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At least 19 recordsLinked to original sources

PubMed1975

Extensions to pedigree analysis I. Likehood calculations for simple and complex pedigrees.

A graph theoretic definition of pedigrees is given and a distinction drawn between simple and complex pedigrees. Algorithms are presented to calculate the likeihood of any kind of pedigree, assuming only segregation at a finite set of loci, nonassortative mating and no environmental correlations; multiple births and consanguineous marriages are explicity allowed for. The formulation given can lead to more powerful genetic counselling, segregation analysis and linkage analysis.

Genetic Linkage↗

PubMed2026

Fault-tolerant pedigree reconstruction from pairwise kinship relations.

MOTIVATION: Pedigrees reconstructed from biologically related ancient genomes have revealed many insights into (pre)history. To our knowledge, all reported ancient pedigrees have been primarily manually reconstructed, as existing pedigree reconstruction methods are ill-suited for the quality and nature of ancient DNA data. RESULTS: We introduce repare, an open-source software method to automatically reconstruct pedigrees from inferred pairwise kinship relations, which are readily obtainable from ancient genomes. This method reconstructs pedigrees by iteratively incorporating pairwise kinship relations into a set of candidate pedigrees, with pruning and sampling to reduce its search space. It optionally considers supporting information such as haplogroups and skeletal age-at-death estimates. We evaluate this method on a variety of simulated pedigrees with varying error rates and missingness. We also use this method to reconstruct several published pedigrees that were originally manually reconstructed; for one, we present a potential alternative topology. repare optionally incorporates user-inferred pedigree constraints, enabling "human-in-the-loop" reconstruction workflows. Especially when used with these user-inferred constraints, we find that repare represents a powerful and flexible tool for ancient pedigree reconstruction. AVAILABILITY AND IMPLEMENTATION: repare is freely available at https://github.com/Narasimhan-Lab/repare. In addition, source code, benchmark scripts, and benchmark results used in this work are archived at https://doi.org/10.5281/zenodo.19716772.

Pedigree↗

PubMed2026

X chromosome-wide association studies for quantitative trait loci based on the mixture of general pedigrees and additional unrelated individuals.

Genome-wide association studies have successfully identified many genetic variants associated with complex traits. However, most existing methods target autosomes rather than X chromosome, and several existing X chromosome-wide association studies (XWAS) at quantitative trait loci (QTL) largely focus on unrelated individuals, with limited attention to general pedigrees or mixture of general pedigrees and additional unrelated individuals (called the mixed data for brevity). In this study, we propose nine novel methods for XWAS at QTL in the mixed data (${\mathrm{MQX}}_{\mathrm{cat}}$, ${\mathrm{MQZ}}_{\mathrm{max}}$, ${\mathrm{MT}}_{\mathrm{plinkw}}$, ${\mathrm{MT}}_{\mathrm{chenw}}$, $\mathrm{MwM}3\mathrm{VNA}$, ${\mathrm{MQMVX}}_{\mathrm{cat}}$, ${\mathrm{MQMVZ}}_{\mathrm{max}}$, $\mathrm{MpMV}$, and $\mathrm{McMV}$), also applicable to general pedigrees alone. The first four methods test for mean differences across genotypes; the latter four test for differences in both means and variances; $\mathrm{MwM}3\mathrm{VNA}$ tests for variance differences only. All mean-based and mean-variance-based methods incorporate X chromosome inactivation information, and all nine methods consider genetic relatedness in pedigrees. Simulation studies confirm well-controlled type I error rates, and inclusion of pedigrees significantly improves statistical power. Note that there has been no study focusing on X chromosome for the mixed data or general pedigrees from UK Biobank database, so we apply our proposed methods to this dataset, which identify five total cholesterol (TC)-associated and 13 low-density lipoprotein cholesterol (LDL-C)-associated single nucleotide polymorphisms (SNPs). Linkage disequilibrium (LD) analysis reveals that these SNPs fall into three distinct LD blocks. Functional annotation and gene ontology enrichment analysis reveal 16 and 28 enriched pathways for TC-associated and LDL-C-associated genes, respectively. These methods provide robust and powerful tools for XWAS at QTL in both mixed data and general pedigrees.

