Deficiency of the minor spliceosome component U4atac snRNA secondarily results in ciliary defects in human and zebrafish.

In the human genome, about 750 genes contain one intron excised by the minor spliceosome. This spliceosome comprises its own set of snRNAs, among which U4atac. Its noncoding gene, RNU4ATAC, has been found mutated in Taybi-Linder (TALS/microcephalic osteodysplastic primordial dwarfism type 1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes. These rare developmental disorders, whose physiopathological mechanisms remain unsolved, associate ante- and post-natal growth retardation, microcephaly, skeletal dysplasia, intellectual disability, retinal dystrophy, and immunodeficiency. Here, we report bi-allelic RNU4ATAC mutations in five patients presenting with traits suggestive of the Joubert syndrome (JBTS), a well-characterized ciliopathy. These patients also present with traits typical of TALS/RFMN/LWS, thus widening the clinical spectrum of RNU4ATAC-associated disorders and indicating ciliary dysfunction as a mechanism downstream of minor splicing defects. Intriguingly, all five patients carry the n.16G>A mutation, in the Stem II domain, either at the homozygous or compound heterozygous state. A gene ontology term enrichment analysis on minor intron-containing genes reveals that the cilium assembly process is over-represented, with no less than 86 cilium-related genes containing at least one minor intron, among which there are 23 ciliopathy-related genes. The link between RNU4ATAC mutations and ciliopathy traits is supported by alterations of primary cilium function in TALS and JBTS-like patient fibroblasts, as well as by u4atac zebrafish model, which exhibits ciliopathy-related phenotypes and ciliary defects. These phenotypes could be rescued by WT but not by pathogenic variants-carrying human U4atac. Altogether, our data indicate that alteration of cilium biogenesis is part of the physiopathological mechanisms of TALS/RFMN/LWS, secondarily to defects of minor intron splicing.

Measuring the Efficiency of Purging by non-random Mating in Human Populations.

Human populations harbor a high concentration of deleterious genetic variants. Here, we tested the hypothesis that non-random mating practices affect the distribution of these variants, through exposure in the homozygous state, leading to their purging from the population gene pool. To do so, we produced whole-genome sequencing data for two pairs of Asian populations exhibiting different alliance rules and rates of inbreeding, but with similar effective population sizes. The results show that populations with higher rates of inbred matings do not purge deleterious variants more efficiently. Purging therefore has a low efficiency in human populations, and different mating practices lead to a similar mutational load.

Mutations in the non-coding RNU4ATAC gene affect the homeostasis and function of the Integrator complex.

Various genetic diseases associated with microcephaly and developmental defects are due to pathogenic variants in the U4atac small nuclear RNA (snRNA), a component of the minor spliceosome essential for the removal of U12-type introns from eukaryotic mRNAs. While it has been shown that a few RNU4ATAC mutations result in impaired binding of essential protein components, the molecular defects of the vast majority of variants are still unknown. Here, we used lymphoblastoid cells derived from RNU4ATAC compound heterozygous (g.108_126del;g.111G>A) twin patients with MOPD1 phenotypes to analyze the molecular consequences of the mutations on small nuclear ribonucleoproteins (snRNPs) formation and on splicing. We found that the U4atac108_126del mutant is unstable and that the U4atac111G>A mutant as well as the minor di- and tri-snRNPs are present at reduced levels. Our results also reveal the existence of 3'-extended snRNA transcripts in patients' cells. Moreover, we show that the mutant cells have alterations in splicing of INTS7 and INTS10 minor introns, contain lower levels of the INTS7 and INTS10 proteins and display changes in the assembly of Integrator subunits. Altogether, our results show that compound heterozygous g.108_126del;g.111G>A mutations induce splicing defects and affect the homeostasis and function of the Integrator complex.

Tracking clusters of patients over time enables extracting information from medico-administrative databases.

CONTEXT: Identifying clusters (i.e., subgroups) of patients from the analysis of medico-administrative databases is particularly important to better understand disease heterogeneity. However, these databases contain different types of longitudinal variables which are measured over different follow-up periods, generating truncated data. It is therefore fundamental to develop clustering approaches that can handle this type of data. OBJECTIVE: We propose here cluster-tracking approaches to identify clusters of patients from truncated longitudinal data contained in medico-administrative databases. MATERIAL AND METHODS: We first cluster patients at each age. We then track the identified clusters over ages to construct cluster-trajectories. We compared our novel approaches with three classical longitudinal clustering approaches by calculating the silhouette score. As a use-case, we analyzed antithrombotic drugs used from 2008 to 2018 contained in the Échantillon Généraliste des Bénéficiaires (EGB), a French national cohort. RESULTS: Our cluster-tracking approaches allow us to identify several cluster-trajectories with clinical significance without any imputation of data. The comparison of the silhouette scores obtained with the different approaches highlights the better performances of the cluster-tracking approaches. CONCLUSION: The cluster-tracking approaches are a novel and efficient alternative to identify patient clusters from medico-administrative databases by taking into account their specificities.

