotype in only three families. In 15 of 18 families, segregation was partly or completely defective. The p.E148Q allele was not transmitted to 14 of 19 (74%) affected children. CONCLUSIONS: No evidence of preferential transmission of p.E148Q from heterozygous parents to their affected offspring was observed. MEFV is not associated with the clinical manifestations of several patients carrying this variant. Considering p.E148Q to be a benign polymorphism should reduce the possibility of false‐positive diagnoses, while highlighting genetic heterogeneity in FMF

ABCB6 Polymorphisms are not Overly Represented in Patients with Porphyria

International audienceThe Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted

MEFV gene variations in patients with systemic lupus erythematosus

Objective The aim of this study was to investigate the frequency of familial Mediterranean fever (FMF)-associated MEFV gene variations in patients with systemic lupus erythematosus (SLE)

An informatics approach to analyzing the incidentalome

PURPOSE: Next-generation sequencing (NGS) has transformed genetic research and is poised to revolutionize clinical diagnosis. However, the vast amount of data and inevitable discovery of incidental findings require novel analytic approaches. We therefore implemented for the first time a strategy that utilizes an a priori structured framework and a conservative threshold for selecting clinically relevant incidental findings. METHODS: We categorized 2016 genes linked with Mendelian diseases into “bins” based on clinical utility and validity, and used a computational algorithm to analyze 80 whole genome sequences in order to explore the use of such an approach in a simulated real-world setting. RESULTS: The algorithm effectively reduced the number of variants requiring human review and identified incidental variants with likely clinical relevance. Incorporation of the Human Gene Mutation Database (HGMD) improved the yield for missense mutations, but also revealed that a substantial proportion of purported disease-causing mutations were misleading. CONCLUSIONS: This approach is adaptable to any clinically relevant bin structure, scalable to the demands of a clinical laboratory workflow, and flexible with respect to advances in genomics. We anticipate that application of this strategy will facilitate pre-test informed consent, laboratory analysis, and post-test return of results in a clinical context