Quantitative Trait Loci↗

PubMed1977

Ascertainment in the sequential sampling of pedigrees.

One aim in the analysis of pedigree data may be to infer the mode of inheritance of a characteristic. If only "interesting" pedigrees are analysed, the ascertainment bias may lead to some modes of inheritance being unintentionally preferred. Also, it is clearly most efficient in attempting to make such inferences, if a decision on whether to continue sampling a pedigree is made conditional on the types of individuals who have been observed; an a priori decision to examine 500 members of a pedigree may lead to much wasted effort, since the pedigree may prove to be largely uninformative. The present paper shows that provided all observed families are included in the analysis, even those which appeared "uninteresting" or "sporadic" and were not sampled further, and provided a decision to continue sampling is made conditional on types observed up to that point, the correct likelihood for the mode of inheritance may be easily computed. This opens the way for a more detailed study of the wider problem of optimal samplings rules on pedigrees.

Computers↗

PubMed2026

[Pathogenicity analysis and prenatal genetic counseling for five Chinese pedigrees harboring a hemizygous c.-32C>G variant of FGF13 gene].

OBJECTIVE: To explore the pathogenicity and prenatal counseling strategies for five Chinese pedigrees harboring a hemizygous c.-32C>G (NM_001139500.2) variant of fibroblast growth factor 13 (FGF13) gene. METHODS: Five Chinese pedigrees found to carry a hemizygous c.-32C>G variant of the FGF13 gene at the Prenatal Diagnosis Center of Henan Provincial People's Hospital between January 2024 and January 2025 were selected as study subjects. The pedigrees had undergone prenatal diagnosis for a family history of genetic disorders, abnormal fetal ultrasound findings, or advanced maternal age. A retrospective analysis was carried out, wherein clinical data for all members of the pedigrees were obtained through the medical records system and outpatient visit system. Peripheral blood samples were collected from all pedigree members, and amniotic fluid samples were obtained from the probands. Following extraction of genomic DNA, prenatal diagnosis was performed using chromosomal microarray analysis (CMA) and trio whole-exome sequencing (trio-WES). Sanger sequencing was used to determine the carrier status for the candidate variant, and Mini-Mental State Examination (MMSE) was used to assess the cognitive function of hemizygous individuals carrying the FGF13 gene c.-32C>G variant. Pathogenicity of candidate variant was assessed based on guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the hospital (Ethics No.: 2021-171). RESULTS: CMA and trio-WES revealed no pathogenic variants in all probands, whilst trio-WES and Sanger sequencing had identified 11 male individuals carrying a hemizygous c.-32C>G variant of the FGF13 gene from the five pedigrees, which included six adult males, a young boy, and four fetuses. One fetus had undergone termination of pregnancy due to hydrocephalus, one was born pre-term at 34+1 weeks of gestation owing to maternal hypertension, and other two were delivered at full term. Follow-up of the survived males revealed no phenotypic manifestations related to language or intellectual impairment. Among these, three adult males underwent the MMSE assessment, all of whom showed normal cognitive function. Search of the gnomAD database suggested the carrier frequency of FGF13 c.-32C>G variant in the East Asian population to be 0.125%, with 11 hemizygous males documented. Three male patients harboring the variant showed severe intellectual disability. Both in vitro and in vivo studies suggested that it could reduce the translation levels of FGF13 protein. Based on the ACMG guidelines, it was classified as variant of uncertain significance (BS4+PS3_Supporting). CONCLUSION: There is insufficient evidence to classify the FGF13 c.-32C>G as a pathogenic variant in clinical practice, and its presence should not be considered an indication for pregnancy termination due to major birth defects.