COL4A1/COL4A2 and inherited platelet disorder gene variants in fetuses showing intracranial hemorrhage.

BACKGROUND: Variants of COL4A1/COL4A2 genes have been reported in fetal intracranial hemorrhage (ICH) cases but their prevalence and characteristics have not been established in a large series of fetuses. Fetal neonatal alloimmune thrombocytopenia is a major acquired ICH factor but the prevalence and characteristics of inherited platelet disorder (IPD) gene variants leading to thrombocytopenia are unknown. Herein, we screened COL4A1/COL4A2 and IPD genes in a large series of ICH fetuses. METHODS: A cohort of 194 consecutive ICH fetuses were first screened for COL4A1/COL4A2 variants. We manually curated a list of 64 genes involved in IPD and investigated them in COL4A1/COL4A2 negative fetuses, using exome sequencing data from 101 of these fetuses. RESULT: Pathogenic variants of COL4A1/COL4A2 genes were identified in 36 fetuses (19%). They occurred de novo in 70% of the 32 fetuses for whom parental DNA was available. Pathogenic variants in two megakaryopoiesis genes (MPL and MECOM genes) were identified in two families with recurrent and severe fetal ICH, with variable extraneurological pathological features. CONCLUSION: Our study emphasizes the genetic heterogeneity of fetal ICH and the need to screen both COL4A1/COL4A2 and IPD genes in the etiological investigation of fetal ICH to allow proper genetic counseling.

Multiethnic genome-wide association study of differentiated thyroid cancer in the EPITHYR consortium.

Incidence of differentiated thyroid carcinoma (DTC) varies considerably between ethnic groups, with particularly high incidence rates in Pacific Islanders. DTC is one of the cancers with the highest familial risk suggesting a major role of genetic risk factors, but only few susceptibility loci were identified so far. In order to assess the contribution of known DTC susceptibility loci and to identify new ones, we conducted a multiethnic genome-wide association study (GWAS) in individuals of European ancestry and of Oceanian ancestry from Pacific Islands. Our study included 1554 cases/1973 controls of European ancestry and 301 cases/348 controls of Oceanian ancestry from seven population-based case-control studies participating to the EPITHYR consortium. All participants were genotyped using the OncoArray-500K Beadchip (Illumina). We confirmed the association with the known DTC susceptibility loci at 2q35, 8p12, 9q22.33 and 14q13.3 in the European ancestry population and suggested two novel signals at 1p31.3 and 16q23.2, which were associated with thyroid-stimulating hormone levels in previous GWAS. We additionally replicated an association with 5p15.33 reported previously in Chinese and European populations. Except at 1p31.3, all associations were in the same direction in the population of Oceanian ancestry. We also observed that the frequencies of risk alleles at 2q35, 5p15.33 and 16q23.2 were significantly higher in Oceanians than in Europeans. However, additional GWAS and epidemiological studies in Oceanian populations are needed to fully understand the highest incidence observed in these populations.

New insights into minor splicing-a transcriptomic analysis of cells derived from TALS patients.

Minor intron splicing plays a central role in human embryonic development and survival. Indeed, biallelic mutations in RNU4ATAC, transcribed into the minor spliceosomal U4atac snRNA, are responsible for three rare autosomal recessive multimalformation disorders named Taybi-Linder (TALS/MOPD1), Roifman (RFMN), and Lowry-Wood (LWS) syndromes, which associate numerous overlapping signs of varying severity. Although RNA-seq experiments have been conducted on a few RFMN patient cells, none have been performed in TALS, and more generally no in-depth transcriptomic analysis of the ∼700 human genes containing a minor (U12-type) intron had been published as yet. We thus sequenced RNA from cells derived from five skin, three amniotic fluid, and one blood biosamples obtained from seven unrelated TALS cases and from age- and sex-matched controls. This allowed us to describe for the first time the mRNA expression and splicing profile of genes containing U12-type introns, in the context of a functional minor spliceosome. Concerning RNU4ATAC-mutated patients, we show that as expected, they display distinct U12-type intron splicing profiles compared to controls, but that rather unexpectedly mRNA expression levels are mostly unchanged. Furthermore, although U12-type intron missplicing concerns most of the expressed U12 genes, the level of U12-type intron retention is surprisingly low in fibroblasts and amniocytes, and much more pronounced in blood cells. Interestingly, we found several occurrences of introns that can be spliced using either U2, U12, or a combination of both types of splice site consensus sequences, with a shift towards splicing using preferentially U2 sites in TALS patients' cells compared to controls.

