Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome

Background: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. Methods: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. Results: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case–control status and genomic kinship coefficient. Conclusions: In this case–control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents

Estimating the Total Pathogenic Allele Frequency of Autosomal Recessive Disorders in Case of Consanguinity

Objective: Estimating the total allele frequency of all pathogenic alleles of an autosomal recessive disease is not possible if only mutational data of a sample of affected individuals are available. However, if the affected individuals come from a population where consanguinity is not uncommon, this total allele frequency can be estimated by additionally using the positive individual inbreeding coefficients or an estimate of the population inbreeding coefficient. In this paper, we propose two estimators. Methods/Results: We propose to estimate the total allele frequency by a conditional maximum likelihood estimator if a part of the affected individuals in the sample comes from consanguineous marriages with known inbreeding coefficients. A simulation study shows that this estimator is unbiased and robust. We propose a second estimator which is based on an estimate of the population inbreeding coefficient. The method is applied to mutational data and individual inbreeding coefficients of Tunisian patients with congenital adrenal hyperplasia. Conclusion: Additionally using individual inbreeding coefficients or an estimate of the population inbreeding coefficient makes it possible to estimate the total allele frequency. Since consanguinity is commonly practiced in many parts of the world, the estimators proposed in the paper are of practical importance

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome

Background: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high-and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness

Disease burden and management of Crigler-Najjar syndrome: Report of a world registry

Background and Aims Crigler-Najjar syndrome (CNS) is a disorder of bilirubin conjugation leading to brain damage and death without treatment. Although cohort studies of limited size have been published, uncertainty about outcome, co-morbidities, occurence of liver fibrosis and treatment outcome remains. With this worldwide cohort study, we aim to add substantial knowledge to the previously published data. Methods Anonymized retrospective data of CNS patients were collected in a web-based registry platform. Results Clinical data of 221 CNS patients (46% female, severe phenotype n = 209) were collected. At the time of analysis, 59 CNS patients were deceased. Mean serum total bilirubin (TB) was 300 μmoL/L, mean conjugated bilirubin (CB) 14.4 μmoL/L. The incidence of neurologic symptoms was 10.7%. Elevated alanine aminotransferase (ALT, \u3e70 U/L) was present in 43/221 (19.5%) and the mean gamma-glutamyl transpeptidase (GGT) was 54 U/L. CB and TB did not correlate with aspartate aminotransferase (AST), ALT or GGT. TB was higher in males than in females (316 vs. 287 μmol/L; p \u3c .001). Cholelithiasis was detected in 14 of 91 ultrasound examinations. In 5 of 31 CNS patients with liver fibrosis evaluation advanced fibrosis and significant higher AST were detected. Liver transplantation (LT) was performed in 26 CNS patients at the median age of 9 years (0–32 years). A subgroup of 75 CNS patients showed high TB (444 ± 141 μmoL/L) and high mortality/morbidity because of inadequate access to treatment. Conclusions This largest cohort of CNS patients to date shows the urgent need to globally expand access to therapy and gives insight into the clinical course and outcome of different treatment strategies. However, some questions need ongoing examination, especially regarding liver fibrosis and the timing of LT