Adult↗

PubMed1992

Do bilineal pedigrees represent a problem for linkage analysis? Basic principles and simulation results for single-gene diseases with no heterogeneity.

Some investigators have expressed concern--especially for psychiatric disorders--that bilineal pedigrees should not be included in linkage studies. This study compares the "informativeness" of bilineal and unilineal families for a homogeneous single-gene disorder. Three approaches were used: (1) simulation studies of three-generation pedigrees, (2) calculation of expected lod scores (ELODs) in nuclear families, and (3) calculation of Fisher's information number I(theta) in nuclear families. The simulation studies in (1) permitted a realistic comparison between bilineal datasets and purely unilineal ones. The calculations in nuclear families in (2) and (3) then made it possible to analyze the sources of information loss in bilineal families. Overall, in datasets of five three-generation pedigrees each, the drop in mean maximum lod score was approximately 50% from purely unilineal datasets to extremely bilineal ones. In less-extreme bilineal datasets, which are closer to most real data than the extremely bilineal ones, the drops in lod score were very small--less than 10% in some, and practically zero in others. The details will vary, depending on size and structure of the pedigree, genetic model, true value of the recombination fraction, and informativeness of the marker. However, these results imply that the information loss due to bilineality is not necessarily very great. The nuclear-family calculations showed that for phase-known matings there is relatively little information loss in bilineal families, but for phase-unknown matings there the loss is much greater. In conclusion, for single-gene disorders with no genetic heterogeneity, whereas bilineal families can be less informative than comparable unilineal families, they are not so much less informative that they should automatically be discarded from linkage datasets. The implications of bilineal pedigrees for linkage studies of heterogeneous disorders are also discussed.

Computer Simulation↗

PubMed2026

Pedigree-assisted genotype imputation enables cost-effective genomic prediction in Penaeus vannamei.

Genomic selection in Penaeus vannamei has long been constrained by the high cost of dense genotyping. To address this limitation, we evaluated genotype imputation from a low-density 1 K panel to a medium-density 55 K panel of the "Yellow Sea Array No. 1" and examined its impact on genomic prediction for harvest body weight in P. vannamei. A four-generation pedigree including 30 great-grandparents, 39 grandparents, 100 parents, and 608 offspring was genotyped using the 55 K panel. A two-step experimental design was implemented to (i) assess the performance of different imputation algorithms under reference population scenarios with varying proportions of siblings, and (ii) compare six alternative reference population structures incorporating parents, ancestors, and siblings. Genotype imputation using the pedigree-based method FImpute v3.0 consistently achieved higher accuracy than the population-based method Beagle v5.5. Using this pedigree-assisted approach, imputation accuracy increased from 0.73 when only parental genotypes were used to 0.84 with the inclusion of 10% siblings, and subsequently plateaued at 0.87-0.90 when sibling representation reached 20%. Across the six reference population structures, imputation accuracy was primarily driven by the availability of parental genotypes, ranging from 0.50 to 0.56 in the absence of parents to 0.88-0.89 when both parents and ancestral generations were included. Accuracy remained high when both parents were available (0.84-0.87 with siblings; 0.73 without siblings) but declined substantially when only one parent was genotyped (0.65-0.68). Imputation accuracy was positively associated with both minor allele frequency (MAF) and linkage disequilibrium (max r2LD), with LD exerting the stronger influence. Heritability estimates derived from imputed 55 K genotypes were highly consistent with those obtained from the original 55 K data (0.39 ± 0.14 vs. 0.41 ± 0.14), indicating that genotype imputation did not compromise variance component estimation. In predictive ability analyses, pedigree-based BLUP (PBLUP) achieved higher predictive ability than genomic BLUP (GBLUP) based on the 1 K panel, with predictive abilities of 0.42-0.44 for PBLUP compared with 0.34-0.35 for GBLUP. Using imputed genotypes for genomic prediction further improved predictive ability relative to the true 1 K panel, yielding values ranging from 0.35 to 0.47. Notably, when parental genotypes were included in the reference population, GBLUP based on imputed genotypes surpassed the predictive ability of PBLUP and approached that achieved with the original 55 K genotypes (0.45-0.47). Collectively, these results provide the first empirical evidence that low- to medium-density genotype imputation, combined with pedigree information, can effectively support genomic prediction in P. vannamei. This study establishes a cost-efficient and scalable framework for implementing genomic selection in P. vannamei and provides a practical reference for the application of genomic selection in other aquaculture species with constrained breeding budgets.