Novel Chronic Mouse Model of Cerebral Cavernous Malformations.

Background and Purpose- Cerebral cavernous malformations (CCMs) are vascular malformations of the brain that lead to cerebral hemorrhages. A pharmacological treatment is needed especially for patients with nonoperable deep-seated lesions. We and others obtained CCM mouse models that were useful for mechanistic studies and rapid trials testing the preventive effects of candidate drugs. The shortened lifespan of acute mouse models hampered evaluation of compounds that would not only prevent lesion appearance but also cure preexisting lesions. Indirubin-3'-monoxime previously demonstrated its efficacy to reverse the cardiac phenotype of ccm2m201 zebrafish mutants and to prevent lesion development in an acute CCM2 mouse model. In the present article, we developed and characterized a novel chronic CCM2 mouse model and evaluated the curative therapeutic effect of indirubin-3'-monoxime after CCM lesion development. Methods- The chronic mouse model was obtained by a postnatal induction of brain-endothelial-cell-specific ablation of the Ccm2 gene using the inducible Slco1c1-CreERT2 mouse line. Results- We obtained a fully penetrant novel CCM chronic mouse model without any obvious off-target phenotypes and compatible with long-term survival. By 3 months of age, CCM lesions ranging in size from small isolated lesions to multiple caverns developed throughout the brain. Lesion burden was quantified in animals from 1 week to 5 months of age. Clear signs of intracerebral hemorrhages were noticed in brain-endothelial-cell-specific ablation of the Ccm2 gene. In contrast with its preventive effect in the acute CCM2 mouse model, a 20 mg/kg indirubin-3'-monoxime treatment for 3 weeks in 3-month old animals neither had any beneficial effect on the lesion burden nor alleviated cerebral hemorrhages. Conclusions- The brain-endothelial-cell-specific ablation of the Ccm2 gene chronic model is a strongly improved disease model for the CCM community whose challenge today is to decipher which candidate drugs might have a curative effect on patients' preexisting lesions. Visual Overview- An online visual overview is available for this article.

Strategies for phasing and imputation in a population isolate.

In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these populations where only a subsample of representative individuals is sequenced and then genotypes are imputed into the rest of the population. Gene mapping in such populations thus requires high-quality genetic imputation and preliminary phasing. To identify an effective study design, we compare by simulation a range of phasing and imputation software and strategies. We simulated 1,115,604 variants on chromosome 10 for 477 members of the large complex pedigree of Campora, a village within the established isolate of Cilento in southern Italy. We assessed the phasing performance of identical by descent based software ALPHAPHASE and SLRP, LD-based software SHAPEIT2, SHAPEIT3, and BEAGLE, and new software EAGLE that combines both methodologies. For imputation we compared IMPUTE2, IMPUTE4, MINIMAC3, BEAGLE, and new software PBWT. Genotyping errors and missing genotypes were simulated to observe their effects on the performance of each software. Highly accurate phased data were achieved by all software with SHAPEIT2, SHAPEIT3, and EAGLE2 providing the most accurate results. MINIMAC3, IMPUTE4, and IMPUTE2 all performed strongly as imputation software and our study highlights the considerable gain in imputation accuracy provided by a genome sequenced reference panel specific to the population isolate.

Loss of VPS13C Function in Autosomal-Recessive Parkinsonism Causes Mitochondrial Dysfunction and Increases PINK1/Parkin-Dependent Mitophagy.

Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Six Novel Loci Associated with Circulating VEGF Levels Identified by a Meta-analysis of Genome-Wide Association Studies.

Vascular endothelial growth factor (VEGF) is an angiogenic and neurotrophic factor, secreted by endothelial cells, known to impact various physiological and disease processes from cancer to cardiovascular disease and to be pharmacologically modifiable. We sought to identify novel loci associated with circulating VEGF levels through a genome-wide association meta-analysis combining data from European-ancestry individuals and using a dense variant map from 1000 genomes imputation panel. Six discovery cohorts including 13,312 samples were analyzed, followed by in-silico and de-novo replication studies including an additional 2,800 individuals. A total of 10 genome-wide significant variants were identified at 7 loci. Four were novel loci (5q14.3, 10q21.3, 16q24.2 and 18q22.3) and the leading variants at these loci were rs114694170 (MEF2C, P = 6.79 x 10(-13)), rs74506613 (JMJD1C, P = 1.17 x 10(-19)), rs4782371 (ZFPM1, P = 1.59 x 10(-9)) and rs2639990 (ZADH2, P = 1.72 x 10(-8)), respectively. We also identified two new independent variants (rs34528081, VEGFA, P = 1.52 x 10(-18); rs7043199, VLDLR-AS1, P = 5.12 x 10(-14)) at the 3 previously identified loci and strengthened the evidence for the four previously identified SNPs (rs6921438, LOC100132354, P = 7.39 x 10(-1467); rs1740073, C6orf223, P = 2.34 x 10(-17); rs6993770, ZFPM2, P = 2.44 x 10(-60); rs2375981, KCNV2, P = 1.48 x 10(-100)). These variants collectively explained up to 52% of the VEGF phenotypic variance. We explored biological links between genes in the associated loci using Ingenuity Pathway Analysis that emphasized their roles in embryonic development and function. Gene set enrichment analysis identified the ERK5 pathway as enriched in genes containing VEGF associated variants. eQTL analysis showed, in three of the identified regions, variants acting as both cis and trans eQTLs for multiple genes. Most of these genes, as well as some of those in the associated loci, were involved in platelet biogenesis and functionality, suggesting the importance of this process in regulation of VEGF levels. This work also provided new insights into the involvement of genes implicated in various angiogenesis related pathologies in determining circulating VEGF levels. The understanding of the molecular mechanisms by which the identified genes affect circulating VEGF levels could be important in the development of novel VEGF-related therapies for such diseases.

Genetic variants modulating CRIPTO serum levels identified by genome-wide association study in Cilento isolates.

Cripto, the founding member of the EGF-CFC genes, plays an essential role in embryo development and is involved in cancer progression. Cripto is a GPI-anchored protein that can interact with various components of multiple signaling pathways, such as TGF-ß, Wnt and MAPK, driving different processes, among them epithelial-mesenchymal transition, cell proliferation, and stem cell renewal. Cripto protein can also be cleaved and released outside the cell in a soluble and still active form. Cripto is not significantly expressed in adult somatic tissues and its re-expression has been observed associated to pathological conditions, mainly cancer. Accordingly, CRIPTO has been detected at very low levels in the plasma of healthy volunteers, whereas its levels are significantly higher in patients with breast, colon or glioblastoma tumors. These data suggest that CRIPTO levels in human plasma or serum may have clinical significance. However, very little is known about the variability of serum levels of CRIPTO at a population level and the genetic contribution underlying this variability remains unknown. Here, we report the first genome-wide association study of CRIPTO serum levels in isolated populations (n = 1,054) from Cilento area in South Italy. The most associated SNPs (p-value<5*10-8) were all located on chromosome 3p22.1-3p21.3, in the CRIPTO gene region. Overall six CRIPTO associated loci were replicated in an independent sample (n = 535). Pathway analysis identified a main network including two other genes, besides CRIPTO, in the associated regions, involved in cell movement and proliferation. The replicated loci explain more than 87% of the CRIPTO variance, with 85% explained by the most associated SNP. Moreover, the functional analysis of the main associated locus identified a causal variant in the 5'UTR of CRIPTO gene which is able to strongly modulate CRIPTO expression through an AP-1-mediate transcriptional regulation.

Relationship inference from the genetic data on parents or offspring: A comparative study.