Animals↗

PubMed1992

Sampling genotypes on complex pedigrees with phenotypic constraints: the origin of the B allele among the Polar Eskimos.

Exact probability calculations are often infeasible on large complex pedigrees. Conditional independences, however, occurring as a natural consequence of Mendelian inheritance of genetic traits, define a locally dependent Markov random field on the state space of all genotypic configurations on the pedigree. The underlying Markov chain is irreducible for most traits determined by a diallelic locus. For a given pedigree and a known genetic model, the Gibbs sampler can be used to obtain good estimates of the posterior distribution of genotypes given the observed data. The areas of pedigree analysis to which such an approach would be most directly relevant include genetic counselling and selective animal breeding, together with questions about ancestral genotypes and the ancestral paths of rare alleles. The method is illustrated by tracing the ancestral paths of a rare allele in a simple diallelic system on a highly complex Eskimo pedigree.

ABO Blood-Group System↗

PubMed1992

Pedigree analysis of children with phonology disorders.

This study examined 87 pedigrees of individuals with histories of preschool phonology disorders. Results confirmed previous reports that speech and language disorders aggregate in families, with a higher incidence of males affected than females. Significantly more family members with dyslexia and learning disabilities, but not stuttering or hearing impairment, were found in pedigrees of individuals with phonology disorders than in pedigrees of nondisabled individuals. Probands with and without additional language problems did not differ in the incidence of affected family members. Nuclear family members demonstrated a higher incidence of disorders than when all family members were considered, with brothers of probands most often affected. Pedigrees of female probands had more affected members in their nuclear families than pedigrees of male probands.

Adolescent↗

PubMed2025

Whole-exome sequencing uncovers the genetic basis of hereditary concomitant exotropia in ten Chinese pedigrees.

PURPOSE: To explore possible pathogenic genes for concomitant exotropia using whole-exome sequencing. METHODS: In this study, 47 individuals from 10 concomitant exotropia (including intermittent exotropia and constant exotropia) pedigrees were enrolled. Whole-exome sequencing was used to screen mutational profiles in 25 affected individuals and 10 unaffected individuals. Sanger sequencing and in silico analysis were performed for all participants. Two target genes were used to capture the sequences of 220 sporadic samples. RESULTS: All 10 concomitant exotropia pedigrees presented autosomal dominant inheritance with childhood onset (3.35 ± 1.51 years old). Eleven different missense variants were identified among seven potential pathogenic genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that cosegregated with pedigree members. All variants were predicted to be deleterious and had low frequencies in the general population. Distinct variants of COL4A2 were present in three pedigrees, and distinct variants of SYNE1 were present in two pedigrees. Fifteen variants in AUTS2 and four variants in GTDC2 were identified in 220 patients with sporadic concomitant exotropia using a target-capture sequencing approach. CONCLUSION: This is the first study to explore the genetic mechanism of concomitant exotropia and identify seven associated genes (COL4A2, SYNE1, LOXHD1, AUTS2, GTDC2, HERC2 and CDH3) that may be candidate genes causing concomitant exotropia. More samples and in-depth studies are needed to verify these findings.

Adult↗

PubMed1978

Inbreeding as measured by isonymy, pedigrees, and population size in Törbel, Switzerland.

Törbel provides an interesting test case for the study of the relationship between inbreeding measured by pedigrees and inbreeding measured by isonymy. At the start of this investigation, we were aware that isonymy could introduce biases into the calculation of the inbreeding coefficient in either direction. However, it was expected that in Switzerland, inbreeding from isonymy would be an overestimate due to patrilocal residence and polyphyletic names. One way of dealing with this problem [13] was not to be concerned with the absolute value of inbreeding but only in the difference between estimates. Any bias introduced in the estimate itself disappears in such comparisons, so that a trend of inbreeding can be ascertained correctly. However, it was considered equally important to subject several populations to both a complete pedigree analysis and an isonymic analysis to determine the relationship between estimates of inbreeding. Despite the fact that several authors (Swedlund [18], for example) warned users of isonymy to exercise caution, the careless application of isonymy still persists. In the present study, estimates of inbreeding from isonymy were brought into line with other methods based on pedigree analysis and population size. However, it was possible to do this only in Törbel where pedigree depth was extensive and relatively complete. Similar corrections are possible only when the distribution of mono- and polyphyletic names is known and when migration data are reliable. If the trouble is taken to make these corrections, the same time and effort might as well be spent in pedigree analysis (when fairly complete ascertainment is possible) to achieve the same end result.

Consanguinity↗

PubMed2024

BICEP: Bayesian inference for rare genomic variant causality evaluation in pedigrees.

Next-generation sequencing is widely applied to the investigation of pedigree data for gene discovery. However, identifying plausible disease-causing variants within a robust statistical framework is challenging. Here, we introduce BICEP: a Bayesian inference tool for rare variant causality evaluation in pedigree-based cohorts. BICEP calculates the posterior odds that a genomic variant is causal for a phenotype based on the variant cosegregation as well as a priori evidence such as deleteriousness and functional consequence. BICEP can correctly identify causal variants for phenotypes with both Mendelian and complex genetic architectures, outperforming existing methodologies. Additionally, BICEP can correctly down-weight common variants that are unlikely to be involved in phenotypic liability in the context of a pedigree, even if they have reasonable cosegregation patterns. The output metrics from BICEP allow for the quantitative comparison of variant causality within and across pedigrees, which is not possible with existing approaches.

Pedigree↗

PubMed1992

Analysis of the DNA duplication 17p11.2 in Charcot-Marie-Tooth neuropathy type 1 pedigrees: additional evidence for a third autosomal CMT1 locus.

We have restudied two clinically typical Charcot-Marie-Tooth neuropathy type 1 (CMT1; also known as hereditary motor and sensory neuropathy 1) pedigrees that were previously reported to be unlinked to the regions of proximal chromosome 1q and chromosome 17p by multipoint linkage analyses. In these two pedigrees, there is no evidence for linkage to additional DNA markers that flank and span the CMT1A locus on chromosome 17p11.2, and a duplication associated with CMT1A is not present in these pedigrees. These findings confirm that the CMT1 locus in these two pedigrees does not map to chromosome 17p11.2 or 1q, and provide further evidence for the existence of a third autosomal locus for CMT1.

Charcot-Marie-Tooth Disease↗

PubMed1992

A 17th-century founder gives rise to a large north American pedigree of autosomal dominant spinocerebellar ataxia not linked to the SCA1 locus on chromosome 6.

There have been three reports since 1969 of members of a "W" family with autosomal dominant spinocerebellar ataxia (SCA), and various conclusions have been drawn about the nosology. This pedigree has been traced back over 300 years through 11 generations. Although phenotypically similar to the disorder in the Schut-Swier, Nino, and other kindreds, the disorder in the W family is not linked to the SCA1 locus on chromosome 6, as reported in those hereditary ataxia pedigrees. The W family represents the largest such North American kindred yet reported. We examined 33 family members of a distantly related branch of the W family, determined the cumulative age of onset, and projected the number of present-day gene carriers. Two cases illustrate the spectrum of symptoms among family members. Age of onset and presenting symptom, however, seem to correlate both in our patients and in those previously reported. Between 2,000 and 5,000 individuals are estimated to be at risk of developing the disorder within this pedigree alone. The pedigree reported here will be valuable in the identification and cloning of a gene for hereditary ataxia, designated "SCA2" at the Eleventh International Workshop on Human Gene Mapping.