Relationship inference in a population is of interest for many areas of research from anthropology to genetics. It is possible to directly infer the relationship between the two individuals in a couple from their genetic data or to indirectly infer it from the genetic data of one of their offspring. For this reason, one can wonder if it is more advantageous to sample couples or single individuals to study relationships of couples in a population. Indeed, sampling two individuals is more informative than sampling one as we are looking at four haplotypes instead of two, but it also doubles the cost of the study and is a more complex sampling scheme. To answer this question, we performed simulations of 1000 trios from 10 different relationships using real human haplotypes to have realistic genome-wide genetic data. Then, we compared the genome sharing coefficients and the relationship inference obtained from either a pair of individuals or one of their offspring using both single-point and multi-point approaches. We observed that for relationships closer than 1st cousin, pairs of individuals were more informative than one of their offspring for relationship inference, and kinship coefficients obtained from single-point methods gave more accurate or equivalent genome sharing estimations. For more remote relationships, offspring were more informative for relationship inference, and inbreeding coefficients obtained from multi-point methods gave more accurate genome sharing estimations. In conclusion, relationship inference on a parental pair or on one of their offspring provides complementary information. When possible, sampling trios should be encouraged as it could allow spanning a wider range of potential relationships.

Clinical and demographic factors and outcome of amyotrophic lateral sclerosis in relation to population ancestral origin.

BACKGROUND: To review how the phenotype and outcome of amyotrophic lateral sclerosis (ALS) change with variations in population ancestral origin (PAO). Knowledge of how PAO modifies ALS phenotype may provide important insight into the risk factors and pathogenic mechanisms of the disease. METHODS: We performed a systematic review and meta-analysis of the literature concerning differences in phenotype and outcome of ALS that relate to PAO. RESULTS: A review of 3111 records identified 78 population-based studies. The 40 that were included covered 40 geographical areas in 10 subcontinents. Around 12,700 ALS cases were considered. The results highlight the phenotypic heterogeneity of ALS at time of onset [age, sex ratio (SR), bulbar onset], age at diagnosis, occurrence of comorbidities in the first year after diagnosis, and outcome (survival). Subcontinent is a major explanatory factor for the variability of the ALS phenotype in population-based studies. Some markers of ALS phenotype were homogeneously distributed in western countries (SR, mean age at onset/diagnosis) but their distributions in other subcontinents were remarkably different. Other markers presented variations in European subcontinents (familial ALS, bulbar onset) and in other continents. As a consequence, ALS outcome strongly varied, with a median survival time from onset ranging from 24 months (Northern Europe) to 48 months (Central Asia). DISCUSSION: This review sets the scene for a collaborative study involving a wide international consortium to investigate, using a standard methodology, the link between ancestry, environment, and ALS phenotype.

FSuite: exploiting inbreeding in dense SNP chip and exome data.

UNLABELLED: FSuite is a user-friendly pipeline developed for exploiting inbreeding information derived from human genomic data. It can make use of single nucleotide polymorphism chip or exome data. Compared with other software, the advantage of FSuite is that it provides a complete suite of scripts to describe and use the inbreeding information. It includes a module to detect inbred individuals and estimate their inbreeding coefficient, a module to describe the proportion of different mating types in the population and the individual probability to be offspring of different mating types that can be useful for population genetic studies. It also allows the identification of shared regions of homozygosity between affected individuals (homozygosity mapping) that can be used to identify rare recessive mutations involved in monogenic or multifactorial diseases. AVAILABILITY AND IMPLEMENTATION: FSuite is developed in Perl and uses R functions to generate graphical outputs. This pipeline is freely available under GNU GPL license at: http://genestat.cephb.fr/software/index.php/FSuite.

Inbreeding coefficient estimation with dense SNP data: comparison of strategies and application to HapMap III.

BACKGROUND/AIMS: If the parents of an individual are related, it is possible for the individual to have received at 1 locus 2 identical-by-descent alleles that are copies of a single allele carried by the parents' common ancestor. The inbreeding coefficient measures the probability of this event and increases with increasing relatedness between the parents. It is traditionally computed from the observed inbreeding loops in the genealogies and its accuracy thus depends on the depth and reliability of the genealogies. With the availability of genome-wide genetic data, it has become possible to compute a genome-based inbreeding coefficient f, and different methods have been developed to estimate f and identify inbred individuals in a sample from the observed patterns of homozygosity at markers. METHODS: For this paper, we performed simulations with known genealogies using different SNP panels with different levels of linkage disequilibrium (LD) to compare several estimators of f, including single-point estimates, methods based on the length of runs of homozygosity (ROHs) and different methods that use hidden Markov models (HMMs). We also compared the performances of some of these estimators to identify inbred individuals in a sample using either HMM likelihood ratio tests or an adapted version of the ERSA software. RESULTS: Single-point methods were found to have higher standard deviations than other methods. ROHs gave the best estimates provided the correct length threshold is known. HMMs on sparse data gave equivalent or better results than HMMs modeling LD. Provided LD is correctly accounted for, the inbreeding estimates were very similar using the different SNP panels. The HMM likelihood ratio tests were found to perform better at detecting inbred individuals in a sample than the adapted ERSA. All methods accurately detected inbreeding up to second-cousin offspring. We applied the best method on release 3 of the HapMap phase III project, found up to 4% of inbred individuals, and created HAP1067, an unrelated and outbred dataset of this release. CONCLUSIONS: We recommend using HMMs on multiple sparse maps to estimate and detect inbreeding in large samples. If the sample of individuals is too small to estimate allele frequencies, we advise to estimate them on reference panels or to use 1,500-kb ROHs. Finally, we suggest to investigators using HapMap to be careful with inbred individuals, especially in the GIH (Gujarati Indians from Houston in Texas) population.

Does anonymous sperm donation increase the risk for unions between relatives and the incidence of autosomal recessive diseases due to consanguinity?

In France gamete donation and notably sperm donation are anonymous. It has been claimed that anonymous artificial insemination by donor (AID) could highly contribute to an increase in the level of consanguinity and the incidence of autosomal recessive diseases, due to the unions between offspring of anonymous donors, unaware of their biological kinship, with the special case of unions between half-siblings. The actual incidence of consanguinity due to AID was compared with that resulting from the two other main sources of consanguinity and recessive diseases, i.e. voluntary unions between related individuals or inadvertent unions between the offspring of a common unknown male ancestor (false paternity). From these data, we estimated that expected unions in France between half sibs per year are 0.12 between offspring of sperm donors (1.2 every 10 years) and 0.5 between offspring of common male ancestors through false paternity (5 every 10 years). More generally, the inadvertent unions between false paternity offspring are roughly four times more frequent than those resulting from anonymous AID. We estimated that in the future, when AID has been in practice for several generations, out the 820 000 annual births in France, respectively, 6 and 25 births will be consanguineous through an unknown common ancestor related to anonymous AID and to a false paternity, both of which are negligible when compared with the 1256 children born from first-degree cousins. About 672 children per year are born with a recessive genetic disease due to the panmictic risk and additional affected cases due to consanguinity would be 34.54 for first-cousin offspring, 0.33 for offspring of individuals related due to false paternity and 0.079 for offspring of individuals related due to anonymous AID. Anonymous AID would therefore be responsible for 0.46% of consanguineous births and for 0.01% of recessive diseases. Therefore, the effect of anonymous AID on half-sibling unions, consanguinity and recessive disease incidence can be regarded as marginal.

An AluYa5 Insertion in the 3'UTR of COL4A1 and Cerebral Small Vessel Disease.

Importance: Cerebral small vessel diseases (CSVDs) account for one-fifth of stroke cases. Numerous familial cases remain unresolved after routine screening of known CSVD genes. Objective: To identify novel genes and mechanisms associated with familial CSVD. Design, Setting, and Participants: This 2-stage study involved linkage analysis and a case-control study; linkage analysis and whole exome and genome sequencing were used to identify candidate gene variants in 2 large families with CSVD (9 patients with CSVD). Then, a case-control analysis was conducted on 246 unrelated probands, including probands from these 2 families and 244 additional probands. All probands (clinical onset

Could inbred cases identified in GWAS data succeed in detecting rare recessive variants where affected sib-pairs have failed?

To detect fully penetrant rare recessive variants that could constitute Mendelian subentities of complex diseases, we propose a novel strategy, the HBD-GWAS strategy, which can be applied to genome-wide association study (GWAS) data. This strategy first involves the identification of inbred individuals among cases using the genome-wide SNP data and then focuses on these inbred affected individuals and searches for genomic regions of shared homozygosity by descent that could harbor rare recessive disease-causing variants. In this second step, analogous to homozygosity mapping, a heterogeneity lod-score, HFLOD, is computed to quantify the evidence of linkage provided by the data. In this paper, we evaluate this strategy theoretically under different scenarios and compare its performances with those of linkage analysis using affected sib-pair (ASP) data. If cases affected by these Mendelian subentities are not enriched in the sample of cases, the HBD-GWAS strategy has almost no power to detect them, unless they explain an important part of the disease prevalence. The HBD-GWAS strategy outperforms the ASP linkage strategy only in a very limited number of situations where there exists a strong allelic heterogeneity. When several rare recessive variants within the same gene are involved, the ASP design indeed often fails to detect the gene, whereas, by focusing on inbred individuals using the HBD-GWAS strategy, the gene might be detected provided very large samples of cases are available.

Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.

Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.