Adult↗

PubMed1992

Linkage analysis of glucokinase gene with NIDDM in Caucasian pedigrees.

NIDDM has a strong genetic component, as evidenced by the high level of concordance between identical twins. The nature of the genetic predisposition has remained largely unknown. Recently, the glucokinase gene locus on chromosome 7p has been shown to be linked to a subtype of NIDDM known as MODY in French and British pedigrees, and glucokinase mutations have been identified. To study the relationship between the glucokinase gene and NIDDM, we performed a linkage analysis in 12 Caucasian pedigrees ascertained through a proband with classical NIDDM. The LINKAGE program was used under four models, including autosomal dominant and recessive, with individuals with glucose intolerance counted as either affected or of unknown status. Linkage was significantly rejected with the dominant models (LOD scores -4.65, -4.25), and was unlikely with the recessive model when glucose intolerance was considered as affected (LOD score -1.38). These findings suggest that mutations in or near the glucokinase gene are unlikely to be the major cause of the inherited predisposition to NIDDM in Caucasian pedigrees, but do not exclude a role for this locus with a polygenic model, or a major role in some pedigrees.

Adult↗

PubMed1992

Dyslipidemias among normoglycemic members of familial NIDDM pedigrees.

OBJECTIVE: To examine the hypothesis that hyperinsulinemia among relatives of NIDDM probands will increase the prevalence of DLPs, we measured insulin levels and examined the frequency of DLPs among NIDDM pedigree members. RESEARCH DESIGN AND METHODS: We performed 2-h 75-g OGTTs and measured lipid and insulin levels of 287 family members and 86 spouses from 16 large Utah pedigrees ascertained for greater than or equal to 2 siblings with NIDDM. RESULTS: One-hour insulin levels were higher among 206 family members with NGT than among 65 NGT spouses (483.3 vs. 361.7 pM, P = 0.05). Among the NGT family members, 32% had cholesterol levels at or above the age- and sex-specific 90th percentile level defined by the LRC studies, 33% had HDL levels less than or equal to 10th percentile, and 20% had triglyceride levels greater than or equal to 90th percentile. DLP (any of the three abnormalities) was found among 58% of NGT family members, which was significantly higher than the expected 27% (P less than 0.00001) and the prevalence among spouses of 45% (P less than 0.05). By NCEP criteria for hyperlipidemia, 40% of family members met criteria for diet and/or pharmacological therapy. CONCLUSIONS: Normoglycemic members of NIDDM pedigrees have a high prevalence of DLPs, which approaches the prevalence in patients with NIDDM. Our data suggest that members of NIDDM pedigrees should be screened carefully for lipid abnormalities.

Adult↗

PubMed1992

Estimating polygenic models for multivariate data on large pedigrees.

We have developed algorithms for the likelihood estimation of additive genetic models for quantitative traits on large pedigrees. The approach uses the expectation L-maximization (EM) algorithm, but avoids intensive computation. In this paper, we focus on extensions of previous work to the case of multivariate data. We exemplify the approach by analyses of bivariate data on a four-generation, 949-member pedigree of the snail Lymnaea elodes, and on a three-generation pedigree of the guppy Poecilia reticulata containing about 400 individuals.

Algorithms↗

PubMed1977

Linking of medical records to form pedigrees.

The human pedigree provides a highly organized representation of historical family morbidity. In order to allow for careful analysis of large numbers of pedigrees, we have developed an interactive computer system for their storage, retrieval and statistical review. The system is capable of integration with our computerized medical record through the use of a common classification (ICHPPC) for patient morbidity. This linkage of pedigrees to clinical data may allow a richer utilization of the clinical experience within Family Practice for the support of research into disease patterns within the family.

Computers↗